Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.

Introduction

The musculoskeletal system includes muscles, bones, ligaments, tendons, cartilage, and other load-bearing tissues. These tissues are connected through specialized interfaces whose mechanical, physical, and biochemical gradients are essential for coordinated movement and tissue homeostasis. 1 As the body’s principal mechanical framework and mechanosensory network, the musculoskeletal system supports force transmission, locomotion, posture, repair, and metabolic adaptation. Disorders such as osteoporosis, osteoarthritis (OA), and sarcopenia are highly prevalent and constitute a major cause of disability worldwide. 2 , 3 Their biology depends on the precise spatial and temporal organization of signaling, transcriptional, metabolic, and stress-response pathways. At the cellular scale, muscle contraction and bone loading are translated into nuclear deformation, cytoskeletal remodeling, and mechano-signaling programs. 4 , 5 These processes unfold in a crowded intracellular environment where biomolecules must be organized without depending exclusively on membrane-bound organelles. 6 Advances in super-resolution imaging, live-cell tracking, and single-molecule analysis have made this organization experimentally accessible and have accelerated the study of liquid-liquid phase separation (LLPS). 7 , 8 LLPS provides one route through which biomolecules self-organize into membraneless condensates. It therefore offers a useful framework for linking molecular biophysics to musculoskeletal physiology and disease.

Biomolecular condensates are cellular assemblies that lack surrounding membranes but maintain distinct compositions, dynamics, and functions. LLPS describes a subset of condensate-forming processes in which biomolecules demix into dense and dilute phases, often producing dynamic, liquid-like droplets. This distinction matters because many intracellular bodies exhibit condensate-like behavior without meeting all criteria for equilibrium LLPS, and some pathological assemblies mature into gel-like, solid-like, or amyloid-like states. In cells, condensates contribute to subcellular compartmentalization and cellular function. 9 For instance, condensates organize promoter and super-enhancer elements during gene regulation. 10 , 11 In innate immunity, cyclic GMP-AMP synthase forms DNA-induced condensates that activate antiviral signaling. 12 In the nervous system, condensate assembly contributes to the postsynaptic density and synaptic signaling. 13 , 14 In the cytoskeletal context, phase-separation-related mechanisms localize KANK proteins at focal adhesion edges to modulate actin organization, 15 and condensates within the mitotic spindle contribute to cell-cycle progression. 16 Under stress, stress granules (SGs) assemble as condensates that coordinate adaptive cellular responses, 17 and septins form dynamic liquid-like assemblies involved in cell polarity. 18 Disease-associated mutations, aberrant post-translational modifications, and age-related stress can alter condensate composition or material state. 19 Examples include Tau condensation and aggregation in Alzheimer’s disease and disrupted phase behavior of the p53 tetramerization domain in oncogenesis. 20 , 21 Despite intense work in cell biology and other disease areas, condensate biology in the musculoskeletal system remains fragmented. 22 Current evidence links condensate dysregulation to osteoporosis, 23 osteoarthritis, 24 bone tumors, 25 muscle degeneration, 26 and neurodegenerative diseases that affect neuromuscular function, 27 but the strength of causal evidence differs across models and diseases.

This review synthesizes and critically evaluates current evidence on biomolecular condensates in musculoskeletal diseases, with LLPS discussed as a major but not exclusive mechanism of condensate formation. We address osteoporosis, osteoarthritis, sarcopenia, bone tumors, soft tissue sarcomas, and neuromusculoskeletal disorders (Fig. 1 ), with attention to the experimental basis for each proposed mechanism. In osteoporosis, RUNX2-related condensates may organize enhancer-promoter contacts and support osteoblast differentiation. In muscular dystrophy, proteins such as hnRNPDL and TDP-43 can shift from dynamic condensates to less reversible assemblies that interfere with RNA processing, autophagy, and myogenic differentiation. In Ewing sarcoma, EWSR1::FLI1 condensates recruit BRG1/BAF complexes to GGAA microsatellites and activate oncogenic transcriptional programs. These examples also illustrate a recurring problem in the field: condensate formation is often observed alongside disease phenotypes, but causality requires perturbations that specifically alter condensate assembly, material state, or client recruitment without globally disrupting protein function. We discuss post-translational modifications, RNA scaffolding, physicochemical conditions, and mechanical inputs that tune condensates in musculoskeletal contexts. We also assess condensate-targeted strategies, including GSK-J4, nilotinib, and biomaterial-based modulation, while emphasizing unresolved issues of target selectivity, tissue delivery, and in vivo validation. Fig. 1 Biomolecular condensates in musculoskeletal diseases. Biomolecular condensates and LLPS-related mechanisms have been implicated in a broad spectrum of musculoskeletal disorders, including neuromuscular diseases, bone pathologies, skeletal conditions, bone tumors, and soft tissue sarcomas

Biomolecular condensates: formation, material states, and functions

From liquid-liquid phase separation to biomolecular condensates

Phase behavior has long provided a physical language for describing matter, including the gas, liquid, and solid states of water. In cells, the same physical principles help explain how biomolecules can organize reactions without membrane boundaries. As early as 1899, Edmund Beecher Wilson proposed that cytoplasmic substances might behave as liquids or liquid mixtures with distinct chemical activities. 28 This idea anticipated a central problem in modern cell biology: how cells create specialized reaction spaces within a crowded cytoplasm and nucleoplasm. Classical organelles, such as the nucleus, endoplasmic reticulum, Golgi apparatus, and lysosomes, solve this problem through lipid membranes and compartment-specific functions. 29 Membraneless compartments provide a second solution. Structures such as the nucleolus, Cajal bodies, nuclear speckles, and SGs lack lipid bilayers but maintain distinct composition, morphology, and dynamics. 30 , 31 Early observations that Cajal bodies behaved like semi-fluid droplets suggested that physical material properties could stabilize such compartments. 32 A decisive advance came from studies of RNA- and protein-rich P granules in C. elegans embryos, which showed liquid-like behavior and provided experimental and theoretical evidence that LLPS can drive condensate formation. 33

LLPS is therefore an important mechanism for forming membrane-free cellular structures, but it should be placed within the broader concept of biomolecular condensates. When local concentration and interaction valency exceed a threshold, selected macromolecules can separate from the surrounding dilute phase and form a dense phase with distinct composition and material behavior. 34 Many condensates show liquid-like exchange, but others become viscoelastic, gel-like, solid-like, or amyloid-like under stress, mutation, or aging. This material-state continuum helps distinguish physiological condensates from irreversible pathological aggregates and explains how normal compartments can harden into toxic assemblies. 35 Condensate biology therefore integrates thermodynamics, kinetics, molecular interactions, and cellular regulation across transcription, RNA metabolism, signaling, and stress adaptation. 36 Known membraneless organelles implicated in musculoskeletal diseases are summarized in Table 1 . Table 1 Known membraneless organelles in musculoskeletal system diseases Membraneless organelle Key molecules Mechanism Function Reference Paraspeckles MATR3 and PABPN1 The PABPN1-MATR3 functional axis regulates paraspeckles through Neat1 Maintain the normal number of paraspeckles and mediate the nuclear retention and editing of specific transcripts 171 MEN ε/β and lncRNA MEN ε/β lncRNA functions as a “scaffold” to assemble paraspeckles Regulate muscle cell differentiation 166 Neat1 Mechanical stimulation upregulates the expression of lncRNA Neat1, promoting the assembly of paraspeckles Inhibit Smurf1 mRNA translation via sequestration to enhance osteogenic differentiation 97 Nuclear speckles DGK-ζ DGK-ζ interacts with PLCβ1 in the nucleolus to regulate nuclear lipid signaling Regulate the process of skeletal muscle cell differentiation 167 PABPN1 Mutant PABPN1 aberrantly accumulates at the periphery of nuclear speckles to form inclusions Cause post-transcriptional defects that propel myofiber pathology 170 Stress granules HuR The RNA-binding protein HuR undergoes LLPS to incorporate into stress granule condensates Protect β-catenin mRNA to promote osteogenic differentiation 23 TIA1 IL-1β stimulation induces the assembly of stress granules in osteoarthritic chondrocytes Delay COX-2 mRNA translation to control inflammation and cartilage degradation 24 TDP-43 and p35 TDP-43 is cleaved to generate a 35 kD fragment that promotes stress granule formation Anti-inflammatory, promotes proliferation, and enhances the anti-apoptotic ability of chondrocytes 111 GRP78 The chaperone protein GRP78 induces stress granule formation Promote drug-resistant survival and bone metastasis recurrence 133 SQSTM1 and TIA1 The TIA1-N357S variant enhances LLPS and inhibits the autophagic clearance of stress granule dynamics Impaired stress granule clearance contributes to myotoxicity. 174 P-bodies YTHDF2 m 6 A-modified TM4SF1 mRNA induces LLPS of YTHDF1-3, promoting the formation of P-bodies Degrade TM4SF1 mRNA to regulate skeletal muscle development 90 SYK SYK localizes to P-bodies during TGF-β-induced epithelial-mesenchymal transition Restore epithelial phenotype and promote tumor bone metastasis colonization 135 Nucleus HMGB1 Frameshift mutations in HMGB1 cause abnormal LLPS and lead to nucleolar abnormalities Cause multiple system developmental malformations 113 LLPS liquid-liquid phase separation

Formation mechanisms and experimental evidence for condensates

Multivalent weak interactions are a principal driver of LLPS. Individually, these contacts between proteins, nucleic acids, or both are weak and transient, but collectively they generate cooperative networks that can stabilize condensates. 19 , 37 Once concentration, valency, or interaction strength crosses a threshold, a dense phase can form alongside a dilute phase. 38 – 41 This threshold behavior explains why small changes in protein abundance, RNA binding, post-translational modification, or environmental conditions can markedly alter condensate assembly. 42 Evidence for LLPS, however, requires careful interpretation. 1,6-hexanediol can perturb condensates, but it can also affect membranes, chromatin, and hydrophobic interactions; its use alone does not prove LLPS. 43 Similarly, purified protein assays are valuable for defining phase behavior, but they may not reproduce the crowded, mechanically loaded, and matrix-rich environments of bone, cartilage, or skeletal muscle. Stronger evidence generally requires convergent tests, including endogenous tagging, concentration-dependent phase diagrams, FRAP or single-particle tracking, valency-disrupting mutations, rescue experiments, and disease-relevant in vivo or human-cell models.

Intrinsically disordered regions (IDRs) are major molecular elements that enable multivalency. These regions have low sequence complexity and high conformational flexibility, are enriched in selected amino acids, and lack stable tertiary structure. 44 , 45 Their flexibility allows multiple weak interaction sites to engage simultaneously, while repetitive or low-complexity motifs increase valency. 44 , 46 IDRs are also sensitive to pH, ionic strength, post-translational modifications, and pathogenic mutations. For example, D378N/H mutations in the prion-like domain of hnRNPDL disrupt electrostatic balance, accelerate aggregation, impair function, and cause limb-girdle muscular dystrophy type 1 G. 46 – 48 Short-range interactions within IDRs can form transient local structures that further shape phase behavior, as shown by the C-terminal alpha-helix that supports TDP-43 LLPS. 49 , 50 Folded domains complement IDRs by providing stable binding surfaces, nucleation points, and higher-order scaffolding. 51 – 53 Nucleophosmin illustrates this synergy: its N-terminal folded domain mediates pentamerization, which enables subsequent IDR-driven phase separation during client binding. 54 , 55

Other sequence features also tune condensate assembly. Low-complexity domains (LCDs), which are enriched for a limited set of amino acids, often overlap functionally with IDRs and are strongly influenced by the intracellular environment. The saturation concentration for phase separation can depend on the combined contributions of tyrosine residues in prion-like domains (PrLDs) and arginine residues in arginine-rich RNA-binding regions. 56 In addition to tyrosine-arginine interactions, arginine can promote phase separation through arginine-arginine contacts and heterotypic interactions with residues such as glutamine and serine. Polar residues add further specificity: glutamine can stabilize condensates through sequence-specific contacts, whereas glycine increases backbone flexibility and facilitates favorable neighboring interactions. 57 , 58 These findings extend the classical stickers-and-spacers model by showing that condensate formation arises from a distributed interaction network rather than from a small set of sticker residues alone.

Regulation of condensate assembly and material properties

Condensate assembly is dynamically regulated by nucleic acids, post-translational modifications, metabolites, and physicochemical parameters. These factors tune the assembly, dissolution, material properties, and biological output of phase-separated compartments (Fig. 2 ). Fig. 2 Assembly mechanisms of biomolecular condensates. Biomolecular condensates can form through networks of weak, multivalent intermolecular interactions, including cation-anion interactions, cation–π interactions, π–π stacking, dipole-dipole interactions, and hydrophobic forces. These interactions are underpinned by characteristic molecular features that confer multivalency, including intrinsically disordered regions/low-complexity domains, repetitive modular domains, and RNA-binding domains. Such features promote higher-order collective assemblies and can support LLPS when dense and dilute phases form. Environmental cues, such as salt concentration, pH, protein or RNA concentration thresholds, and post-translational modifications, dynamically regulate condensate initiation, stability, and material properties

RNA: from core scaffolds to bidirectional regulators

The components of LLPS systems are often described as scaffolds and clients. 59 RNA can act as a scaffold by recruiting and concentrating RNA-binding proteins. For example, m 6 A-modified RNA promotes YTHDF2 recruitment and phase separation. 60 RNA can also define condensate identity and prevent inappropriate droplet fusion. Whi3 forms distinct condensates with different mRNAs; droplets carrying different mRNAs do not readily fuse, whereas droplets carrying the same mRNA can coalesce. 61 RNA sequence and length can further influence material transitions. Homopolymeric RNA aggregation can promote liquid-to-solid transitions in multicomponent condensates, a process linked to Huntington’s disease and ALS. 62

RNA regulates LLPS in a concentration-dependent and context-dependent manner. At low concentrations, mRNA can support transcriptional condensates through electrostatic interactions with positively charged MED1. 63 At excessive concentrations, RNA can instead inhibit FUS phase separation. 63 , 64 Beyond these general effects, lncRNAs provide more specialized control of chromatin-associated condensates and gene expression. 65 In skeletal muscle, lncRNAs influence proliferation and differentiation by modulating condensate behavior. For example, lnc-RMG regulates myogenic phase separation by producing miR-133a-3p, reducing MEIS2 abundance, and relieving transcriptional repression of TGF-β signaling. 66 Similarly, maternally expressed gene 3 supports SUZ12 phase separation and stabilizes Polycomb repressive complex 2, thereby limiting atrophy-associated and lipid-accumulation programs and preserving muscle quality and metabolic balance. 67

Post-translational modifications: chemical switches for fine-tuning phase separation

Post-translational modifications add a major regulatory layer by changing protein charge, conformation, interaction interfaces, and valency. 68 Phosphorylation is especially common in IDRs and introduces negatively charged phosphate groups that can weaken or reorganize electrostatic interactions. 69 For example, phosphorylation of p53 at S392 reduces intermolecular interactions within droplets and increases droplet fluidity. 70 Acetylation can also regulate phase behavior; acetylation of the autophagy-related protein RB1CC1 modulates its phase separation and influences autophagosome formation. 71 Arginine methylation alters cation-pi interaction capacity and can reduce hnRNPA2 phase separation by disrupting arginine-mediated contacts. 72 SUMOylation, ubiquitination, ADP-ribosylation, and other modifications introduce additional multivalent interaction modules and thereby reshape condensate assembly and function. 68 , 69 , 73

Sensitive modulation by physicochemical parameters

The intracellular microenvironment is tightly regulated, and small changes in physicochemical parameters can strongly influence LLPS dynamics (Fig. 3 ). Increased osmotic pressure compresses cell volume and alters hydration, molecular concentration, and molecular crowding, thereby favoring phase separation. Temperature also regulates LLPS; even changes of about 1 °C can trigger droplet coalescence or dissolution in proteins such as BuGZ, DEAD-box helicase 4, hnRNPA1, and FUS, illustrating the sensitivity of condensate assembly. 22 pH affects electrostatic attraction and repulsion by altering protonation states of charged residues in proteins or RNA. For example, the IDR of galectin-3 regulates self-assembly through pH-dependent protonation, promoting aggregation at neutral pH and ligand dissociation at acidic pH. 74 Ionic strength primarily acts through charge screening. Low ionic strength favors electrostatic attraction, whereas higher ionic strength often weakens these interactions and suppresses LLPS. 75 Cation identity also matters. Highly hydrated cations such as Zn 2+ and Al 3+ can promote Tau phase separation even at high ionic strength, probably by altering solvent-water structure and dynamics rather than by direct coordination alone. 76 Fig. 3 Phase diagram and regulatory principles of liquid-liquid phase separation. a The binodal (coexistence) line in the phase diagram, governed by factors such as temperature and pH, separates the one-phase and two-phase regimes. Within the two-phase regime, LLPS produces a dilute phase with concentration C L and a dense phase with concentration C D . At fixed temperature and pH, C L and C D remain constant, whereas the volume fractions of the dilute ( f L ) and dense (f D ) phases vary with the system’s average concentration ( C avg ), following the lever rule: f L = ( C D − C avg )/( C D − C L ) and f D = ( C avg − C L )/( C D − C L ). b Representative example showing the biphasic effect of ATP on the turbidity of the prion-like domain of TDP-43. Low ATP concentrations promote liquid-liquid phase separation and increase turbidity, whereas high concentrations dissolve phase-separated droplets and suppress phase separation. c Schematic illustrating the effects of different cations on Tau condensate formation. Cations are ordered by increasing hydration strength, reflecting their varying capacities to modulate protein phase separation

ATP: a concentration-dependent bifunctional regulator

ATP, beyond its role as an energy currency, functions as a bidirectional regulator of LLPS. 77 , 78 Using TDP-43 as an example, ATP at low concentrations promotes LLPS by engaging arginine residues in the PrLD of TDP-43 via its hydrophobic purine ring and negatively charged triphosphate chain. This bivalent interaction synergistically enhances hydrophobic effects, strengthening intermolecular attraction and supporting droplet formation. Conversely, at high concentrations, ATP saturates arginine binding sites, coating the PrLD with negatively charged triphosphate groups. This introduces long-range electrostatic repulsion and disrupts hydrophobic interactions essential for condensate integrity, resulting in dissolution. 79 The same phenomenon can also occur with FUS protein. 80 , 81

External signals: connecting cellular stress to adaptive responses

In addition to endogenous metabolites and intracellular microenvironmental regulation, condensate assembly helps cells respond rapidly to external signals. Oxidative stress, heat shock, and extracellular mechanical stiffness can alter condensate formation and material properties. For example, arsenic-induced oxidative stress drives YTHDF2 phase separation, a process that contributes to arsenic toxicity. 82 Heat shock can induce LLPS of NEDD4-binding partner 1, which protects cells under stress conditions. 83 The mechanical and physical environment also regulates condensates. In Drosophila muscle, Tono acts as a mechanically sensitive transcriptional regulator. It detects compressive forces generated by myofibril and mitochondrial growth within the muscle nucleus, triggering LLPS to form nucleoplasmic droplets that regulate developmental transcriptional switches, sarcomere maturation, and mitochondrial functionality. 84

Condensate assembly is a cooperative process driven by multivalent weak interactions and regulated by IDRs, low-complexity domains, folded domains, RNAs and their modifications, post-translational modifications, metabolites, and the cellular microenvironment. LLPS is a useful mechanistic model when these interactions produce liquid-like demixing, but condensates can also acquire more complex material states. This framework couples molecular structure with cellular function and creates vulnerabilities that may contribute to disease. Clarifying the molecular rules that define condensate formation, maturation, and dissolution may support therapeutic strategies that modulate pathological condensates without disrupting physiological ones.

Core functions of biomolecular condensates in the musculoskeletal system

After describing condensate formation and regulation, we now focus on the cellular roles and physiological functions of condensates in the musculoskeletal system. Biomolecular condensates contribute to transcriptional regulation, post-transcriptional regulation, signal transduction, epigenetic regulation, and stimulus responses (Fig. 4 ). In some examples, the underlying mechanism has been directly linked to LLPS; in others, the safer interpretation is that condensate organization is involved, with the precise material mechanism still requiring validation. Fig. 4 Representative regulatory roles of biomolecular condensates in musculoskeletal biology. Transcriptional regulation: RUNX2 forms condensates that bridge the rs4683184-containing enhancer and promoter regions, supporting the assembly of transcriptional machinery and activation of downstream genes. Post-transcriptional regulation: Condensates contribute to alternative splicing and exon inclusion; their specific roles in musculoskeletal tissues remain to be fully defined. Signal transduction: Wnt activation promotes the degradation of phase-separated signalosome condensates, releasing β-catenin for nuclear translocation and target gene regulation. Epigenetic regulation: SUZ12- and lncRNA-associated condensates selectively recruit EZH2 and EED, promoting Polycomb-mediated histone modifications within the nucleus. Cellular stress response: Accumulation of misfolded proteins at the endoplasmic reticulum triggers eIF2α-mediated signaling and promotes SG assembly

Transcriptional regulation

Within the musculoskeletal system, one well-studied role of biomolecular condensates is transcriptional regulation. Condensates can either activate or repress transcription depending on their composition and recruited clients. During muscle proliferation, TAZ forms dynamic nuclear condensates through phase-separation-related mechanisms and recruits Smad7 and β-catenin, thereby inhibiting myogenic gene expression. 85 Conversely, transcriptional condensates can concentrate core transcription factors, coactivators, and RNA polymerase II into local hubs that activate gene programs. 86 , 87 In osteoblasts, RUNX2 phase separation bridges the rs4683184 enhancer and the XCR1 promoter, promoting osteogenic differentiation. 88 In skeletal muscle, MEF2D undergoes beta-domain-mediated LLPS and liquid-to-solid transition to form spatially segregated transcriptional hubs that recruit basal transcription machinery and myogenic factors during staged muscle development. 89

Post-transcriptional regulation

Biomolecular condensates also regulate post-transcriptional gene expression by controlling mRNA localization, stability, and translation. They can sequester selected mRNAs and inhibit translation. For example, YTHDF2 undergoes LLPS and transports N6-methyladenosine (m 6 A)-modified TM4SF1 mRNA to P-bodies for degradation, thereby reducing TM4SF1-mediated inhibition of myocyte differentiation. 90 In myopathy, abnormally accumulated cellular prion protein (PrPᶜ) undergoes phase separation after binding specific miRNAs. These miRNA-bound condensates target the 3’ UTRs of ATG genes and inhibit autophagy-related translation. 26 Condensates can also protect transcripts from degradation. Nucleolin-based condensates stabilize HIF-1α mRNA and increase protein expression. 91 Current musculoskeletal studies mainly address mRNA localization, protection, and degradation, whereas condensate roles in RNA modification, splicing, editing, and translation remain less defined. 26

Signal transduction

Biomolecular condensates participate in signal transduction by concentrating pathway components in space and time. During TGF-beta signaling, disheveled-binding antagonist of β-catenin 1 forms cytoplasmic LLPS-driven condensates that enrich CK2 and inhibit Wnt/β-catenin signaling. 92 At the neuromuscular junction, Rapsyn drives LLPS through multivalent tetratricopeptide-repeat interactions, forming dynamic condensates that recruit acetylcholine receptors, cytoskeletal proteins, and signaling molecules to support synaptic transmission. 93 During early muscle injury, 11,12-epoxyeicosatrienoic acid diffuses into the repair microenvironment and amplifies FGF-FGFR signaling by enhancing fibroblast growth factor condensation. 94

Epigenetic regulation

In musculoskeletal tissues, LLPS-linked condensates also contribute to epigenetic regulation. During muscle development, maternally expressed gene 3 promotes SUZ12 LLPS and stabilizes Polycomb repressive complex 2. This enhances H3K27me3 at the Fhl3 and Rnf128 loci, limits fast-twitch fiber transition and fat infiltration, and helps preserve oxidative muscle function and mass. 67 Condensates can also repress transcription through physical compartmentalization. In myoblasts, the C-terminal IDR of MEIS2 mediates LLPS and forms nuclear condensates that bind the transforming growth factor-beta receptor II promoter and inhibit transcription. 66 Similarly, lethal (3) malignant brain tumor-like protein 2 forms nuclear condensates through its C-terminal IDR and polybasic region. These condensates recruit repressive components and sequester the promoter of interferon-induced protein with tetratricopeptide repeats 2, suppressing oncogenic transcription and exerting tumor-suppressive activity. 95

Stimulus response

Cells use condensate assembly to respond quickly to external stimuli. SGs are a classic example because they assemble rapidly during stress and support cytoprotection. 96 In human OA chondrocytes, IL-1β induces endoplasmic reticulum stress and eIF2α phosphorylation, leading to SG assembly. These SGs sequester COX-2 mRNA and delay inflammatory protein production, thereby buffering premature inflammatory responses. 24 Paraspeckles are also mechanosensitive. In osteoblasts, the lncRNA NEAT1 responds to mechanical stimulation and supports morphological and functional adaptation of paraspeckles under altered gravitational conditions. 97 In muscle, hypoxia triggers nucleolin translocation from the nucleus to the cytoplasm and reduces its phase-separation capacity, thereby altering gene-expression control. 91

Together, biomolecular condensates provide spatial and temporal control over musculoskeletal development, homeostasis, and stress adaptation. They coordinate epigenetic regulation, transcription, RNA metabolism, signal transduction, and stimulus responses. Important gaps remain, including how condensate size, composition, fluidity, and material state determine function in specific musculoskeletal cell types. Future work should also move beyond isolated condensates and examine how multiple condensates compete for clients, exchange signals, and respond collectively to mechanical cues. Because current musculoskeletal studies focus heavily on transcriptional regulation, additional work is needed to define condensate functions at post-transcriptional, metabolic, tissue, and organismal levels.

Biomolecular condensates in musculoskeletal disorders

Biomolecular condensates organize cellular biochemistry, and their dysregulation has been associated with several bone and musculoskeletal diseases. The strength of this association varies across disease settings. In some sarcomas, fusion proteins or transcription factors form condensates that recruit chromatin regulators and activate oncogenic programs, providing relatively direct mechanistic links. In osteoarthritis, SGs correlate with inflammatory signaling and chondrocyte survival, but whether they initiate disease or buffer injury-induced stress remains less certain. In osteoporosis and muscle atrophy, condensate-related mechanisms connect genetic variation, RNA metabolism, mechanical loading, and cell differentiation, yet many observations still require causal validation in human-relevant systems. Here, we review biomolecular condensates in bone diseases, bone tumors, soft tissue sarcomas, skeletal muscle disorders, and neuromuscular disorders, focusing on both mechanistic insights and the limits of current evidence.

Biomolecular condensates in bone disease

Bone provides mechanical protection, supports muscle attachment, and converts muscle contraction into movement through load-bearing architecture. 98 Bone diseases disrupt these functions through degenerative, inflammatory, developmental, or metabolic mechanisms and can cause disability, reduced quality of life, complications, and substantial health-care burden. 99 , 100 Condensate biology is relevant because osteoblast differentiation, chondrocyte stress responses, mechanical loading, and RNA regulation all depend on spatially organized molecular assemblies. The following sections summarize condensate-related mechanisms in osteoporosis, osteoarthritis, and congenital skeletal disorders (Table 2 ). Table 2 Biomolecular condensates in bone diseases Disease Subcellular localization Core molecule Recruited factors Phenotype Function Osteoporosis 23 Cytoplasm HuR β-catenin, G3BP1, TIA1 Decreased bone mineral density, reduced bone formation, and impaired osteogenic differentiation Enrich and stabilize β-catenin mRNA, recruit β-catenin Osteoporosis 88 Nucleus RUNX2 Enhancer element, XCR1 promoter Impaired osteogenic differentiation and decreased mineralization capacity Mediate long-range chromatin interactions between enhancers and promoters, activate XCR1 gene transcription Osteoporosis 104 Cytoplasm Plectin Annexin A2 Promote osteoblast differentiation and reverse bone loss Enrichment and activation of osteogenic protein Annexin A2 Osteoarthritis 24 Cytoplasm TIA1, HuR COX-2 mRNA COX-2 protein expression is delayed but persistently enhanced, PGE2 secretion is increased Sequester COX-2 mRNA and delay its translation Osteoarthritis 111 Cytoplasm TDP-43 RACK1 Increased chondrocyte proliferation, decreased secretion of inflammatory factors, inhibited apoptosis Prevent RACK1 from activating the downstream MTK1–MKK3/6–p38/JNK signaling pathway BPTAS 113 Nucleus HMGB1 FIB1 Brachydactyly, polydactyly, tibial hypoplasia, craniofacial anomalies Induce nucleolar stress, inhibit rRNA transcription and protein translation BPTAS brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome

Osteoporosis

Osteoporosis is a chronic metabolic bone disease characterized by reduced bone mineral density, deterioration of bone microarchitecture, and increased fracture susceptibility. It causes pain, limits activity, and increases disability risk. A central challenge is to identify mechanistic biomarkers that can be translated into clinical practice. 101 Biomolecular condensates formed through LLPS may provide such biomarkers because they report functional molecular states rather than protein abundance alone. 102

At the genetic level, osteoporosis risk loci identified by genome-wide association studies are often located in non-coding regions whose functions are difficult to interpret. 103 RUNX2 condensates provide one mechanistic example. Through LLPS, RUNX2 can bridge the rs4683184 enhancer and the distal XCR1 promoter, activate GPCR signaling, and promote osteoblast differentiation. 88 Condensates also regulate mRNA fate in osteoblasts. HuR forms SGs that capture and stabilize beta-catenin mRNA during aging, thereby preserving osteogenic differentiation; loss of HuR granules contributes to functional decline. 23 NEAT1-dependent paraspeckles retain Smurf1 mRNA in the nucleus under mechanical loading, stabilizing RUNX2 and supporting osteocyte differentiation. Unloading or aging decreases NEAT1 expression, disrupts paraspeckles, and contributes to osteoporosis. 97 A cytoskeletal mechanism has also been described: plectin undergoes IDR-mediated LLPS and sequesters annexin A2, enhancing osteogenic gene expression and bone formation in vitro and in vivo. The phase-separating plectin region (residues 1967-2185) alleviated bone loss in ovariectomized and mechanically unloaded mice. 104 These findings suggest that condensates integrate genetic, RNA, cytoskeletal, and mechanical inputs during bone formation.

The osteoporosis literature shows that condensates can mediate distinct and sometimes opposite RNA outcomes, including nuclear retention, translational repression, transcript stabilization, and cytoplasmic signaling. The rules that determine these outcomes remain unclear. NEAT1 illustrates this complexity. In osteoblasts, altered mechanical loading can also increase NEAT1 expression, allowing NEAT1 to sponge miR-466f-3p, derepress HK2, activate autophagy, and potentially promote osteoporosis. 105 In osteoclasts, differentiation stimuli upregulate NEAT1 in a dose-dependent manner, and excessive activation can reduce bone mass and increase osteoporosis risk. 106 Future work should determine when NEAT1-containing condensates protect bone and when they promote bone loss. The mechanisms connecting mechanical force, NEAT1 expression, paraspeckle integrity, and LLPS also require clarification. BMP2-inducible kinase, which is associated with bone differentiation and forms cytoplasmic condensates, is another example whose downstream pathway remains insufficiently defined. 107

Osteoarthritis

OA causes progressive joint pain, stiffness, restricted mobility, deformity, and secondary muscle atrophy, substantially reducing quality of life. 108 Existing treatments do not reliably halt disease progression, so mechanisms that control chondrocyte stress responses remain important therapeutic targets. 109 Biomolecular condensates, especially SGs, have therefore become a relevant focus in OA research. Transcriptomic analyses using machine learning have also identified condensate-related genes as potential diagnostic biomarkers linked to immune imbalance and chondrocyte degeneration. 110

In OA, SGs appear to regulate inflammatory responses and chondrocyte survival through a time-dependent sequestration-and-release mechanism. In IL-1β-stimulated human OA chondrocytes, IL-1β induces eIF2α phosphorylation and SG assembly. HuR binds COX-2 mRNA and recruits it into SGs, where the transcript is stabilized but temporarily withheld from translation. COX-2 protein synthesis increases only after SG disassembly and mRNA release, making SGs post-transcriptional regulators of the IL-1β-COX-2 pathway. 24 SGs also regulate apoptotic and stress signaling. A p35 fragment of TDP-43 promotes RACK1 expression and recruitment into SGs, limiting activation of the pro-apoptotic and pro-inflammatory p38/JNK MAPK pathway. This attenuates inflammation and apoptosis in chondrocytes and may support proliferation through pathways such as LIMK1-actin signaling. 111 These findings suggest that SG modulation could help preserve chondrocyte function, although disease-stage specificity and safety require further validation.

Congenital skeletal disorders

Congenital skeletal disorders are characterized by bone fragility, recurrent fractures, progressive deformity, and multisystem complications that impair mobility and quality of life. Emerging evidence links LLPS and membraneless organelles to both chondrogenesis and osteogenesis. In chondrocytes, Sox9 recruits the 54-kD nuclear RNA-binding protein p54nrb to paraspeckles. p54nrb supports Sox9-mediated transcription of genes such as Col2a1 and, through its RNA-recognition motif, ensures proper splicing of newly transcribed Col2a1 pre-mRNA. Coupling transcription and splicing is essential for chondrocyte differentiation. 112 Dysregulation of this mechanism is associated with skeletal dysplasias such as campomelic dysplasia, chondrodysplasia, and dwarfism. Rare-disease evidence further supports a condensate mechanism. In brachyphalangy-polydactyly-tibial aplasia syndrome, frameshift mutations in the C-terminal acidic tail of HMGB1 cause aberrant phase separation. Mutant HMGB1 accumulates in the nucleolar granular compartment, displaces NPM1, encases FIB1, disrupts nucleolar organization, impairs rRNA synthesis and protein translation, and induces cytotoxicity. 113

Overall, condensates appear to participate in chondrocyte differentiation, transcriptional control, growth-factor signaling, and extracellular matrix regulation. Dysregulated condensates involving SOX9, RUNX2, RNA-binding proteins, or nucleolar components may contribute to impaired osteogenic or chondrogenic differentiation and to rare congenital bone phenotypes (Fig. 5 ). Systematic studies of condensate composition, dynamics, and functional consequences are still limited, leaving the molecular basis of LLPS-related skeletal abnormalities incompletely defined. Fig. 5 Roles of biomolecular condensates in bone diseases. a Osteoporosis. Apigenin treatment increases HuR abundance in senescent osteoblasts and promotes its condensation. HuR-containing condensates stabilize β-catenin mRNA and support the β‑catenin-RUNX2 signaling axis, alleviating osteoporotic progression. Conversely, mechanical unloading disrupts paraspeckle integrity, leading to Smurf1-mediated ubiquitination and degradation of RUNX2. At the cytoskeletal level, linker protein plectin undergoes phase separation to form condensates that sequester annexin A2, which is associated with upregulation of RUNX2 and osteogenic genes such as Ocn and Alp. b Osteoarthritis. Under OA-associated stress, a p35 fragment generated by caspase-3-mediated cleavage of TDP-43 promotes RACK1-dependent SG formation and modulates p38/JNK signaling, influencing inflammatory and apoptotic responses in chondrocytes. Upon IL-1β stimulation, HuR is recruited into SGs and binds COX-2 mRNA, suppressing its translation. Reduction in inflammatory stimuli leads to SG disassembly and restoration of COX-2 translation. c Chondrocyte function. Paraspeckle condensates recruit p54nrb and Sox9 to regulate Col2a1 transcription; dysregulation of this process is implicated in congenital skeletal disorders

Biomolecular condensates in bone tumors

Primary bone tumors and bone metastases disrupt bone architecture, compromise mechanical stability, and cause skeletal-related events such as pathological fracture, spinal cord compression, and bone pain. 114 , 115 These complications markedly increase disability and mortality. Tumor invasion can also disrupt tendon-bone and ligament-bone interfaces, weakening load transfer across the musculoskeletal system. Because several bone tumors depend on transcriptional reprogramming, stress adaptation, and microenvironmental sensing, condensate biology provides a useful framework for understanding tumor progression and treatment resistance (Table 3 ). Table 3 Biomolecular condensates in bone tumors Disease Subcellular localization Core molecule Recruited factors Phenotype Function Osteosarcoma 120 Nucleus HOXB8, FOSL1 Pol II, BRD4, MED1 Tumor metastasis and chemoresistance Drive the core regulatory circuit, promote the transcriptional elongation of oncogenes Osteosarcoma 95 Nucleus L3MBTL2 Components of Polycomb repressive complex 1.6 Tumor suppression; inhibition of tumor growth and metastasis Recruit PRC1.6 components and repress pro-oncogenic transcription Ewing sarcoma 125 Nucleus ARID1A BAF chromatin remodeling complex, EWSR1::FLI1 Enhance tumor cell proliferation, invasion, and migration; accelerate tumor growth in vivo Create a chromatin remodeling hub that increases accessibility and activate oncogene transcription Ewing sarcoma 126 Nucleus EWSR1::FLI1 BAF chromatin remodeling complex Promote the proliferation, migration, and invasion of tumor cells. Activate oncogenic transcriptional programs, remodel chromatin accessibility Metastatic bone tumor 92 Cytoplasm DACT1 CK2 Increased colonization and growth of cancer cells in the bone, promote metastases Sequester CK2 kinase and inhibit the Wnt/β-catenin signaling pathway Metastatic bone tumor 133 Cytoplasm GRP78 Core chaperone proteins of endoplasmic reticulum stress Maintain survival under hypoxia/ hypoglycemia stress Pause global translation and reprogram the proteome Metastatic bone tumor 135 Cytoplasm SYK RNA-binding protein, autophagy-related factor Promote breast cancer metastasis P-bodies are cleared through autophagy, thereby promoting mesenchymal–epithelial transition

Osteosarcoma

Osteosarcoma, a common primary malignant bone tumor that predominantly affects children and adolescents, continues to be treated with standard chemotherapy regimens established in the 1970s, with no substantial improvement in survival rates over recent decades. The high degree of genetic heterogeneity and pathological complexity of osteosarcoma has led to repeated failures in clinical trials of targeted therapies and immunotherapies directed against oncogenic signaling pathways. 116 , 117 More critically, the co-occurrence of lung metastasis and chemoresistance has become a central challenge in improving patient survival. 118

In osteosarcoma, condensates can either suppress or promote tumor progression depending on the molecular scaffold involved. Ubiquitin-conjugating enzyme E2O binds the polybasic region of L3MBTL2 and mediates its polyubiquitination and degradation, causing loss of this tumor suppressor. 95 , 119 Under physiological conditions, L3MBTL2 forms nuclear condensates that recruit Polycomb repressive complex 1.6 components and transcriptionally repress pro-oncogenic genes through its Pho-binding pocket. Arsenic trioxide inhibits UBE2O activity, stabilizes L3MBTL2, enhances L3MBTL2 condensate formation, and thereby restores tumor-suppressive activity. 95 By contrast, oncogenic condensates can drive osteosarcoma metastasis and chemoresistance. HOXB8 and FOSL1 form IDR-mediated nuclear condensates at super-enhancers, increase chromatin accessibility, recruit RNA polymerase II, and activate metastasis- and drug resistance-associated genes. The H3K27 demethylase inhibitor GSK-J4 binds the HOXB8 IDR, disrupts its phase separation, and reverses invasive osteosarcoma phenotypes. 120 WDR3 condensates also promote osteosarcoma progression, and nilotinib inhibits tumor growth by interfering with WDR3 condensate formation. 121

The dual role of condensates in osteosarcoma pathogenesis, metastasis, and drug resistance is increasingly being uncovered, providing new insights into the molecular mechanisms of this disease. Current studies support the function of condensates in dynamically assembling transcriptional complexes with either tumor-suppressive or oncogenic roles and have begun to explore small-molecule interventions targeting disease-associated phase behavior. To translate these discoveries into clinical applications, several challenges must be addressed: first, most research has focused on transcriptional regulation, leaving the roles of condensates in post-translational modifications, cross-talk between signaling pathways, and remodeling of the tumor microenvironment poorly understood. Second, more clinically relevant models, such as patient-derived organoids or orthotopic metastasis models, are needed to validate condensate-targeted therapies. Advancing these efforts will help connect mechanistic studies of condensates to precision treatment strategies.

Ewing sarcoma

Ewing sarcoma is the second most common primary malignant bone tumor in children and adolescents. Its most characteristic molecular event is an oncogenic fusion protein resulting from a chromosomal translocation, making it a well-defined model for discussing condensate-driven oncogenic transcription. The most prevalent fusion type, EWSR1::FLI1, combines the low-complexity domains of the EWSR1 RNA-binding protein with the DNA-binding domain of the ETS transcription factor FLI1. 122 , 123 The weak interactions between these two critical structural domains cooperatively promote LLPS of the fusion protein.

EWSR1::FLI1 forms intranuclear condensates through its N-terminal PrLD, where dense tyrosine residues act as molecular stickers. These dynamic condensates recruit the BAF chromatin-remodeling complex to GGAA microsatellite repeat elements and activate oncogenic transcription. 124 , 125 ARID1A, the DNA-binding core subunit of the BAF complex, contains an N-terminal low-complexity/PrLD-like region that interacts with the EWSR1::FLI1 PrLD through tyrosine-tyrosine contacts. Cooperative phase separation of these PrLDs creates transcriptional factories that concentrate transcriptional machinery and chromatin remodelers. 125 , 126 The FLI1 DNA-binding domain increases the rigidity of EWSR1-PrLD condensates through electrostatic interactions and promotes beta-sheet structures positive for Thioflavin T staining, a process linked to tumor-cell invasiveness. Conversely, DNA binding can limit interaction between the DNA-binding domain and the PrLD through steric hindrance, indicating reciprocal regulation between DNA binding and phase separation. 122 Enrichment of ARID1A/EWSR1-FLI1 condensates in Ewing sarcoma patient tissues, but not normal tissues, further supports a tumor-specific role for phase separation. 125 , 127 High-throughput screening identified abemaciclib (LY2835219) as a compound that dissolves these oncogenic condensates through the lysosomal pathway, reverses aberrant gene expression, and offers a therapeutic opportunity for Ewing sarcoma. 128 Further work is needed to determine how condensate targeting affects chemoresistance, downstream transcriptional states, and immune-based therapies.

Metastatic bone tumor

During the progression of tumors, bones are among the most common sites of metastasis for many cancers, particularly breast and prostate cancer. 129 The five-year survival rate for localized osteosarcoma can reach 70% with current combination therapies, whereas the five-year survival rate for metastatic osteosarcoma is considerably lower. 130 , 131 During bone metastasis, tumor cells must adapt to the highly specialized bone marrow microenvironment, where hypoxia, low glucose availability, and abundant cytokines collectively form a complex regulatory network. 132 Recent studies have revealed that LLPS of biomacromolecules plays a central role in the adaptability and plasticity of tumor cells. Particularly in multiple stages of bone metastasis, LLPS dynamically regulates key signaling pathways through the formation of membraneless organelles, thereby influencing tumor cell survival, phenotypic switching, and eventual colonization.

Biomolecular condensates mediate multiple aspects of cellular sensing within the bone microenvironment. Under the stressful conditions of hypoxia and low glucose in the bone marrow, disseminated tumor cells activate the unfolded protein response, notably upregulating the 78-kD glucose-regulated protein (GRP78), a UPR chaperone to form SGs, which maintain proteostasis and promote cell survival. 133 These GRP78-positive condensates assemble during acute stress and disassemble upon adaptation, highlighting the dynamic regulatory role of condensates in response to microenvironmental pressures. TGF-β signaling plays a central role in breast cancer bone metastasis, supporting tumor cell colonization and progression. 134 Shinde et al. showed that during TGF-β-induced epithelial-mesenchymal transition, SYK activity is substantially enhanced and localizes to P-bodies. SYK promotes autophagy-mediated clearance of LLPS-derived P-bodies, driving mesenchymal-epithelial transition and thereby supporting metastatic outgrowth. Inhibition of SYK activity or loss of the autophagy-related gene ATG7 prevents P-body clearance, impairs mesenchymal-epithelial transition, and suppresses metastasis. 135 These findings indicate that the formation and clearance of LLPS-driven P-bodies are essential for regulating phenotypic plasticity. In terms of signal reprogramming, TGF-β signaling can also induce the expression of DACT1, which undergoes phase separation via its IDRs to form cytoplasmic biomolecular condensates. These DACT1 condensates do not colocalize with known organelles but sequester the Wnt pathway-activating kinase casein kinase 2, thereby inhibiting Wnt signaling and enhancing the bone-metastatic potential of breast and prostate cancer cells. 92 This LLPS-mediated sequestration of casein kinase 2 provides a tunable mechanism for signaling insulation, which may be more effective than simple protein-protein inhibition alone.

Studies of biomolecular condensates in bone tumors reveal their roles as regulatory assemblies that influence oncogenic transcription, cellular adaptation, and metastatic fitness (Fig. 6 ). In osteosarcoma, condensates show a dual role, with tumor-suppressive L3MBTL2 condensates and oncogenic HOXB8/FOSL1 hubs dynamically shaping tumor progression and chemoresistance. Ewing sarcoma is driven by the EWSR1::FLI1 fusion oncoprotein, whose PrLD-containing condensates act as neomorphic transcriptional factories that hijack chromatin remodeling to enforce a malignant state. Within the metastatic bone niche, condensates support tumor cell resilience through SG assembly, regulate phenotypic plasticity via clearance of P-bodies, and rewire signaling networks by sequestering key kinases. Future research must move beyond correlative observations to dissect the structural grammar of oncogenic condensates, clarify their interplay with the tumor microenvironment, and develop therapeutic approaches that precisely target the formation, composition, or dissolution of pathological assemblies. 136 , 137 Fig. 6 Roles of biomolecular condensates in bone tumors. a Adaptation to the bone marrow microenvironment. TGF-β signaling induces DACT1 expression, which undergoes IDR-mediated phase separation to form cytoplasmic condensates that suppress Wnt signaling by limiting β-catenin nuclear translocation—a process linked to enhanced metastatic traits. TGF-β also promotes SYK-mediated P-body degradation, supporting tumor growth. Under stress conditions such as hypoxia and low glucose, upregulated GRP78 assembles into survival-promoting SGs. b Transcriptional regulation in osteosarcoma. The tumor-suppressive L3MBTL2 condensate, which normally inhibits TNF/NF-κB signaling, is polyubiquitinated and degraded by the highly expressed E2 enzyme UBE2O. Conversely, condensates at super-enhancer regions increase chromatin accessibility and recruit RNA polymerase II, activating metastasis- and drug resistance–associated genes. c Oncogenic condensates in Ewing sarcoma. The EWSR1::FLI1 fusion protein forms condensates that recruit the BAF chromatin-remodeling complex to GGAA microsatellite repeats, driving oncogenic transcription. ARID1A acts as a molecular bridge via a shared N-terminal prion-like domain, stabilizing these transcriptional condensates

Biomolecular condensates in soft tissue sarcomas

Soft tissue sarcomas can compromise musculoskeletal function, particularly when they arise in the limbs, trunk wall, or near joints and neurovascular structures. 138 , 139 Recurrence near joints or other functional structures can cause severe limb dysfunction. 140 The following sections review condensate-related mechanisms in soft tissue sarcomas, focusing on how LLPS-associated fusion oncoproteins remodel transcriptional programs and signaling pathways. This perspective may help identify vulnerabilities in treatment-resistant disease.

Low-grade fibromyxoid sarcoma

Low-grade fibromyxoid sarcoma is a rare malignancy that typically arises in deep soft tissues of the proximal extremities or trunk in young adults. 141 Its rarity contributes to limited clinical experience and frequent diagnostic delay. More than 90% of cases carry a recurrent translocation that generates the FUS-CREB3L2 fusion oncoprotein. 142 , 143 This chimeric protein contains canonical transmembrane domains and IDRs. 143 IDRs within the FUS moiety drive LLPS at the endoplasmic reticulum membrane and initiate regulated intramembrane proteolysis, which releases the N-terminal fragment. 144 After nuclear translocation, this fragment undergoes LLPS and assembles transcriptional condensates that concentrate coactivators, recruit chromatin remodelers, and activate a fibromyxoid sarcoma-specific gene-expression program. 144 , 145 Although no targeted therapy is currently available, preclinical inhibition of fusion-oncoprotein nuclear translocation suppresses malignant phenotypes and may offer a therapeutic route.

Synovial sarcoma

Synovial sarcoma is another rare yet highly aggressive soft tissue sarcoma, accounting for 5%–10% of all soft tissue sarcomas. 146 – 148 A major clinical concern is its metastatic propensity, and outcomes are poor once dissemination occurs. 149 , 150 The oncogenic driver of synovial sarcoma is the SS18–SSX fusion gene. 151 The QPGY domain of SS18, enriched in tyrosine residues, mediates LLPS and drives the formation of dynamic nuclear condensates. In parallel, SS18–SSX forms a stable heterodimer with BRG1, the catalytic subunit of the canonical BAF chromatin-remodeling complex, through its conserved SNH domain. 152 LLPS-driven condensates may synergistically enrich BRG1, thereby enhancing local assembly in the crowded nuclear environment. SS18–SSX hijacks the BAF complex and redirects it to broad Polycomb domains, antagonizing PRC2-mediated silencing and activating bivalent developmental genes. 153 Given the limited efficacy of current treatments, targeting phase separation offers a potential strategy to overcome therapeutic barriers in synovial sarcoma. 154

Myxoid liposarcoma

Liposarcoma, the most common soft tissue sarcoma, is histologically classified into four major subtypes. Among these, the myxoid subtype accounts for approximately 30% of cases and is considered relatively chemosensitive compared with other liposarcoma subtypes. Its hallmark cytogenetic abnormality is the t (12;16) (q13;p11) translocation, which fuses DDIT3 (CHOP) at 12q13 with FUS at 16p11, generating the chimeric FUS-CHOP oncogene. 155 This oncoprotein forms nuclear condensates that strongly colocalize with the super-enhancer marker BRD4 in myxoid liposarcoma cells and actively recruit BRD4 in heterologous systems, a spatial coupling that occurs independently of CHOP’s DNA-binding capacity. 156 These findings reveal a dual-track mechanism: the FUS-derived PrLD orchestrates LLPS to generate a transcriptional hub, while the CHOP domain precisely anchors the complex to genomic target sites. Together, they establish a high local concentration of transcriptional regulators at super-enhancer regions, leading to aberrant activation of oncogenic gene networks. This mechanism clarifies how FUS-CHOP acquires its oncogenic potential and provides a compelling therapeutic rationale for targeting the condensate assembly process in myxoid liposarcoma.

Evidence from fibromyxoid sarcoma, synovial sarcoma, and myxoid liposarcoma supports a shared paradigm in which oncogenic fusion proteins exploit condensate formation to remodel transcriptional programs and chromatin landscapes, thereby driving tumor initiation, progression, and recurrence. The IDRs and PrLDs embedded in these fusion proteins act as molecular scaffolds to nucleate condensates, enrich transcriptional machinery, and rewire epigenetic regulation. While the precise in vivo dynamics of these condensates remain incompletely understood, accumulating findings support their central role in malignant phenotypes and treatment resistance. Targeting condensate formation or downstream condensate-dependent transcriptional machinery thus represents a possible therapeutic route for soft tissue sarcomas.

Biomolecular condensates in skeletal muscle disorders

Skeletal muscle disorders directly impair musculoskeletal structure and function. Clinically, they reduce contractile strength, coordination, limb function, ambulation, and, in severe cases, respiratory capacity. 157 Muscle dysfunction can also aggravate osteoarthritis, osteoporosis, and intervertebral disc degeneration by altering joint loading, increasing fibrosis, impairing bone regeneration, and sustaining inflammation. 158 , 159 The following sections focus on condensate mechanisms that are directly relevant to skeletal muscle development, degeneration, repair, and inherited myopathies (Table 4 ). Table 4 Biomolecular condensates in skeletal muscle disorders Disease Subcellular localization Core molecule Recruited factors Phenotype Function Muscular dystrophy 26 Cellular membrane, cytoplasmic PrPC miR-214-3p/miR-204-5p Autophagy inhibition, abnormal muscle bundle formation Selectively recruit miRNAs, inhibit ATG5 translation, and impair autophagy pathways Muscular dystrophy 172 Nucleus GYS1 RNA Pol II, MyoD Blocked differentiation, impaired regeneration and repair Inhibits glycogen synthesis, drives myogenic gene expression Muscular dystrophy 47 Nucleus hnRNPDL TNPO1, SRSF1 Increase protein insolubility and myofibrillar disorganization Involved in mRNA processing and the regulation of alternative splicing Muscle atrophy 67 Nucleus SUZ12 Components of Polycomb repressive complex 2 Intramuscular fat deposition, mitochondrial dysfunction Catalyzes H3K27me3, repressing the expression of Fhl3 and Rnf128 Muscle atrophy 66 Nucleus MEIS2 Transforming growth factor-β receptor II promoter Delay muscle regeneration Inhibit the expression of TGF-β/SMAD3 pathway Muscle atrophy 90 Cytoplasm YTHDF2 TM4SF1 mRNA Muscle differentiation is hindered Induce degradation of TM4SF1 mRNA Muscle atrophy 163 Nucleus RPS27L IGF1 Muscle mass and cross-sectional area of muscle fibers have significantly increased Activate the downstream signaling pathways Muscle atrophy 89 Nucleus, cytoplasm MEF2D Myogenic regulatory factors Promote the formation of multinucleated myotubes in the early stages of differentiation and accelerate the differentiation process Regulate the transcription of genes related to muscle differentiation and metabolism Muscle atrophy 162 Nucleus PGC-1α Pol II, H3K27ac Alteration in basal oxygen consumption of skeletal muscle Assemble transcriptional hubs to efficiently coordinate the transcriptional processes of metabolism-related gene programs Muscle atrophy 85 Nucleus TAZ Smad7, β-catenin Impairment of myotube formation Assemble inhibitory complexes to repress the transcription of muscle differentiation-related genes Muscle atrophy 94 Cell membrane FGF FGFR Characterized by faster clearance of necrotic areas Condensates concentrate FGF and overcome the signal activation threshold. Distinct hereditary myopathy 174 Cytoplasm TIA1 Ubiquitin conjugates, SQSTM1 Presence of rimmed vacuoles and protein aggregates within muscle fibers Leading to the accumulation of toxic proteins and cell death Distinct hereditary myopathy 173 Cytoplasm TDP-43 Autophagy-related protein Myasthenia, vacuolar degeneration Condensates cause abnormal retention of TDP-43 in the cytoplasm

Muscle atrophy

Muscle atrophy causes progressive loss of muscle mass and function, limiting mobility and quality of life. Its mechanisms remain complex and incompletely treatable. Skeletal muscle development requires myoblast proliferation, differentiation, myotube fusion, and maturation into myofibers. 160 Myogenic regulatory factors, including Myf5, MyoD, myogenin, and MRF4, coordinate this process. 161 Condensates help organize the transcriptional and post-transcriptional programs that support myogenesis. MEF2D tunes its own phase separation to coordinate with basal transcription machinery and myogenic factors, enabling lineage specification. 89 PGC-1α forms LLPS-driven nuclear condensates that regulate metabolism-related genes and may be therapeutically relevant in disuse atrophy. 162 lncRNAs such as MEG3 and lnc-RMG indirectly regulate muscle-development genes by modulating LLPS-linked pathways. 66 , 67 TAZ, a Hippo pathway effector, forms phase-separated nuclear condensates and represses muscle-specific gene expression through interactions with Smad7 and beta-catenin. 85 At the post-transcriptional level, METTL3-mediated m 6 A modification of TM4SF1 mRNA promotes recognition by YTHDF2 condensates, leading to mRNA degradation that limits proliferation and supports differentiation. 90 Rps27l also undergoes LLPS and interacts with IGF1 to regulate myogenesis, although its downstream pathways remain unclear. 163

Condensate-dependent nuclear bodies, including paraspeckles and nuclear speckles, act as hubs for RNA metabolism during myogenesis. 164 , 165 During C2C12 myoblast differentiation, transcription of the MEN epsilon/beta locus increases, producing two nuclear isoforms that localize to paraspeckles and scaffold core proteins such as NONO. 166 DGK-ζ, an intranuclear lipid kinase, regulates myogenic differentiation by localizing to nuclear speckles and the nuclear matrix, interacting with signaling molecules such as phosphoinositide-specific phospholipase C beta 1, and tuning the nuclear DG/PA balance. 167 LLPS also contributes to intercellular communication. The macrophage-derived metabolite 11,12-epoxyeicosatrienoic acid is released through Gasdermin D pores and enhances FGF signaling by promoting fibroblast growth factor phase separation. 94 This response supports tissue repair and mitigates age-associated decline in regeneration. Together, these mechanisms show how condensates integrate transcription, RNA processing, metabolism, and intercellular signals during muscle development and atrophy.

Muscular dystrophy

Muscular dystrophies are severe, progressive diseases that lead to muscle degeneration, loss of mobility, and early mortality. Despite genetic insights, effective treatments remain scarce, as the molecular mechanisms driving these conditions are not fully understood. 168 Accumulating evidence suggests that several forms of muscular dystrophy share a core pathological pathway driven by abnormal LLPS mediated by RNA-binding proteins. 169 The central mechanism of this pathway involves the disruption of RNA processing homeostasis within the nucleus, which brings distinct pathogenic factors, such as structural mutations, splicing abnormalities, and metabolic stress, into a common phenotype of impaired myogenesis and muscle fiber degeneration. In limb-girdle muscular dystrophy type 1 G, pathogenic mutations in hnRNPDL or alterations in its alternative splicing isoforms disrupt the protein’s intrinsic phase separation properties, supporting the transition of reversible condensates into insoluble amyloid-like aggregates. This aberrant phase transition promotes hnRNPDL insolubility and functional impairment, potentially leading to dysregulation of RNA processing and ultimately contributing to progressive muscle fiber degeneration. 47 Paraspeckles and nuclear speckles have been implicated in oculopharyngeal muscular dystrophy. 170 , 171 Alanine-expanded PABPN1 accumulates at speckle peripheries to form intranuclear inclusions, leading to PABPN1 and poly(A) RNA depletion, thereby disrupting mRNA processing and transport. 171 PABPN1 also interacts with the nuclear matrix protein MATR3 to regulate selective polyadenylation, intron retention, and stability of the long noncoding RNA NEAT1. 170 NEAT1 serves as a paraspeckle scaffold, and its accumulation increases paraspeckle abundance and drives aberrant RNA editing. 164 Condensate dysregulation not only affects RNA metabolism but also incorporates metabolic regulation into the dystrophic network. GYS1 and NONO/p54nrb form nuclear condensates that co-assemble with MyoD and the transcription initiation complex to regulate the expression of myogenic genes such as myogenin and Tnni2. Disruption of this system leads to pathological glycogen accumulation, mitochondrial dysfunction, and impaired muscle regeneration. 172 Abnormal PrPᶜ condensates specifically bind miR-214-3p, inhibiting the translation of the autophagy gene ATG5, thereby exacerbating muscle cell death and regeneration defects. 26 Overall, these studies establish condensate dysfunction as a unifying pathogenic axis in muscular dystrophies: various genetic or stress-induced factors can convert physiological condensates into cytotoxic aggregates, thereby compromising proteostasis, transcriptional fidelity, and cellular resilience.

Distinct hereditary myopathy

Recent studies on hereditary myopathies highlight that mutations in LCD-containing RNA-binding proteins perturb LLPS behavior and converge on a shared pathway of dysregulated stress-granule homeostasis and impaired proteostasis in skeletal muscle. A representative example is the newly identified G376V variant of TDP-43, which resides in its prion-like LCD and markedly enhances cytoplasmic condensate formation, promotes assembly into higher-order oligomers, and alters condensate morphology. These aberrant phase-separated assemblies accumulate in patient-derived myoblasts and are associated with cryptic exon inclusion and myofibrillar disorganization, ultimately producing a primary muscle-intrinsic degenerative phenotype distinct from ALS. 173 Similarly, pathogenic variants in TIA1, another LCD-containing SG nucleator, such as the N357S allele, shift the phase diagram toward enhanced LLPS and markedly delay SG disassembly. The TIA1-N357S variant synergizes with SQSTM1 mutations to drive pathology: the former impairs SG dynamics by enhancing LLPS, while the latter compromises protein clearance capacity by disrupting autophagic flux. Together, they lead to the accumulation of ubiquitinated proteins within persistent SGs, which gradually evolve into amyloid-like, rimmed vacuole-associated inclusions characteristic of multisystem proteinopathy. 174 These findings delineate a unifying molecular axis in which LCD mutations increase condensate stability and decrease SG dynamics, thereby overwhelming ubiquitin-dependent autophagic clearance. The resulting persistence and pathological hardening of phase-separated RNP assemblies form a mechanistic continuum that explains how distinct genetic lesions, TDP-43 G376V monogenic myopathy versus TIA1-SQSTM1 digenic MSP, produce phenotypically varied yet mechanistically convergent muscle atrophy.

Across muscle atrophy, muscular dystrophies, and hereditary myopathies, condensate dysregulation has emerged as a mechanism that integrates diverse pathogenic drivers into a shared trajectory of muscle fiber degeneration (Fig. 7 ). Under physiological conditions, condensates orchestrate myogenic transcriptional programs, RNA metabolism, and metabolic signaling; however, mutations, cellular stress, or aging can shift these assemblies toward pathological hardening, thereby disrupting RNA homeostasis, proteostasis, and muscle regeneration. Despite this progress, major gaps remain. Most evidence comes from in vitro models, leaving the in vivo behavior of condensates in mature or diseased muscle insufficiently understood. Direct causal links between condensate dysfunction and atrophy require more rigorous biophysical and genetic validation. The upstream signals that regulate condensate dynamics and the molecular composition of these structures remain poorly defined. Addressing these limitations will be important for advancing condensate-based therapeutic strategies for muscle atrophy and myopathies. Fig. 7 Roles of biomolecular condensates in skeletal muscle disorders. a Muscle atrophy. During myoblast differentiation, METTL3-mediated m⁶A modification of TM4SF1 mRNA supports its recognition by YTHDF2-containing condensates, promoting mRNA decay via P-bodies and supporting myogenic differentiation. Under chronic inflammation, lncRNA-associated phase separation recruits Polycomb repressive complex components, leading to histone modifications and indirect regulation of muscle-related gene expression that contributes to muscle mass maintenance. b Muscular dystrophy. Overexpressed cellular prion protein (PrPᶜ) recruits miR-214-3p/miR-204-5p family members into phase-separated condensates that can mature into fibrillar assemblies, associated with autophagy inhibition, muscle cell death, and impaired regeneration. Under glycogen depletion, glycogen synthase 1 translocates to the nucleus and forms condensates that interact with myogenic regulators, modulating transcription of myogenesis-related genes and supporting context-specific muscle regeneration. c Hereditary myopathy. In digenic inheritance-associated myopathy, TIA1 mutations enhance SG assembly, whereas p62 mutations impair their clearance. This leads to persistent SGs enriched in TDP-43 and defective ribosomal products, resulting in increased cytotoxicity and elevated LDH release

Biomolecular condensates in neuromusculoskeletal disorders

The motor system functions as an integrated unit in which the nervous system and musculoskeletal apparatus are tightly coupled. This connection justifies considering selected motor-system disorders when their neurological pathology substantially impairs musculoskeletal performance. The neuromuscular junction provides a clear example. During synapse formation, Rapsyn undergoes LLPS and creates dynamic condensates that concentrate acetylcholine receptors, anchoring proteins, and regulatory signals. 93 , 175 These membraneless compartments support acetylcholine receptor clustering and synaptic maturation. 93 Importantly, congenital myasthenic syndrome mutations in Rapsyn disrupt its phase-separation capacity, directly linking condensate dysfunction to impaired neuromuscular transmission. The neuromuscular junction, therefore, illustrates how LLPS can connect neuronal signaling to musculoskeletal performance.

Amyotrophic lateral sclerosis

ALS is a fatal neurodegenerative disorder characterized by progressive motor-neuron loss, muscle atrophy, paralysis, and respiratory failure. Average survival after diagnosis is typically 2–5 years, and no curative treatment is available. 176 Aberrant condensate assembly is closely linked to ALS pathogenesis, with TDP-43 aggregation into irreversible amyloid fibrils recognized as a key pathological mechanism. These aggregates sequester normal TDP-43 and disrupt essential cellular processes, causing proteotoxic stress and neuronal death. 177 Recent studies have clarified how TDP-43 aggregation occurs. TDP-43 first concentrates within SGs beyond a critical threshold, and oxidative stress then triggers intra-droplet phase separation from RNA and G3BP1, producing a TDP-43-enriched liquid phase. This phase undergoes liquid-to-solid transition as low-complexity domains shift from alpha-helical to beta-sheet conformations, eventually forming insoluble aggregates with pathological phosphorylation and ubiquitination. 178 This mechanism has been validated in cellular models, mouse models, and patient samples. External factors can further accelerate pathology. Nanoscale polystyrene particles induce oxidative stress, retain TDP-43 in the cytoplasm, and promote phosphorylated pathological aggregates that cause neuronal injury and ALS-like behavioral deficits in mice. 179 Hyperosmotic stress similarly favors TDP-43 liquid-to-solid transition when protective factors are absent, suggesting that enhancing condensate dynamics may be therapeutically useful. 180

Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disorder characterized by choreiform movements, cognitive decline, and neuropsychiatric symptoms. 181 Its motor manifestations directly affect gait, coordination, and skeletal muscle use, which makes the disease relevant to neuromusculoskeletal dysfunction. Mutant huntingtin impairs autophagosome formation by disrupting the phase-separation properties of SQSTM1 droplets and altering phagophore membrane curvature. This defect promotes toxic protein accumulation, energy depletion, and oxidative stress. 182 Although the primary pathology is neuronal, condensate dysfunction may therefore worsen motor-system performance by disturbing autophagy and proteostasis at the neuron-muscle interface. These findings support a focused, rather than general, role for condensates in Huntington’s disease.

Parkinson’s disease

Parkinson’s disease is a rapidly growing neurodegenerative disorder whose cardinal motor features arise from degeneration of dopaminergic neurons in the substantia nigra pars compacta. 183 – 185 These motor deficits directly impair posture, gait, coordination, and skeletal muscle control. A key molecular event is α-synuclein aggregation, which can begin when α-synuclein undergoes LLPS to form liquid-like droplets. These droplets can mature through liquid-to-solid transition into beta-sheet-rich oligomers, fibrils, and hydrogel-like matrices that stabilize pathological aggregates. 186 De novo macrocyclic peptides can induce α-synuclein LLPS by interacting mainly with its C-terminal region and altering droplet maturation. 187 Conversely, β-synuclein co-condenses with α-synuclein, reduces protein mobility within condensates, blocks droplet fusion, and suppresses amyloid maturation. 188 Thus, condensate-mediated alpha-synuclein assembly is relevant to Parkinsonian motor dysfunction, but its musculoskeletal relevance is indirect and mediated through neuronal control of movement. 189 , 190

Aberrant condensate assembly has emerged as a pathophysiological mechanism in diverse musculoskeletal disorders. Evidence from osteoporosis, osteoarthritis, skeletal developmental anomalies, bone and soft tissue tumors, and muscle or injury-related conditions suggests that condensates govern cellular events such as chromatin organization, transcriptional regulation, stress responses, and signaling dynamics. Dysregulated condensates can disrupt the balance between bone formation and resorption, contribute to aberrant chondrocyte homeostasis, support malignant transformation, and impair muscle regeneration. Biomolecular condensates also provide a framework linking genetic mutations, epigenetic alterations, and environmental stressors to disease onset and progression. These insights expand musculoskeletal pathobiology beyond traditional linear signaling pathways and identify pathological condensates as possible therapeutic targets. Future studies should focus on the spatiotemporal regulation of condensates, their cross-talk with mechanical and metabolic cues, and their druggability.

Clinical translation of biomolecular condensate biology

Prognostic model development

Condensate biology may also inform prognosis and therapy guidance in musculoskeletal disease. Rather than measuring molecular abundance alone, condensate-based biomarkers could capture functional states such as scaffold recruitment, material hardening, stress-granule persistence, or oncogenic transcriptional hub formation. 191 – 194 Existing LLPS-related risk models outside the musculoskeletal field, including esophageal adenocarcinoma, provide methodological proof of principle but are not direct disease analogs. 195 In musculoskeletal oncology, multi-omics data from osteosarcoma and related tumors could be used to build condensate-related prognostic models that predict survival, reflect tumor microenvironmental states, and nominate drug sensitivities. However, direct biomarker studies across osteoporosis, OA, muscle disease, and neuromuscular disorders remain limited. Future models should therefore be anchored to musculoskeletal cohorts and validated against condensate-specific biology rather than using generic LLPS gene lists alone. 121 , 195

Targeting pathological condensates

As described above, aberrant condensate assembly or maturation can contribute to the pathogenesis and progression of several musculoskeletal disorders. Therapeutic strategies that target disease-associated condensates, therefore, represent a possible route for treating these diseases, provided that physiological condensates are preserved. This approach has gained traction in oncology, where interventions that disrupt IDRs or alter condensate dynamics have shown efficacy. For example, Xie et al. developed a series of FOXM1-interfering peptides based on its IDR1 structure; among these, FIP4, which contains a phosphomimetic S376 residue, effectively disrupts FOXM1 phase separation, suppressing tumor cell proliferation, migration, and invasion while enhancing immunogenic gene expression. 196 Similarly, SI-2 binds directly to the IDR of SRC-3, blocking its interaction with NSD2 and disrupting the SRC-3/NSD2 complex in multiple myeloma, thereby resensitizing cells to bortezomib and promoting apoptosis. 197 Beyond conventional small-molecule inhibitors, innovative condensate-targeting modalities continue to emerge. For instance, a near-infrared light-controlled system employing upconversion nanoparticles can induce DNA phase separation and generate singlet oxygen, synergistically damaging glioma cell DNA and suppressing tumor growth. 198 Alternatively, peptide-based coacervates formed via phase separation have been used to engineer immune cell surfaces for enhanced antibody display and targeted cancer cell killing. 199

Some compounds can also promote phase separation for therapeutic benefit. icFSP1 induces FSP1 phase separation, suppresses its anti-ferroptosis activity, and strongly potentiates ferroptosis under GPX4 inhibition, suggesting an anticancer strategy. 200 By contrast, the conventional enzymatic inhibitor iFSP1 does not overcome resistance linked to aberrant protein localization, illustrating why the condensate state can matter beyond catalytic activity. 200 , 201 In skeletal tumors, GSK-J4 disrupts HOXB8/FOSL1 condensates and blocks super-enhancer-driven oncogenic transcription in metastatic or therapy-resistant osteosarcoma. 120 Nilotinib interferes with WDR3 phase separation and modulates the RASSF1A-Hippo pathway, spliceosome function, lysosomal degradation, and immune-microenvironment features to inhibit osteosarcoma progression. 121 High-throughput screening and imaging-based platforms further support the discovery of condensate-modulating molecules. 128 , 202

Translation of musculoskeletal disease faces several barriers. First, target definition is difficult because physiological condensates support normal transcription, RNA metabolism, DNA repair, and stress responses. Selectivity will likely require disease-enriched scaffolds, mutation-dependent condensates, or pathological material states such as persistent, hardened, or mislocalized assemblies. A second strategy is to target condensate-specific clients, post-translational modifications, or upstream signals rather than the phase transition itself. Local delivery may further reduce toxicity for intra-articular, intratumoral, or biomaterial-based applications. Tissue access is another barrier: mineralized bone, avascular cartilage, fibrotic muscle, and the neuromuscular junction impose different diffusion, retention, and clearance constraints. Finally, condensate modulators may have narrow dose windows, context-dependent effects, and uncertain pharmacokinetics because condensate partitioning can alter local drug concentration. Therapeutic studies should therefore measure condensate behavior, downstream function, tissue distribution, and off-target effects in parallel.

Condensate-inspired delivery systems

Therapeutic biomacromolecules hold great promise for treating a wide spectrum of diseases; however, their clinical translation has long been hampered by inefficient intracellular delivery. Condensate-inspired strategies provide a new means of overcoming this bottleneck, offering distinct advantages over conventional delivery methods. For instance, histones and Chol-ssDNA can undergo LLPS at defined ratios and concentrations to form core–shell condensates that efficiently encapsulate negatively charged drugs via electrostatic interactions. These complexes are internalized through a receptor-independent macropinocytosis pathway, while simultaneously providing protective shielding and prolonged in vivo retention, thereby markedly enhancing drug delivery efficiency and therapeutic efficacy. 203 Similarly, early studies showed that LLPS-driven conjugated peptides readily traverse cellular membranes and rapidly recruit diverse macromolecules. 204 Building on this, subsequent work employed modular design of phase-separating peptides to tune the physicochemical properties of coacervate microdroplets, resulting in a universal and efficient platform with programmable release kinetics for intracellular macromolecule delivery. 205

Traditional delivery systems often trap proteins in endosomes and prevent efficient cytoplasmic release. By contrast, the light-responsive phase-separating fluorescent molecule PPFM undergoes Norrish type II photolysis after 405 nm irradiation, triggering condensate disassembly and protein release. 206 Phase separation can also be used at the cell membrane to enhance drug enrichment and uptake. One system anchors a targeting component to cancer-cell receptors and initiates in situ co-phase separation of a drug-conjugated partner. The resulting condensates create high local drug concentration, enter cells through clathrin-independent endocytosis, and release cytotoxic drugs after lysosomal acidification. 207 Another approach uses alkaline phosphatase-catalyzed dephosphorylation and self-assembly of the phosphopeptide KYp to induce lipid-protein phase separation at the cell membrane, increasing membrane permeability and peptide-drug internalization. 208 These strategies show how LLPS can support electrostatic assembly, enzyme-triggered self-assembly, drug enrichment, and controlled uptake.

Condensate-inspired delivery platforms may be useful for musculoskeletal disorders, but in vivo translation remains difficult. In OA, therapeutic efficacy is limited by the dense, negatively charged, and avascular cartilage matrix, which restricts particle penetration, and by rapid clearance through synovial fluid turnover. 209 , 210 A system that works in monolayer chondrocyte culture may fail in intact cartilage because of size exclusion, electrostatic trapping, enzymatic degradation, and nonuniform loading during joint movement. Dense tendon and mineralized bone pose different barriers, including poor vascular access, fibrotic scarring, mineral binding, and slow convective transport. 211 Safety is also unresolved. Phase-separating carriers may alter local protein condensation, inflammatory signaling, or extracellular matrix organization, especially after repeated dosing. Future studies should therefore move from proof-of-concept uptake assays to explants, mechanically loaded cartilage or tendon models, large-animal joints, and disease models that measure tissue penetration, residence time, release kinetics, immune activation, and functional recovery.

Hydrogel-induced modulation of intracellular condensates

The physical properties of the extracellular environment, especially matrix stiffness, can regulate intracellular condensates and provide a materials-based route to modulate cell behavior. YAP, a key mechanosensing transcriptional coactivator, undergoes LLPS and forms condensates in response to stiff extracellular matrices. 212 , 213 Hydrogels can exploit this principle by tuning mechanical cues that influence condensate formation. Reprogramming-responsive hydrogels with autonomous stiffness changes trigger YAP condensate formation at key stages of cellular reprogramming and accelerate induction of pluripotent stem cells. 214 Similarly, hydrogel elastic modulus regulates transcription-factor recruitment through YAP-mediated LLPS and promotes osteogenic differentiation of human bone marrow stromal cells, suggesting relevance for bone regeneration. 215

These findings suggest a material-condensate-cell fate axis. Instead of directly targeting proteins with chemical agents, smart biomaterials may manipulate intracellular condensates by controlling matrix mechanics. Applications to muscular dystrophy, tendon repair, cartilage regeneration, and arthritis remain early. Future studies should test how defined mechanical signals regulate condensates in musculoskeletal cells and whether correcting condensate behavior improves tissue repair.

Challenges and prospects

Human-relevant musculoskeletal models for clinical translation

Muscle tissue contains multiple cell types, and current isolation methods can introduce non-target-cell contamination, reducing the purity and yield of populations such as muscle stem cells. These cells are difficult to maintain in a quiescent state in vitro and often activate, differentiate, or undergo apoptosis, leading to loss of regenerative potential. As a result, many studies still rely on animal models. This creates a translational gap because condensate behavior observed in animal or simplified culture systems may not reflect human clinical tissue.

More physiologically relevant human models are needed, but they must be designed around the specific questions that condensate studies ask. Muscle organoids, 3D myotube cultures, patient-derived induced pluripotent stem cells, bone-on-chip systems, cartilage explants, and osteoblast-osteoclast-immune co-cultures can better preserve cell-cell interactions, extracellular matrix stiffness, nutrient gradients, and mechanical loading than conventional two-dimensional cultures. Each model also has limits. Organoids may lack vascularization, innervation, immune components, and mature force generation; 3D cultures can be difficult to image at subcellular resolution; and patient-derived systems vary with donor age, disease stage, medication exposure, and genetic background. For condensate research, model validation should include not only lineage markers and tissue morphology, but also condensate-specific readouts such as endogenous localization, material properties, FRAP recovery, stress responsiveness, and rescue by phase-deficient mutants. When these models are combined with single-cell RNA sequencing, spatial transcriptomics, proteomics, and well-annotated clinical biobanks, they can help determine whether condensates observed in vitro also exist in diseased human tissue and whether they drive pathology rather than simply accompany it.

Live imaging and mechanical regulation of condensates

Tissues such as muscle, bone, cartilage, and the neuromuscular junction are mechanically active and structurally complex. Several mechanosensitive condensate regulators are particularly relevant to human musculoskeletal tissues. YAP and TAZ are key mechanosensitive transcriptional regulators that respond to matrix stiffness and cytoskeletal tension. Emerging studies further suggest that TAZ or YAP-associated condensates can translate mechanical cues into transcriptional outputs. 85 , 212 , 213 NEAT1-dependent paraspeckles respond to mechanical loading in osteoblasts and control Smurf1 mRNA retention, thereby affecting RUNX2 stability. 97 RUNX2 itself forms condensate-like assemblies that connect non-coding variants to osteogenic gene regulation. 88 In Drosophila muscle, Tono senses compressive forces generated during myofibril and mitochondrial growth and forms nucleoplasmic droplets that regulate developmental transcription. 84 Osmotic and metabolic changes also feed into mechanosensitive condensate biology; mechano-dependent sorbitol accumulation can support condensate formation, suggesting that load may regulate condensates through both force transmission and intracellular solute balance. 212 Altered loading in osteoporosis, sarcopenia, disuse, or muscle injury may therefore change condensate thresholds, residence time, or client recruitment. Real-time, high-resolution observation of these events in vivo remains difficult, and causal links between condensate behavior and outcomes such as bone strength or muscle contractility remain incomplete.

To address these limitations, future studies should combine condensate-sensitive biosensors, endogenous fluorescent tagging, optogenetic control of condensate assembly, and super-resolution live-cell imaging. Mechanical stimulation platforms should be matched to tissue context: cyclic stretch for muscle, compression for cartilage, fluid shear or substrate stiffness gradients for bone cells, and engineered neuromuscular junction systems for synaptic organization. AI-assisted image analysis and physical modeling can help quantify condensate number, size, fusion, dissolution, and molecular exchange under defined loading regimens. These approaches would make it possible to test whether altered mechanical load changes condensates directly, whether the effect is mediated through YAP/TAZ, NEAT1, RUNX2, Tono, osmotic adaptation, or metabolic pathways, and whether correcting condensate behavior restores musculoskeletal function.

Physical properties and functions of condensates

The physical properties of musculoskeletal condensates, including viscoelasticity, interfacial tension, and stiffness, remain poorly understood, especially in mechanosensing and spatiotemporal regulation. 216 Microfluidic devices can model fluid shear stress, stretch systems can impose cyclic strain, and atomic force microscopy and microrheology-based approaches can help quantify condensate or condensate-associated mechanics. Fluorescence correlation spectroscopy can measure molecular dynamics, while molecular dynamics simulations can clarify assembly and dissolution at the molecular level. Combining these approaches may establish causal links between mechanical stimulation, condensate material properties, and cellular function. Such knowledge should improve understanding of muscle atrophy, osteoporosis, arthritis, and related disorders and guide more selective therapeutic strategies.

Conclusion

Biomolecular condensates are an organizing principle in the musculoskeletal system, but their disease relevance varies by context and by evidence strength. Dynamic condensates regulate gene expression, signal transduction, stress adaptation, and tissue repair. When their composition, material state, localization, or clearance is altered, they may contribute to congenital skeletal abnormalities, muscle atrophy, osteosarcoma, metastatic bone disease, and neuromuscular disorders. In several settings, however, condensates may also represent adaptive responses to stress rather than primary disease drivers. Progress will depend on experiments that separate direct causality from association, define disease-specific condensate features, and validate mechanisms in human-relevant models exposed to realistic mechanical and matrix conditions. Therapeutic translation will require selectivity, local or tissue-aware delivery, pharmacokinetic testing, and long-term safety assessment, because physiological condensates are essential for normal cell function.

These authors contributed equally: Qichen Miao, Ruiqi Gao, Mingyang Huang

Acknowledgements

This study was sponsored by the Young Scientists Project of the National Key R&D Program (2025YFA1309700); the National Natural Science Foundation of China (82572835); the Fundamental Research Funds for the Central Universities (2042025kf0029); and the Hubei Provincial Health and Health Technology Program (WJ2025Q021).

Author contributions

Conceptualization: W.G. Wang and M. Luo; Literature search and reference screening: G.Q. Wang and Q.C. Miao; Writing—original draft: Q.C. Miao; Visualization: R.Q. Gao; Tables and data organization: M.Y. Huang; Writing - review and editing: Q.C. Miao, R.Q. Gao, M.Y. Huang, G.Q. Wang, W.G. Wang and M. Luo; Supervision: W.G. Wang and M. Luo; Funding acquisition: M. Luo, Q.C. Miao, R.Q. Gao and M.Y. Huang contributed equally to this work. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing interests.

References

1. Bonnevie ED Mauck RL Physiology and engineering of the graded interfaces of musculoskeletal junctions Annu. Rev. Biomed. Eng. 2018 20 403 429 10.1146/annurev-bioeng-062117-121113 29641907 PMC7735380 Bonnevie, E. D. & Mauck, R. L. Physiology and engineering of the graded interfaces of musculoskeletal junctions. Annu. Rev. Biomed. Eng. 20 , 403–429 (2018). 29641907 10.1146/annurev-bioeng-062117-121113 PMC7735380

2. La Placa G The impact of microbiota on musculoskeletal injuries Cells 2025 14 554 10.3390/cells14070554 40214507 PMC11988348 La Placa, G. et al. The impact of microbiota on musculoskeletal injuries. Cells 14 , 554 (2025). 40214507 10.3390/cells14070554 PMC11988348

3. Livshits G Kalinkovich A The role of TRIM proteins in chronic inflammation-associated musculoskeletal diseases Ageing Res. Rev. 2025 111 102837 10.1016/j.arr.2025.102837 40684883 Livshits, G. & Kalinkovich, A. The role of TRIM proteins in chronic inflammation-associated musculoskeletal diseases. Ageing Res. Rev. 111 , 102837 (2025). 40684883 10.1016/j.arr.2025.102837

4. Jabre S Hleihel W Coirault C Nuclear Mechanotransduction in Skeletal Muscle Cells 2021 10 318 10.3390/cells10020318 33557157 PMC7913907 Jabre, S., Hleihel, W. & Coirault, C. Nuclear Mechanotransduction in Skeletal Muscle. Cells 10 , 318 (2021). 33557157 10.3390/cells10020318 PMC7913907

5. Espinosa A Casas M Jaimovich E Energy (and reactive oxygen species generation) saving distribution of mitochondria for the activation of atp production in skeletal muscle Antioxidants 2023 12 1624 10.3390/antiox12081624 37627619 PMC10451830 Espinosa, A., Casas, M. & Jaimovich, E. Energy (and reactive oxygen species generation) saving distribution of mitochondria for the activation of atp production in skeletal muscle. Antioxidants 12 , 1624 (2023). 37627619 10.3390/antiox12081624 PMC10451830

6. Lowe M Barr FA Inheritance and biogenesis of organelles in the secretory pathway Nat. Rev. Mol. Cell Biol. 2007 8 429 439 10.1038/nrm2179 17505521 Lowe, M. & Barr, F. A. Inheritance and biogenesis of organelles in the secretory pathway. Nat. Rev. Mol. Cell Biol. 8 , 429–439 (2007). 17505521 10.1038/nrm2179

7. Longfield SF Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles Nat. Commun. 2023 14 7277 10.1038/s41467-023-43130-4 37949856 PMC10638352 Longfield, S. F. et al. Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles. Nat. Commun. 14 , 7277 (2023). 37949856 10.1038/s41467-023-43130-4 PMC10638352

8. Zhao Z Super-resolution imaging of highly curved membrane structures in giant vesicles encapsulating molecular condensates Adv. Mater. 2022 34 e2106633 10.1002/adma.202106633 34710248 Zhao, Z. et al. Super-resolution imaging of highly curved membrane structures in giant vesicles encapsulating molecular condensates. Adv. Mater. 34 , e2106633 (2022). 34710248 10.1002/adma.202106633

9. Boeynaems S Protein phase separation: a new phase in cell biology Trends Cell Biol. 2018 28 420 435 10.1016/j.tcb.2018.02.004 29602697 PMC6034118 Boeynaems, S. et al. Protein phase separation: a new phase in cell biology. Trends Cell Biol. 28 , 420–435 (2018). 29602697 10.1016/j.tcb.2018.02.004 PMC6034118

10. Sabari BR Coactivator condensation at super-enhancers links phase separation and gene control Science 2018 361 eaar3958 10.1126/science.aar3958 29930091 PMC6092193 Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361 , eaar3958 (2018). 29930091 10.1126/science.aar3958 PMC6092193

11. Boija A Transcription factors activate genes through the phase-separation capacity of their activation domains Cell 2018 175 1842 1855.e16 10.1016/j.cell.2018.10.042 30449618 PMC6295254 Boija, A. et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175 , 1842–1855.e16 (2018). 30449618 10.1016/j.cell.2018.10.042 PMC6295254

12. Du M Chen ZJ DNA-induced liquid phase condensation of cGAS activates innate immune signaling Science 2018 361 704 709 10.1126/science.aat1022 29976794 PMC9417938 Du, M. & Chen, Z. J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361 , 704–709 (2018). 29976794 10.1126/science.aat1022 PMC9417938

13. Chen X Wu X Wu H Zhang M Phase separation at the synapse Nat. Neurosci. 2020 23 301 310 10.1038/s41593-019-0579-9 32015539 Chen, X., Wu, X., Wu, H. & Zhang, M. Phase separation at the synapse. Nat. Neurosci. 23 , 301–310 (2020). 32015539 10.1038/s41593-019-0579-9

14. Zeng M Phase transition in postsynaptic densities underlies formation of synaptic complexes and synaptic plasticity Cell 2016 166 1163 1175.e12 10.1016/j.cell.2016.07.008 27565345 PMC5564291 Zeng, M. et al. Phase transition in postsynaptic densities underlies formation of synaptic complexes and synaptic plasticity. Cell 166 , 1163–1175.e12 (2016). 27565345 10.1016/j.cell.2016.07.008 PMC5564291

15. Guo K KANK1 shapes focal adhesions by orchestrating protein binding, mechanical force sensing, and phase separation Cell Rep. 2023 42 113321 10.1016/j.celrep.2023.113321 37874676 Guo, K. et al. KANK1 shapes focal adhesions by orchestrating protein binding, mechanical force sensing, and phase separation. Cell Rep. 42 , 113321 (2023). 37874676 10.1016/j.celrep.2023.113321

16. Ong JY Torres JZ Phase separation in cell division Mol. Cell 2020 80 9 20 10.1016/j.molcel.2020.08.007 32860741 PMC7541545 Ong, J. Y. & Torres, J. Z. Phase separation in cell division. Mol. Cell 80 , 9–20 (2020). 32860741 10.1016/j.molcel.2020.08.007 PMC7541545

17. Yang P G3BP1 is a tunable switch that triggers phase separation to assemble stress granules Cell 2020 181 325 345.e28 10.1016/j.cell.2020.03.046 32302571 PMC7448383 Yang, P. et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell 181 , 325–345.e28 (2020). 32302571 10.1016/j.cell.2020.03.046 PMC7448383

18. Fu W Multivalent interactions of Septin 6 promote the establishment of epithelial cell polarity J. Mol. Cell Biol. 2025 17 mjaf003 10.1093/jmcb/mjaf003 39973116 PMC12256136 Fu, W. et al. Multivalent interactions of Septin 6 promote the establishment of epithelial cell polarity. J. Mol. Cell Biol. 17 , mjaf003 (2025). 39973116 10.1093/jmcb/mjaf003 PMC12256136

19. Wang B Liquid-liquid phase separation in human health and diseases Signal Transduct. Target Ther. 2021 6 290 10.1038/s41392-021-00678-1 34334791 PMC8326283 Wang, B. et al. Liquid-liquid phase separation in human health and diseases. Signal Transduct. Target Ther. 6 , 290 (2021). 34334791 10.1038/s41392-021-00678-1 PMC8326283

20. Chen Y Pathogenic mutation ΔK280 promotes hydrophobic interactions involving microtubule-binding domain and enhances liquid-liquid phase separation of tau Small 2025 21 e2406429 10.1002/smll.202406429 39421885 Chen, Y. et al. Pathogenic mutation ΔK280 promotes hydrophobic interactions involving microtubule-binding domain and enhances liquid-liquid phase separation of tau. Small 21 , e2406429 (2025). 39421885 10.1002/smll.202406429

21. Chen C Fu G Guo Q Xue S Luo SZ Phase separation of p53 induced by its unstructured basic region and prevented by oncogenic mutations in tetramerization domain Int. J. Biol. Macromol. 2022 222 207 216 10.1016/j.ijbiomac.2022.09.087 36108750 Chen, C., Fu, G., Guo, Q., Xue, S. & Luo, S. Z. Phase separation of p53 induced by its unstructured basic region and prevented by oncogenic mutations in tetramerization domain. Int. J. Biol. Macromol. 222 , 207–216 (2022). 36108750 10.1016/j.ijbiomac.2022.09.087

22. Banani SF Lee HO Hyman AA Rosen MK Biomolecular condensates: organizers of cellular biochemistry Nat. Rev. Mol. Cell Biol. 2017 18 285 298 10.1038/nrm.2017.7 28225081 PMC7434221 Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18 , 285–298 (2017). 28225081 10.1038/nrm.2017.7 PMC7434221

23. Huai Y HuR-positive stress granules: Potential targets for age-related osteoporosis Aging Cell 2024 23 e14053 10.1111/acel.14053 38375951 PMC10928564 Huai, Y. et al. HuR-positive stress granules: Potential targets for age-related osteoporosis. Aging Cell 23 , e14053 (2024). 38375951 10.1111/acel.14053 PMC10928564

24. Ansari MY Haqqi TM Interleukin-1β induced stress granules sequester COX-2 mRNA and regulates its stability and translation in human OA chondrocytes Sci. Rep. 2016 6 27611 10.1038/srep27611 27271770 PMC4897887 Ansari, M. Y. & Haqqi, T. M. Interleukin-1β induced stress granules sequester COX-2 mRNA and regulates its stability and translation in human OA chondrocytes. Sci. Rep. 6 , 27611 (2016). 27271770 10.1038/srep27611 PMC4897887

25. Ahn JH Phase separation drives aberrant chromatin looping and cancer development Nature 2021 595 591 595 10.1038/s41586-021-03662-5 34163069 PMC8647409 Ahn, J. H. et al. Phase separation drives aberrant chromatin looping and cancer development. Nature 595 , 591–595 (2021). 34163069 10.1038/s41586-021-03662-5 PMC8647409

26. Tao J Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in myopathy Nat. Commun. 2023 14 8131 10.1038/s41467-023-43826-7 38065962 PMC10709375 Tao, J. et al. Excess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid-liquid phase separation implicated in myopathy. Nat. Commun. 14 , 8131 (2023). 38065962 10.1038/s41467-023-43826-7 PMC10709375

27. Yang C Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules Autophagy 2023 19 1934 1951 10.1080/15548627.2022.2164427 36692217 PMC10283440 Yang, C. et al. Stress granule homeostasis is modulated by TRIM21-mediated ubiquitination of G3BP1 and autophagy-dependent elimination of stress granules. Autophagy 19 , 1934–1951 (2023). 36692217 10.1080/15548627.2022.2164427 PMC10283440

28. Wilson EB The structure of protoplasm Science 1899 10 33 45 10.1126/science.10.237.33 17829686 Wilson, E. B. The structure of protoplasm. Science 10 , 33–45 (1899). 17829686 10.1126/science.10.237.33

29. Liu Y Mitochondria-associated endoplasmic reticulum membranes in human health and diseases MedComm 2025 6 e70259 10.1002/mco2.70259 40584408 PMC12205217 Liu, Y. et al. Mitochondria-associated endoplasmic reticulum membranes in human health and diseases. MedComm 6 , e70259 (2025). 40584408 10.1002/mco2.70259 PMC12205217

30. Mao YS Zhang B Spector DL Biogenesis and function of nuclear bodies Trends Genet. 2011 27 295 306 10.1016/j.tig.2011.05.006 21680045 PMC3144265 Mao, Y. S., Zhang, B. & Spector, D. L. Biogenesis and function of nuclear bodies. Trends Genet. 27 , 295–306 (2011). 21680045 10.1016/j.tig.2011.05.006 PMC3144265

31. Decker CJ Parker R P-bodies and stress granules: possible roles in the control of translation and mRNA degradation Cold Spring Harb. Perspect. Biol. 2012 4 a012286 10.1101/cshperspect.a012286 22763747 PMC3428773 Decker, C. J. & Parker, R. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol. 4 , a012286 (2012). 22763747 10.1101/cshperspect.a012286 PMC3428773

32. Handwerger KE Cordero JA Gall JG Cajal bodies, nucleoli, and speckles in the Xenopus oocyte nucleus have a low-density, sponge-like structure Mol. Biol. Cell 2005 16 202 211 10.1091/mbc.e04-08-0742 15509651 PMC539164 Handwerger, K. E., Cordero, J. A. & Gall, J. G. Cajal bodies, nucleoli, and speckles in the Xenopus oocyte nucleus have a low-density, sponge-like structure. Mol. Biol. Cell 16 , 202–211 (2005). 15509651 10.1091/mbc.E04-08-0742 PMC539164

33. Brangwynne CP Germline P granules are liquid droplets that localize by controlled dissolution/condensation Science 2009 324 1729 1732 10.1126/science.1172046 19460965 Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324 , 1729–1732 (2009). 19460965 10.1126/science.1172046

34. Hyman AA Weber CA Jülicher F Liquid-liquid phase separation in biology Annu. Rev. Cell Dev. Biol. 2014 30 39 58 10.1146/annurev-cellbio-100913-013325 25288112 Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30 , 39–58 (2014). 25288112 10.1146/annurev-cellbio-100913-013325

35. Basha S Mukunda DC Pai AR Mahato KK Assessing amyloid fibrils and amorphous aggregates: a review Int. J. Biol. Macromol. 2025 311 143725 10.1016/j.ijbiomac.2025.143725 40324497 Basha, S., Mukunda, D. C., Pai, A. R. & Mahato, K. K. Assessing amyloid fibrils and amorphous aggregates: a review. Int. J. Biol. Macromol. 311 , 143725 (2025). 40324497 10.1016/j.ijbiomac.2025.143725

36. Alberti S Gladfelter A Mittag T Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates Cell 2019 176 419 434 10.1016/j.cell.2018.12.035 30682370 PMC6445271 Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176 , 419–434 (2019). 30682370 10.1016/j.cell.2018.12.035 PMC6445271

37. Bao L Kang WB Zhu BC Xiao Y Charge arrangement determines the sensitivity of aggregation patterns between peptide-chains to the surrounding ionic environment J. Chem. Inf. Model. 2025 65 950 965 10.1021/acs.jcim.4c02034 39761364 Bao, L., Kang, W. B., Zhu, B. C. & Xiao, Y. Charge arrangement determines the sensitivity of aggregation patterns between peptide-chains to the surrounding ionic environment. J. Chem. Inf. Model. 65 , 950–965 (2025). 39761364 10.1021/acs.jcim.4c02034

38. Yan X Zhang M Wang D Interplay between posttranslational modifications and liquid‒liquid phase separation in tumors Cancer Lett. 2024 584 216614 10.1016/j.canlet.2024.216614 38246226 Yan, X., Zhang, M. & Wang, D. Interplay between posttranslational modifications and liquid‒liquid phase separation in tumors. Cancer Lett. 584 , 216614 (2024). 38246226 10.1016/j.canlet.2024.216614

39. Chen Z Liquid-liquid phase separation of biomacromolecules and its roles in metabolic diseases Cells 2022 11 3023 10.3390/cells11193023 36230986 PMC9562192 Chen, Z. et al. Liquid-liquid phase separation of biomacromolecules and its roles in metabolic diseases. Cells 11 , 3023 (2022). 36230986 10.3390/cells11193023 PMC9562192

40. Rizvi A Revealing nanoscale structure and interfaces of protein and polymer condensates via cryo-electron microscopy Nanoscale 2024 16 16706 16717 10.1039/D4NR01877J 39171763 PMC11392623 Rizvi, A. et al. Revealing nanoscale structure and interfaces of protein and polymer condensates via cryo-electron microscopy. Nanoscale 16 , 16706–16717 (2024). 39171763 10.1039/d4nr01877j PMC11392623

41. Wang W Engineering sequential liquid-liquid phase separation and affinity partitioning for compartmentalization and functionalization of all-aqueous emulsion drops J. Colloid Interface Sci. 2025 698 138136 10.1016/j.jcis.2025.138136 40499379 Wang, W. et al. Engineering sequential liquid-liquid phase separation and affinity partitioning for compartmentalization and functionalization of all-aqueous emulsion drops. J. Colloid Interface Sci. 698 , 138136 (2025). 40499379 10.1016/j.jcis.2025.138136

42. Dubel N Liese S Scherz F Seitz O Exploring the limits of bivalency by DNA-based spatial screening Angew. Chem. Int. Ed. Engl. 2019 58 907 911 10.1002/anie.201810996 30372595 Dubel, N., Liese, S., Scherz, F. & Seitz, O. Exploring the limits of bivalency by DNA-based spatial screening. Angew. Chem. Int. Ed. Engl. 58 , 907–911 (2019). 30372595 10.1002/anie.201810996

43. Zheng T Molecular insights into the effect of 1,6-hexanediol on FUS phase separation EMBO J. 2025 44 2725 2740 10.1038/s44318-025-00431-2 40281357 PMC12084347 Zheng, T. et al. Molecular insights into the effect of 1,6-hexanediol on FUS phase separation. EMBO J. 44 , 2725–2740 (2025). 40281357 10.1038/s44318-025-00431-2 PMC12084347

44. Wang X Levy Y Iwahara J Competition between nucleic acids and intrinsically disordered regions within proteins Acc. Chem. Res. 2025 58 2415 2424 10.1021/acs.accounts.5c00261 40631955 PMC12369953 Wang, X., Levy, Y. & Iwahara, J. Competition between nucleic acids and intrinsically disordered regions within proteins. Acc. Chem. Res. 58 , 2415–2424 (2025). 40631955 10.1021/acs.accounts.5c00261 PMC12369953

45. Holla A Identifying sequence effects on chain dimensions of disordered proteins by integrating experiments and simulations JACS Au 2024 4 4729 4743 10.1021/jacsau.4c00673 39735932 PMC11672150 Holla, A. et al. Identifying sequence effects on chain dimensions of disordered proteins by integrating experiments and simulations. JACS Au 4 , 4729–4743 (2024). 39735932 10.1021/jacsau.4c00673 PMC11672150

46. Xu Q Impact of nonnative interactions on the binding kinetics of intrinsically disordered p53 with MDM2: insights from all-atom simulation and Markov state model analysis J. Chem. Inf. Model 2024 64 5219 5231 10.1021/acs.jcim.3c01833 38916177 Xu, Q. et al. Impact of nonnative interactions on the binding kinetics of intrinsically disordered p53 with MDM2: insights from all-atom simulation and Markov state model analysis. J. Chem. Inf. Model 64 , 5219–5231 (2024). 38916177 10.1021/acs.jcim.3c01833

47. Batlle C hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation Cell Rep. 2020 30 1117 1128.e5 10.1016/j.celrep.2019.12.080 31995753 PMC6996132 Batlle, C. et al. hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation. Cell Rep. 30 , 1117–1128.e5 (2020). 31995753 10.1016/j.celrep.2019.12.080 PMC6996132

48. Moses D Ginell GM Holehouse AS Sukenik S Intrinsically disordered regions are poised to act as sensors of cellular chemistry Trends Biochem. Sci. 2023 48 1019 1034 10.1016/j.tibs.2023.08.001 37657994 PMC10840941 Moses, D., Ginell, G. M., Holehouse, A. S. & Sukenik, S. Intrinsically disordered regions are poised to act as sensors of cellular chemistry. Trends Biochem. Sci. 48 , 1019–1034 (2023). 37657994 10.1016/j.tibs.2023.08.001 PMC10840941

49. Conicella AE Zerze GH Mittal J Fawzi NL ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain Structure 2016 24 1537 1549 10.1016/j.str.2016.07.007 27545621 PMC5014597 Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24 , 1537–1549 (2016). 27545621 10.1016/j.str.2016.07.007 PMC5014597

50. Tong X Liquid-liquid phase separation in tumor biology Signal Transduct. Target Ther. 2022 7 221 10.1038/s41392-022-01076-x 35803926 PMC9270353 Tong, X. et al. Liquid-liquid phase separation in tumor biology. Signal Transduct. Target Ther. 7 , 221 (2022). 35803926 10.1038/s41392-022-01076-x PMC9270353

51. Wang A A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing EMBO J. 2018 37 e97452 10.15252/embj.201797452 29438978 PMC5830921 Wang, A. et al. A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J. 37 , e97452 (2018). 29438978 10.15252/embj.201797452 PMC5830921

52. Kim J Qin S Zhou HX Rosen MK Surface charge can modulate phase separation of multidomain proteins J. Am. Chem. Soc. 2024 146 3383 3395 10.1021/jacs.3c12789 38262618 PMC10859935 Kim, J., Qin, S., Zhou, H. X. & Rosen, M. K. Surface charge can modulate phase separation of multidomain proteins. J. Am. Chem. Soc. 146 , 3383–3395 (2024). 38262618 10.1021/jacs.3c12789 PMC10859935

53. He Z Sommer JU Harmon TS Impact of coiled-coil domains on the phase behavior of biomolecular condensates ACS Macro Lett. 2025 14 413 419 10.1021/acsmacrolett.4c00821 40098319 He, Z., Sommer, J. U. & Harmon, T. S. Impact of coiled-coil domains on the phase behavior of biomolecular condensates. ACS Macro Lett. 14 , 413–419 (2025). 40098319 10.1021/acsmacrolett.4c00821

54. Mitrea DM Structural polymorphism in the N-terminal oligomerization domain of NPM1 Proc. Natl. Acad. Sci. USA 2014 111 4466 4471 10.1073/pnas.1321007111 24616519 PMC3970533 Mitrea, D. M. et al. Structural polymorphism in the N-terminal oligomerization domain of NPM1. Proc. Natl. Acad. Sci. USA 111 , 4466–4471 (2014). 24616519 10.1073/pnas.1321007111 PMC3970533

55. Mitrea DM Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA Elife 2016 5 e13571 10.7554/eLife.13571 26836305 PMC4786410 Mitrea, D. M. et al. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. Elife 5 , e13571 (2016). 26836305 10.7554/eLife.13571 PMC4786410

56. Wang J A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins Cell 2018 174 688 699.e16 10.1016/j.cell.2018.06.006 29961577 PMC6063760 Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174 , 688–699.e16 (2018). 29961577 10.1016/j.cell.2018.06.006 PMC6063760

57. Wake N Expanding the molecular grammar of polar residues and arginine in FUS phase separation Nat. Chem. Biol. 2025 21 1076 1088 10.1038/s41589-024-01828-6 39920231 PMC12772992 Wake, N. et al. Expanding the molecular grammar of polar residues and arginine in FUS phase separation. Nat. Chem. Biol. 21 , 1076–1088 (2025). 39920231 10.1038/s41589-024-01828-6 PMC12772992

58. Rekhi S Expanding the molecular language of protein liquid-liquid phase separation Nat. Chem. 2024 16 1113 1124 10.1038/s41557-024-01489-x 38553587 PMC11230844 Rekhi, S. et al. Expanding the molecular language of protein liquid-liquid phase separation. Nat. Chem. 16 , 1113–1124 (2024). 38553587 10.1038/s41557-024-01489-x PMC11230844

59. Banani SF Compositional control of phase-separated cellular bodies Cell 2016 166 651 663 10.1016/j.cell.2016.06.010 27374333 PMC4967043 Banani, S. F. et al. Compositional control of phase-separated cellular bodies. Cell 166 , 651–663 (2016). 27374333 10.1016/j.cell.2016.06.010 PMC4967043

60. Ries RJ m6A enhances the phase separation potential of mRNA Nature 2019 571 424 428 10.1038/s41586-019-1374-1 31292544 PMC6662915 Ries, R. J. et al. m6A enhances the phase separation potential of mRNA. Nature 571 , 424–428 (2019). 31292544 10.1038/s41586-019-1374-1 PMC6662915

61. Langdon EM mRNA structure determines specificity of a polyQ-driven phase separation Science 2018 360 922 927 10.1126/science.aar7432 29650703 PMC6192030 Langdon, E. M. et al. mRNA structure determines specificity of a polyQ-driven phase separation. Science 360 , 922–927 (2018). 29650703 10.1126/science.aar7432 PMC6192030

62. Mahendran TS Wadsworth GM Singh A Gupta R Banerjee PR Homotypic RNA clustering accompanies a liquid-to-solid transition inside the core of multi-component biomolecular condensates Nat. Chem. 2025 17 1236 1246 10.1038/s41557-025-01847-3 40603603 PMC12714487 Mahendran, T. S., Wadsworth, G. M., Singh, A., Gupta, R. & Banerjee, P. R. Homotypic RNA clustering accompanies a liquid-to-solid transition inside the core of multi-component biomolecular condensates. Nat. Chem. 17 , 1236–1246 (2025). 40603603 10.1038/s41557-025-01847-3 PMC12714487

63. Henninger JE RNA-mediated feedback control of transcriptional condensates Cell 2021 184 207 225.e24 10.1016/j.cell.2020.11.030 33333019 PMC8128340 Henninger, J. E. et al. RNA-mediated feedback control of transcriptional condensates. Cell 184 , 207–225.e24 (2021). 33333019 10.1016/j.cell.2020.11.030 PMC8128340

64. Burke KA Janke AM Rhine CL Fawzi NL Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II Mol. Cell 2015 60 231 241 10.1016/j.molcel.2015.09.006 26455390 PMC4609301 Burke, K. A., Janke, A. M., Rhine, C. L. & Fawzi, N. L. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 60 , 231–241 (2015). 26455390 10.1016/j.molcel.2015.09.006 PMC4609301

65. Rippe K Liquid-liquid phase separation in chromatin Cold Spring Harb. Perspect. Biol. 2022 14 a040683 10.1101/cshperspect.a040683 34127447 PMC8805649 Rippe, K. Liquid-liquid phase separation in chromatin. Cold Spring Harb. Perspect. Biol. 14 , a040683 (2022). 34127447 10.1101/cshperspect.a040683 PMC8805649

66. Yao Y LncRNA RMG controls liquid-liquid phase separation of MEIS2 to regulate myogenesis Int. J. Biol. Macromol. 2025 310 143309 10.1016/j.ijbiomac.2025.143309 40252346 Yao, Y. et al. LncRNA RMG controls liquid-liquid phase separation of MEIS2 to regulate myogenesis. Int. J. Biol. Macromol. 310 , 143309 (2025). 40252346 10.1016/j.ijbiomac.2025.143309

67. Yao Y LncRNA-MEG3 regulates muscle mass and metabolic homeostasis by facilitating SUZ12 liquid-liquid phase separation Adv. Sci. 2025 12 e2417715 10.1002/advs.202417715 PMC12199413 40285575 Yao, Y. et al. LncRNA-MEG3 regulates muscle mass and metabolic homeostasis by facilitating SUZ12 liquid-liquid phase separation. Adv. Sci. 12 , e2417715 (2025). 10.1002/advs.202417715 PMC12199413 40285575

68. Cheng Z Cheng Z Zhang Y Zhang S “Intrinsic disorder-protein modification-LLPS-tumor” regulatory axis: from regulatory mechanisms to precision medicine Biochim Biophys. Acta Rev. Cancer 2025 1880 189242 10.1016/j.bbcan.2024.189242 39672280 Cheng, Z., Cheng, Z., Zhang, Y. & Zhang, S. “Intrinsic disorder-protein modification-LLPS-tumor” regulatory axis: from regulatory mechanisms to precision medicine. Biochim Biophys. Acta Rev. Cancer 1880 , 189242 (2025). 39672280 10.1016/j.bbcan.2024.189242

69. Dyson HJ Wright PE Intrinsically unstructured proteins and their functions Nat. Rev. Mol. Cell Biol. 2005 6 197 208 10.1038/nrm1589 15738986 Dyson, H. J. & Wright, P. E. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell Biol. 6 , 197–208 (2005). 15738986 10.1038/nrm1589

70. Dai Z Li G Chen Q Yang X Ser392 phosphorylation modulated a switch between p53 and transcriptional condensates Biochim. Biophys. Acta Gene Regul. Mech. 2022 1865 194827 10.1016/j.bbagrm.2022.194827 35618207 Dai, Z., Li, G., Chen, Q. & Yang, X. Ser392 phosphorylation modulated a switch between p53 and transcriptional condensates. Biochim. Biophys. Acta Gene Regul. Mech. 1865 , 194827 (2022). 35618207 10.1016/j.bbagrm.2022.194827

71. Yi F Regulation of RB1CC1/FIP200 stability and autophagy function by CREBBP-mediated acetylation in an intrinsically disordered region Autophagy 2023 19 1662 1677 10.1080/15548627.2022.2148432 36394358 PMC10262773 Yi, F. et al. Regulation of RB1CC1/FIP200 stability and autophagy function by CREBBP-mediated acetylation in an intrinsically disordered region. Autophagy 19 , 1662–1677 (2023). 36394358 10.1080/15548627.2022.2148432 PMC10262773

72. Ryan VH Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation Mol. Cell 2018 69 465 479.e7 10.1016/j.molcel.2017.12.022 29358076 PMC5801700 Ryan, V. H. et al. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell 69 , 465–479.e7 (2018). 29358076 10.1016/j.molcel.2017.12.022 PMC5801700

73. Li Z Luo A Xie B The complex network of ADP-ribosylation and DNA repair: emerging insights and implications for cancer therapy Int. J. Mol. Sci. 2023 24 15028 10.3390/ijms241915028 37834477 PMC10573881 Li, Z., Luo, A. & Xie, B. The complex network of ADP-ribosylation and DNA repair: emerging insights and implications for cancer therapy. Int. J. Mol. Sci. 24 , 15028 (2023). 37834477 10.3390/ijms241915028 PMC10573881

74. Sun YC A few charged residues in galectin-3’s folded and disordered regions regulate phase separation Adv. Sci. 2024 11 e2402570 10.1002/advs.202402570 PMC11538691 39248370 Sun, Y. C. et al. A few charged residues in galectin-3’s folded and disordered regions regulate phase separation. Adv. Sci. 11 , e2402570 (2024). 10.1002/advs.202402570 PMC11538691 39248370

75. Vakeri A Lysozyme/alginate interactions: structural and thermodynamic Insights through ITC and SAXS Biomacromolecules 2025 26 4859 4871 10.1021/acs.biomac.5c00270 40698779 Vakeri, A. et al. Lysozyme/alginate interactions: structural and thermodynamic Insights through ITC and SAXS. Biomacromolecules 26 , 4859–4871 (2025). 40698779 10.1021/acs.biomac.5c00270

76. Foressi NN Cruz Rodríguez L Wilke N Celej MS Cation-driven modulation of tau condensates: insights into liquid-liquid phase separation and rheological properties Biomacromolecules 2025 26 3605 3616 10.1021/acs.biomac.5c00193 40439464 Foressi, N. N., Cruz Rodríguez, L., Wilke, N. & Celej, M. S. Cation-driven modulation of tau condensates: insights into liquid-liquid phase separation and rheological properties. Biomacromolecules 26 , 3605–3616 (2025). 40439464 10.1021/acs.biomac.5c00193

77. Kang J Lim L Lu Y Song J A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids PLoS Biol. 2019 17 e3000327 10.1371/journal.pbio.3000327 31188823 PMC6590835 Kang, J., Lim, L., Lu, Y. & Song, J. A unified mechanism for LLPS of ALS/FTLD-causing FUS as well as its modulation by ATP and oligonucleic acids. PLoS Biol. 17 , e3000327 (2019). 31188823 10.1371/journal.pbio.3000327 PMC6590835

78. Liu F Wang J ATP acts as a hydrotrope to regulate the phase separation of NBDY clusters JACS Au 2023 3 2578 2585 10.1021/jacsau.3c00391 37772172 PMC10523361 Liu, F. & Wang, J. ATP acts as a hydrotrope to regulate the phase separation of NBDY clusters. JACS Au 3 , 2578–2585 (2023). 37772172 10.1021/jacsau.3c00391 PMC10523361

79. Dang M Lim L Kang J Song J ATP biphasically modulates LLPS of TDP-43 PLD by specifically binding arginine residues Commun. Biol. 2021 4 714 10.1038/s42003-021-02247-2 34112944 PMC8192790 Dang, M., Lim, L., Kang, J. & Song, J. ATP biphasically modulates LLPS of TDP-43 PLD by specifically binding arginine residues. Commun. Biol. 4 , 714 (2021). 34112944 10.1038/s42003-021-02247-2 PMC8192790

80. Aida H Shigeta Y Harada R The role of ATP in solubilizing RNA-binding protein fused in sarcoma Proteins 2022 90 1606 1612 10.1002/prot.26335 35297101 Aida, H., Shigeta, Y. & Harada, R. The role of ATP in solubilizing RNA-binding protein fused in sarcoma. Proteins 90 , 1606–1612 (2022). 35297101 10.1002/prot.26335

81. Kang J Lim L Song J ATP enhances at low concentrations but dissolves at high concentrations liquid-liquid phase separation (LLPS) of ALS/FTD-causing FUS Biochem. Biophys. Res. Commun. 2018 504 545 551 10.1016/j.bbrc.2018.09.014 30205960 Kang, J., Lim, L. & Song, J. ATP enhances at low concentrations but dissolves at high concentrations liquid-liquid phase separation (LLPS) of ALS/FTD-causing FUS. Biochem. Biophys. Res. Commun. 504 , 545–551 (2018). 30205960 10.1016/j.bbrc.2018.09.014

82. Man J YTHDF2 phase separation promotes arsenite-induced oxidative stress by facilitating YTHDF2-mediated PIK3R2 mRNA degradation Int. J. Biol. Macromol. 2025 318 144936 10.1016/j.ijbiomac.2025.144936 40473165 Man, J. et al. YTHDF2 phase separation promotes arsenite-induced oxidative stress by facilitating YTHDF2-mediated PIK3R2 mRNA degradation. Int. J. Biol. Macromol. 318 , 144936 (2025). 40473165 10.1016/j.ijbiomac.2025.144936

83. Guo X N4BP1 is a nucleocytoplasmic shuttling protein and recognizes aggregates of the ubiquitin-like protein NEDD8 to protect cells under heat shock J. Biol. Chem. 2025 301 110511 10.1016/j.jbc.2025.110511 40701250 PMC12365338 Guo, X. et al. N4BP1 is a nucleocytoplasmic shuttling protein and recognizes aggregates of the ubiquitin-like protein NEDD8 to protect cells under heat shock. J. Biol. Chem. 301 , 110511 (2025). 40701250 10.1016/j.jbc.2025.110511 PMC12365338

84. Zhang X Mechanoresponsive regulation of myogenesis by the force-sensing transcriptional regulator Tono Curr. Biol. 2024 34 4143 4159.e6 10.1016/j.cub.2024.07.079 39163855 Zhang, X. et al. Mechanoresponsive regulation of myogenesis by the force-sensing transcriptional regulator Tono. Curr. Biol. 34 , 4143–4159.e6 (2024). 39163855 10.1016/j.cub.2024.07.079

85. Tripathi S Miyake T Kelebeev J McDermott JC TAZ exhibits phase separation properties and interacts with Smad7 and β-catenin to repress skeletal myogenesis J. Cell Sci. 2022 135 jcs259097 10.1242/jcs.259097 34859820 Tripathi, S., Miyake, T., Kelebeev, J. & McDermott, J. C. TAZ exhibits phase separation properties and interacts with Smad7 and β-catenin to repress skeletal myogenesis. J. Cell Sci. 135 , jcs259097 (2022). 34859820 10.1242/jcs.259097

86. Janssen A Colmenares SU Karpen GH Heterochromatin: guardian of the genome Annu. Rev. Cell Dev. Biol. 2018 34 265 288 10.1146/annurev-cellbio-100617-062653 30044650 Janssen, A., Colmenares, S. U. & Karpen, G. H. Heterochromatin: guardian of the genome. Annu. Rev. Cell Dev. Biol. 34 , 265–288 (2018). 30044650 10.1146/annurev-cellbio-100617-062653

87. Pei G Lyons H Li P Sabari BR Transcription regulation by biomolecular condensates Nat. Rev. Mol. Cell Biol. 2025 26 213 236 10.1038/s41580-024-00789-x 39516712 PMC12186837 Pei, G., Lyons, H., Li, P. & Sabari, B. R. Transcription regulation by biomolecular condensates. Nat. Rev. Mol. Cell Biol. 26 , 213–236 (2025). 39516712 10.1038/s41580-024-00789-x PMC12186837

88. Zhang Y RUNX2 Phase separation mediates long-range regulation between osteoporosis-susceptibility variant and XCR1 to promote osteoblast differentiation Adv. Sci. 2025 12 e2413561 10.1002/advs.202413561 PMC11809430 39704037 Zhang, Y. et al. RUNX2 Phase separation mediates long-range regulation between osteoporosis-susceptibility variant and XCR1 to promote osteoblast differentiation. Adv. Sci. 12 , e2413561 (2025). 10.1002/advs.202413561 PMC11809430 39704037

89. Gönczi M Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis Nat. Commun. 2023 14 1329 10.1038/s41467-023-37017-7 36898987 PMC10006080 Gönczi, M. et al. Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis. Nat. Commun. 14 , 1329 (2023). 36898987 10.1038/s41467-023-37017-7 PMC10006080

90. Ru W METTL3-mediated m6A modification regulates muscle development by promoting TM4SF1 mRNA degradation in P-body via YTHDF2 Int. J. Biol. Macromol. 2025 295 139576 10.1016/j.ijbiomac.2025.139576 39778834 Ru, W. et al. METTL3-mediated m6A modification regulates muscle development by promoting TM4SF1 mRNA degradation in P-body via YTHDF2. Int. J. Biol. Macromol. 295 , 139576 (2025). 39778834 10.1016/j.ijbiomac.2025.139576

91. Wang Y Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb Biochim. Biophys. Acta Mol. Basis Dis. 2025 1871 167706 10.1016/j.bbadis.2025.167706 39933290 Wang, Y. et al. Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb. Biochim. Biophys. Acta Mol. Basis Dis. 1871 , 167706 (2025). 39933290 10.1016/j.bbadis.2025.167706

92. Esposito M TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis Nat. Cell Biol. 2021 23 257 267 10.1038/s41556-021-00641-w 33723425 PMC7970447 Esposito, M. et al. TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nat. Cell Biol. 23 , 257–267 (2021). 33723425 10.1038/s41556-021-00641-w PMC7970447

93. Xing G Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation Neuron 2021 109 1963 1978.e5 10.1016/j.neuron.2021.04.021 34033754 PMC8217331 Xing, G. et al. Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron 109 , 1963–1978.e5 (2021). 34033754 10.1016/j.neuron.2021.04.021 PMC8217331

94. Chi Z Gasdermin D-mediated metabolic crosstalk promotes tissue repair Nature 2024 634 1168 1177 10.1038/s41586-024-08022-7 39260418 Chi, Z. et al. Gasdermin D-mediated metabolic crosstalk promotes tissue repair. Nature 634 , 1168–1177 (2024). 39260418 10.1038/s41586-024-08022-7

95. Zhong L Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma Sci. Adv. 2023 9 eadi0889 10.1126/sciadv.adi0889 37992172 PMC10664996 Zhong, L. et al. Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma. Sci. Adv. 9 , eadi0889 (2023). 37992172 10.1126/sciadv.adi0889 PMC10664996

96. Ivanov P Kedersha N Anderson P Stress granules and processing bodies in translational control Cold Spring Harb. Perspect. Biol. 2019 11 a032813 10.1101/cshperspect.a032813 30082464 PMC6496347 Ivanov, P., Kedersha, N. & Anderson, P. Stress granules and processing bodies in translational control. Cold Spring Harb. Perspect. Biol. 11 , a032813 (2019). 30082464 10.1101/cshperspect.a032813 PMC6496347

97. Liu C The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention Bone Res. 2022 10 18 10.1038/s41413-022-00191-3 35210394 PMC8873336 Liu, C. et al. The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention. Bone Res. 10 , 18 (2022). 35210394 10.1038/s41413-022-00191-3 PMC8873336

98. Lin Y Posttranslational modification in bone homeostasis and osteoporosis MedComm 2025 6 e70159 10.1002/mco2.70159 40170748 PMC11959162 Lin, Y. et al. Posttranslational modification in bone homeostasis and osteoporosis. MedComm 6 , e70159 (2025). 40170748 10.1002/mco2.70159 PMC11959162

99. Imani M Deep learning technique for automatic segmentation of proximal hip musculoskeletal tissues from CT scan images: a MrOS study J. Cachexia Sarcopenia Muscle 2025 16 e13728 10.1002/jcsm.13728 40022453 PMC11871091 Imani, M. et al. Deep learning technique for automatic segmentation of proximal hip musculoskeletal tissues from CT scan images: a MrOS study. J. Cachexia Sarcopenia Muscle 16 , e13728 (2025). 40022453 10.1002/jcsm.13728 PMC11871091

100. Nguyen A Addressing the growing burden of musculoskeletal diseases in the ageing US population: challenges and innovations Lancet Healthy Longev. 2025 6 100707 10.1016/j.lanhl.2025.100707 40381641 Nguyen, A. et al. Addressing the growing burden of musculoskeletal diseases in the ageing US population: challenges and innovations. Lancet Healthy Longev. 6 , 100707 (2025). 40381641 10.1016/j.lanhl.2025.100707

101. Wang XY An updated overview of the search for biomarkers of osteoporosis based on human proteomics J. Orthop. Transl. 2024 49 37 48 10.1016/j.jot.2024.08.015 PMC11488448 39430131 Wang, X. Y. et al. An updated overview of the search for biomarkers of osteoporosis based on human proteomics. J. Orthop. Transl. 49 , 37–48 (2024). 10.1016/j.jot.2024.08.015 PMC11488448 39430131

102. Zuo L Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription Nat. Commun. 2021 12 1491 10.1038/s41467-021-21690-7 33674598 PMC7935978 Zuo, L. et al. Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nat. Commun. 12 , 1491 (2021). 33674598 10.1038/s41467-021-21690-7 PMC7935978

103. Mullin BH Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts Genome Biol. 2020 21 80 10.1186/s13059-020-01997-2 32216834 PMC7098081 Mullin, B. H. et al. Characterisation of genetic regulatory effects for osteoporosis risk variants in human osteoclasts. Genome Biol. 21 , 80 (2020). 32216834 10.1186/s13059-020-01997-2 PMC7098081

104. Zheng K Plectin promotes bone formation via phase separation and sequestering annexin A2 Biochem. Pharm. 2025 242 117403 10.1016/j.bcp.2025.117403 41047030 Zheng, K. et al. Plectin promotes bone formation via phase separation and sequestering annexin A2. Biochem. Pharm. 242 , 117403 (2025). 41047030 10.1016/j.bcp.2025.117403

105. Zhao X Zhao D Geng B Yaobin W Xia Y A novel ceRNA regulatory network involving the long noncoding NEAT1, miRNA-466f-3p and its mRNA target in osteoblast autophagy and osteoporosis J. Mol. Med. 2022 100 1629 1646 10.1007/s00109-022-02255-7 36169673 Zhao, X., Zhao, D., Geng, B., Yaobin, W. & Xia, Y. A novel ceRNA regulatory network involving the long noncoding NEAT1, miRNA-466f-3p and its mRNA target in osteoblast autophagy and osteoporosis. J. Mol. Med. 100 , 1629–1646 (2022). 36169673 10.1007/s00109-022-02255-7

106. Zhang Y lncRNA Neat1 stimulates osteoclastogenesis via sponging miR-7 J. Bone Min. Res. 2020 35 1772 1781 10.1002/jbmr.4039 32353178 Zhang, Y. et al. lncRNA Neat1 stimulates osteoclastogenesis via sponging miR-7. J. Bone Min. Res. 35 , 1772–1781 (2020). 10.1002/jbmr.4039 32353178

107. Hisaoka S Subcellular distribution of bone morphogenetic protein 2-inducible kinase (BMP2K): Regulation by liquid-liquid phase separation and nucleocytoplasmic shuttling Biochem. Biophys. Res. Commun. 2023 649 16 24 10.1016/j.bbrc.2023.01.076 36739695 Hisaoka, S. et al. Subcellular distribution of bone morphogenetic protein 2-inducible kinase (BMP2K): Regulation by liquid-liquid phase separation and nucleocytoplasmic shuttling. Biochem. Biophys. Res. Commun. 649 , 16–24 (2023). 36739695 10.1016/j.bbrc.2023.01.076

108. Glyn-Jones S Osteoarthritis. Lancet 2015 386 376 387 25748615 10.1016/S0140-6736(14)60802-3 Glyn-Jones, S. et al. Osteoarthritis. Lancet 386 , 376–387 (2015). 25748615 10.1016/S0140-6736(14)60802-3

109. Chen Z Intelligent nanomaterials design for osteoarthritis managements Small Methods 2025 9 e2402263 10.1002/smtd.202402263 40159773 Chen, Z. et al. Intelligent nanomaterials design for osteoarthritis managements. Small Methods 9 , e2402263 (2025). 40159773 10.1002/smtd.202402263

110. Li Y Dong B Exploring liquid-liquid phase separation-related diagnostic biomarkers in osteoarthritis based on machine learning algorithms and experiment Immunobiology 2024 229 152825 10.1016/j.imbio.2024.152825 38997894 Li, Y. & Dong, B. Exploring liquid-liquid phase separation-related diagnostic biomarkers in osteoarthritis based on machine learning algorithms and experiment. Immunobiology 229 , 152825 (2024). 38997894 10.1016/j.imbio.2024.152825

111. Huang Y TAR DNA-binding protein 43 inhibits inflammatory response and protects chondrocyte function by modulating RACK1 expression in osteoarthritis Biomed. Pharmacother. 2017 85 362 371 10.1016/j.biopha.2016.11.037 27890430 Huang, Y. et al. TAR DNA-binding protein 43 inhibits inflammatory response and protects chondrocyte function by modulating RACK1 expression in osteoarthritis. Biomed. Pharmacother. 85 , 362–371 (2017). 27890430 10.1016/j.biopha.2016.11.037

112. Hata K Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice J. Clin. Investig. 2008 118 3098 3108 10.1172/JCI31373 18677406 PMC2491455 Hata, K. et al. Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice. J. Clin. Investig. 118 , 3098–3108 (2008). 18677406 10.1172/JCI31373 PMC2491455

113. Mensah MA Aberrant phase separation and nucleolar dysfunction in rare genetic diseases Nature 2023 614 564 571 10.1038/s41586-022-05682-1 36755093 PMC9931588 Mensah, M. A. et al. Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature 614 , 564–571 (2023). 36755093 10.1038/s41586-022-05682-1 PMC9931588

114. Gu X Targeting cancer-induced skeletal damage: a holistic approach to understanding pathophysiology, mechanisms, and management solutions Am. J. Cancer Res. 2025 15 1494 1516 10.62347/QFHJ2430 40371144 PMC12070097 Gu, X. et al. Targeting cancer-induced skeletal damage: a holistic approach to understanding pathophysiology, mechanisms, and management solutions. Am. J. Cancer Res. 15 , 1494–1516 (2025). 40371144 10.62347/QFHJ2430 PMC12070097

115. Mesny E State-of-the-art of multidisciplinary approach of bone metastasis-directed therapy: review and challenging questions for preparation of a GEMO practice guidelines Cancer Metastasis Rev. 2025 44 45 10.1007/s10555-025-10262-6 40220136 PMC11993453 Mesny, E. et al. State-of-the-art of multidisciplinary approach of bone metastasis-directed therapy: review and challenging questions for preparation of a GEMO practice guidelines. Cancer Metastasis Rev. 44 , 45 (2025). 40220136 10.1007/s10555-025-10262-6 PMC11993453

116. Merchant MS Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors Clin. Cancer Res. 2016 22 1364 1370 10.1158/1078-0432.CCR-15-0491 26534966 PMC5027962 Merchant, M. S. et al. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin. Cancer Res. 22 , 1364–1370 (2016). 26534966 10.1158/1078-0432.CCR-15-0491 PMC5027962

117. Tawbi HA Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial Lancet Oncol. 2017 18 1493 1501 10.1016/S1470-2045(17)30624-1 28988646 PMC7939029 Tawbi, H. A. et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 18 , 1493–1501 (2017). 28988646 10.1016/S1470-2045(17)30624-1 PMC7939029

118. Kager L Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols J. Clin. Oncol. 2003 21 2011 2018 10.1200/JCO.2003.08.132 12743156 Kager, L. et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J. Clin. Oncol. 21 , 2011–2018 (2003). 12743156 10.1200/JCO.2003.08.132

119. Ullah K Zubia E Narayan M Yang J Xu G Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset FEBS J. 2019 286 2018 2034 10.1111/febs.14708 30468556 Ullah, K., Zubia, E., Narayan, M., Yang, J. & Xu, G. Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset. FEBS J. 286 , 2018–2034 (2019). 30468556 10.1111/febs.14708

120. Lu B Pharmacological inhibition of core regulatory circuitry liquid-liquid phase separation suppresses metastasis and chemoresistance in osteosarcoma Adv. Sci. 2021 8 e2101895 10.1002/advs.202101895 PMC8529446 34432948 Lu, B. et al. Pharmacological inhibition of core regulatory circuitry liquid-liquid phase separation suppresses metastasis and chemoresistance in osteosarcoma. Adv. Sci. 8 , e2101895 (2021). 10.1002/advs.202101895 PMC8529446 34432948

121. Li M WDR3 undergoes phase separation to mediate the therapeutic mechanism of Nilotinib against osteosarcoma J. Exp. Clin. Cancer Res. 2025 44 201 10.1186/s13046-025-03456-x 40646517 PMC12247437 Li, M. et al. WDR3 undergoes phase separation to mediate the therapeutic mechanism of Nilotinib against osteosarcoma. J. Exp. Clin. Cancer Res. 44 , 201 (2025). 40646517 10.1186/s13046-025-03456-x PMC12247437

122. Selig EE Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain Proc. Natl. Acad. Sci. USA 2025 122 e2221823122 10.1073/pnas.2221823122 40377985 PMC12107149 Selig, E. E. et al. Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain. Proc. Natl. Acad. Sci. USA 122 , e2221823122 (2025). 40377985 10.1073/pnas.2221823122 PMC12107149

123. Hou C Tsodikov OV Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites Nucleic Acids Res. 2025 53 gkaf205 10.1093/nar/gkaf205 40131773 PMC11934925 Hou, C. & Tsodikov, O. V. Structure and cooperative formation of a FLI1 filament on contiguous GGAA DNA sites. Nucleic Acids Res. 53 , gkaf205 (2025). 40131773 10.1093/nar/gkaf205 PMC11934925

124. Shorter J Prion-like domains program Ewing’s Sarcoma Cell 2017 171 30 31 10.1016/j.cell.2017.09.010 28938120 PMC5639709 Shorter, J. Prion-like domains program Ewing’s Sarcoma. Cell 171 , 30–31 (2017). 28938120 10.1016/j.cell.2017.09.010 PMC5639709

125. Kim YR Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma Nat. Commun. 2024 15 6569 10.1038/s41467-024-51050-0 39095374 PMC11297139 Kim, Y. R. et al. Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma. Nat. Commun. 15 , 6569 (2024). 39095374 10.1038/s41467-024-51050-0 PMC11297139

126. Sohn EJ Libich DS Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma Mol. Oncol. 2025 19 961 964 10.1002/1878-0261.13742 39344201 PMC11977654 Sohn, E. J. & Libich, D. S. Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma. Mol. Oncol. 19 , 961–964 (2025). 39344201 10.1002/1878-0261.13742 PMC11977654

127. Johnson CN Insights into molecular diversity within the FUS/EWS/TAF15 protein family: unraveling phase separation of the N-terminal low-complexity domain from RNA-binding protein EWS J. Am. Chem. Soc. 2024 146 8071 8085 10.1021/jacs.3c12034 38492239 PMC11156192 Johnson, C. N. et al. Insights into molecular diversity within the FUS/EWS/TAF15 protein family: unraveling phase separation of the N-terminal low-complexity domain from RNA-binding protein EWS. J. Am. Chem. Soc. 146 , 8071–8085 (2024). 38492239 10.1021/jacs.3c12034 PMC11156192

128. Wang Y Dissolution of oncofusion transcription factor condensates for cancer therapy Nat. Chem. Biol. 2023 19 1223 1234 10.1038/s41589-023-01376-5 37400539 Wang, Y. et al. Dissolution of oncofusion transcription factor condensates for cancer therapy. Nat. Chem. Biol. 19 , 1223–1234 (2023). 37400539 10.1038/s41589-023-01376-5

129. Fornetti J Welm AL Stewart SA Understanding the Bone in Cancer Metastasis J. Bone Miner. Res. 2018 33 2099 2113 10.1002/jbmr.3618 30476357 Fornetti, J., Welm, A. L. & Stewart, S. A. Understanding the Bone in Cancer Metastasis. J. Bone Miner. Res. 33 , 2099–2113 (2018). 30476357 10.1002/jbmr.3618

130. Jaffe N Puri A Gelderblom H Osteosarcoma: evolution of treatment paradigms Sarcoma 2013 2013 203531 10.1155/2013/203531 23781130 PMC3678494 Jaffe, N., Puri, A. & Gelderblom, H. Osteosarcoma: evolution of treatment paradigms. Sarcoma 2013 , 203531 (2013). 23781130 10.1155/2013/203531 PMC3678494

131. Sturge J Caley MP Waxman J Bone metastasis in prostate cancer: emerging therapeutic strategies Nat. Rev. Clin. Oncol. 2011 8 357 368 10.1038/nrclinonc.2011.67 21556025 Sturge, J., Caley, M. P. & Waxman, J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat. Rev. Clin. Oncol. 8 , 357–368 (2011). 21556025 10.1038/nrclinonc.2011.67

132. Xin Z Immune mediated support of metastasis: implication for bone invasion Cancer Commun. 2024 44 967 991 10.1002/cac2.12584 PMC11492328 39003618 Xin, Z. et al. Immune mediated support of metastasis: implication for bone invasion. Cancer Commun. 44 , 967–991 (2024). 10.1002/cac2.12584 PMC11492328 39003618

133. Bartkowiak K Disseminated tumor cells persist in the bone marrow of breast cancer patients through sustained activation of the unfolded protein response Cancer Res. 2015 75 5367 5377 10.1158/0008-5472.CAN-14-3728 26573792 Bartkowiak, K. et al. Disseminated tumor cells persist in the bone marrow of breast cancer patients through sustained activation of the unfolded protein response. Cancer Res. 75 , 5367–5377 (2015). 26573792 10.1158/0008-5472.CAN-14-3728

134. Zhang L EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation Nat. Commun. 2022 13 2543 10.1038/s41467-022-30105-0 35538070 PMC9091212 Zhang, L. et al. EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nat. Commun. 13 , 2543 (2022). 35538070 10.1038/s41467-022-30105-0 PMC9091212

135. Shinde A Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer Cancer Res. 2019 79 1831 1843 10.1158/0008-5472.CAN-18-2636 30733195 PMC6467765 Shinde, A. et al. Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer. Cancer Res. 79 , 1831–1843 (2019). 30733195 10.1158/0008-5472.CAN-18-2636 PMC6467765

136. Ji K Mayernik L Moin K Sloane BF Acidosis and proteolysis in the tumor microenvironment Cancer Metastasis Rev. 2019 38 103 112 10.1007/s10555-019-09796-3 31069574 PMC6886241 Ji, K., Mayernik, L., Moin, K. & Sloane, B. F. Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev. 38 , 103–112 (2019). 31069574 10.1007/s10555-019-09796-3 PMC6886241

137. Alsamraae M Cook LM Emerging roles for myeloid immune cells in bone metastasis Cancer Metastasis Rev. 2021 40 413 425 10.1007/s10555-021-09965-3 33855680 Alsamraae, M. & Cook, L. M. Emerging roles for myeloid immune cells in bone metastasis. Cancer Metastasis Rev. 40 , 413–425 (2021). 33855680 10.1007/s10555-021-09965-3

138. Gamboa AC Gronchi A Cardona K Soft-tissue sarcoma in adults: an update on the current state of histiotype-specific management in an era of personalized medicine CA Cancer J. Clin. 2020 70 200 229 32275330 10.3322/caac.21605 Gamboa, A. C., Gronchi, A. & Cardona, K. Soft-tissue sarcoma in adults: an update on the current state of histiotype-specific management in an era of personalized medicine. CA Cancer J. Clin. 70 , 200–229 (2020). 32275330 10.3322/caac.21605

139. Crompton JG Ogura K Bernthal NM Kawai A Eilber FC Local control of soft tissue and bone sarcomas J. Clin. Oncol. 2018 36 111 117 10.1200/JCO.2017.75.2717 29220297 Crompton, J. G., Ogura, K., Bernthal, N. M., Kawai, A. & Eilber, F. C. Local control of soft tissue and bone sarcomas. J. Clin. Oncol. 36 , 111–117 (2018). 29220297 10.1200/JCO.2017.75.2717

140. Smith HG Patterns of disease relapse in primary extremity soft-tissue sarcoma Br. J. Surg. 2016 103 1487 1496 10.1002/bjs.10227 27503444 Smith, H. G. et al. Patterns of disease relapse in primary extremity soft-tissue sarcoma. Br. J. Surg. 103 , 1487–1496 (2016). 27503444 10.1002/bjs.10227

141. Geramizadeh B Zare Z Dehghanian AR Bolandparvaz S Marzban M Huge mesenteric low-grade fibromyxoid sarcoma: a case report and review of the literature Rare Tumors 2018 10 2036361318777031 10.1177/2036361318777031 29854356 PMC5971385 Geramizadeh, B., Zare, Z., Dehghanian, A. R., Bolandparvaz, S. & Marzban, M. Huge mesenteric low-grade fibromyxoid sarcoma: a case report and review of the literature. Rare Tumors 10 , 2036361318777031 (2018). 29854356 10.1177/2036361318777031 PMC5971385

142. Panagopoulos I The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma Genes Chromosomes Cancer 2004 40 218 228 10.1002/gcc.20037 15139001 Panagopoulos, I. et al. The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer 40 , 218–228 (2004). 15139001 10.1002/gcc.20037

143. Matsuyama A Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens Am. J. Surg. Pathol. 2006 30 1077 1084 10.1097/01.pas.0000209830.24230.1f 16931951 Matsuyama, A. et al. Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens. Am. J. Surg. Pathol. 30 , 1077–1084 (2006). 16931951 10.1097/01.pas.0000209830.24230.1f

144. Wang X Aberrant phase separation drives membranous organelle remodeling and tumorigenesis Mol. Cell 2025 85 1852 1867.e10 10.1016/j.molcel.2025.04.001 40273917 Wang, X. et al. Aberrant phase separation drives membranous organelle remodeling and tumorigenesis. Mol. Cell 85 , 1852–1867.e10 (2025). 40273917 10.1016/j.molcel.2025.04.001

145. Möller E FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1 Clin. Cancer Res. 2011 17 2646 2656 10.1158/1078-0432.CCR-11-0145 21536545 Möller, E. et al. FUS-CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1. Clin. Cancer Res. 17 , 2646–2656 (2011). 21536545 10.1158/1078-0432.CCR-11-0145

146. Toro JR Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases Int. J. Cancer 2006 119 2922 2930 10.1002/ijc.22239 17013893 Toro, J. R. et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: an analysis of 26,758 cases. Int. J. Cancer 119 , 2922–2930 (2006). 17013893 10.1002/ijc.22239

147. Mastrangelo G Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions Cancer 2012 118 5339 5348 10.1002/cncr.27555 22517534 Mastrangelo, G. et al. Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer 118 , 5339–5348 (2012). 22517534 10.1002/cncr.27555

148. Gazendam AM Synovial sarcoma: a clinical review Curr. Oncol. 2021 28 1909 1920 10.3390/curroncol28030177 34069748 PMC8161765 Gazendam, A. M. et al. Synovial sarcoma: a clinical review. Curr. Oncol. 28 , 1909–1920 (2021). 34069748 10.3390/curroncol28030177 PMC8161765

149. de Necochea-Campion R Metastatic biomarkers in synovial sarcoma Biomark. Res. 2017 5 4 10.1186/s40364-017-0083-x 28191313 PMC5297148 de Necochea-Campion, R. et al. Metastatic biomarkers in synovial sarcoma. Biomark. Res. 5 , 4 (2017). 28191313 10.1186/s40364-017-0083-x PMC5297148

150. Orbach D Regional lymph node invasion in pediatric non-rhabdomyosarcoma soft tissue sarcoma: an international cohort study from the International Soft Tissue Sarcoma Consortium EClinicalMedicine 2025 87 103409 10.1016/j.eclinm.2025.103409 40823500 PMC12355411 Orbach, D. et al. Regional lymph node invasion in pediatric non-rhabdomyosarcoma soft tissue sarcoma: an international cohort study from the International Soft Tissue Sarcoma Consortium. EClinicalMedicine 87 , 103409 (2025). 40823500 10.1016/j.eclinm.2025.103409 PMC12355411

151. Ren C Liu J Hornicek FJ Yue B Duan Z Advances of SS18-SSX fusion gene in synovial sarcoma: emerging novel functions and therapeutic potentials Biochim. Biophys. Acta Rev. Cancer 2024 1879 189215 10.1016/j.bbcan.2024.189215 39528099 Ren, C., Liu, J., Hornicek, F. J., Yue, B. & Duan, Z. Advances of SS18-SSX fusion gene in synovial sarcoma: emerging novel functions and therapeutic potentials. Biochim. Biophys. Acta Rev. Cancer 1879 , 189215 (2024). 39528099 10.1016/j.bbcan.2024.189215

152. Cheng Y Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas Nat. Commun. 2022 13 2724 10.1038/s41467-022-30447-9 35585082 PMC9117659 Cheng, Y. et al. Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas. Nat. Commun. 13 , 2724 (2022). 35585082 10.1038/s41467-022-30447-9 PMC9117659

153. McBride MJ The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma Cancer Cell 2018 33 1128 1141.e7 10.1016/j.ccell.2018.05.002 29861296 PMC6791822 McBride, M. J. et al. The SS18-SSX fusion oncoprotein hijacks BAF complex targeting and function to drive synovial sarcoma. Cancer Cell 33 , 1128–1141.e7 (2018). 29861296 10.1016/j.ccell.2018.05.002 PMC6791822

154. Anchondo GM Parker K Bruce A Cortez E Su LE The SS18-SSX fusion oncoprotein: friend and foe in targeted therapy for synovial sarcoma Oncol. Res 2025 33 1001 1005 10.32604/or.2025.060573 40296913 PMC12033998 Anchondo, G. M., Parker, K., Bruce, A., Cortez, E. & Su, L. E. The SS18-SSX fusion oncoprotein: friend and foe in targeted therapy for synovial sarcoma. Oncol. Res 33 , 1001–1005 (2025). 40296913 10.32604/or.2025.060573 PMC12033998

155. Tornin J FUS-CHOP promotes invasion in myxoid liposarcoma through a SRC/FAK/RHO/ROCK-dependent pathway Neoplasia 2018 20 44 56 10.1016/j.neo.2017.11.004 29190494 PMC5747526 Tornin, J. et al. FUS-CHOP promotes invasion in myxoid liposarcoma through a SRC/FAK/RHO/ROCK-dependent pathway. Neoplasia 20 , 44–56 (2018). 29190494 10.1016/j.neo.2017.11.004 PMC5747526

156. Owen I The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation J. Cell Sci. 2021 134 jcs258578 10.1242/jcs.258578 34357401 PMC8445604 Owen, I. et al. The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation. J. Cell Sci. 134 , jcs258578 (2021). 34357401 10.1242/jcs.258578 PMC8445604

157. Li X Targeting drug delivery system to skeletal muscles: a comprehensive review of different approaches J. Cachexia Sarcopenia Muscle 2025 16 e13691 10.1002/jcsm.13691 39910928 PMC11799587 Li, X. et al. Targeting drug delivery system to skeletal muscles: a comprehensive review of different approaches. J. Cachexia Sarcopenia Muscle 16 , e13691 (2025). 39910928 10.1002/jcsm.13691 PMC11799587

158. Wen ZQ Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases Mil. Med. Res. 2023 10 54 37941072 10.1186/s40779-023-00485-5 PMC10634069 Wen, Z. Q. et al. Insights into the underlying pathogenesis and therapeutic potential of endoplasmic reticulum stress in degenerative musculoskeletal diseases. Mil. Med. Res. 10 , 54 (2023). 37941072 10.1186/s40779-023-00485-5 PMC10634069

159. Julien A Direct contribution of skeletal muscle mesenchymal progenitors to bone repair Nat. Commun. 2021 12 2860 10.1038/s41467-021-22842-5 34001878 PMC8128920 Julien, A. et al. Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat. Commun. 12 , 2860 (2021). 34001878 10.1038/s41467-021-22842-5 PMC8128920

160. Yin L Skeletal muscle atrophy: from mechanisms to treatments Pharm. Res. 2021 172 105807 10.1016/j.phrs.2021.105807 34389456 Yin, L. et al. Skeletal muscle atrophy: from mechanisms to treatments. Pharm. Res. 172 , 105807 (2021). 10.1016/j.phrs.2021.105807 34389456

161. Zammit PS Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis Semin. Cell Dev. Biol. 2017 72 19 32 10.1016/j.semcdb.2017.11.011 29127046 Zammit, P. S. Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis. Semin. Cell Dev. Biol. 72 , 19–32 (2017). 29127046 10.1016/j.semcdb.2017.11.011

162. Pérez-Schindler J RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates Proc. Natl. Acad. Sci. USA 2021 118 e2105951118 10.1073/pnas.2105951118 34465622 PMC8433555 Pérez-Schindler, J. et al. RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates. Proc. Natl. Acad. Sci. USA 118 , e2105951118 (2021). 34465622 10.1073/pnas.2105951118 PMC8433555

163. Liu X RPS27L enhances myogenesis and muscle mass by targeting IGF1 through liquid-liquid phase separation Adv. Sci. 2025 12 e12354 10.1002/advs.202512354 PMC12667544 40886325 Liu, X. et al. RPS27L enhances myogenesis and muscle mass by targeting IGF1 through liquid-liquid phase separation. Adv. Sci. 12 , e12354 (2025). 10.1002/advs.202512354 PMC12667544 40886325

164. Wang Y Chen LL Organization and function of paraspeckles Essays Biochem 2020 64 875 882 10.1042/EBC20200010 32830222 Wang, Y. & Chen, L. L. Organization and function of paraspeckles. Essays Biochem 64 , 875–882 (2020). 32830222 10.1042/EBC20200010

165. Zhang M SRRM2 phase separation drives assembly of nuclear speckle subcompartments Cell Rep. 2024 43 113827 10.1016/j.celrep.2024.113827 38381607 Zhang, M. et al. SRRM2 phase separation drives assembly of nuclear speckle subcompartments. Cell Rep. 43 , 113827 (2024). 38381607 10.1016/j.celrep.2024.113827

166. Sunwoo H MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles Genome Res. 2009 19 347 359 10.1101/gr.087775.108 19106332 PMC2661813 Sunwoo, H. et al. MEN epsilon/beta nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19 , 347–359 (2009). 19106332 10.1101/gr.087775.108 PMC2661813

167. Evangelisti C Subnuclear localization and differentiation-dependent increased expression of DGK-zeta in C2C12 mouse myoblasts J. Cell Physiol. 2006 209 370 378 10.1002/jcp.20744 16897754 Evangelisti, C. et al. Subnuclear localization and differentiation-dependent increased expression of DGK-zeta in C2C12 mouse myoblasts. J. Cell Physiol. 209 , 370–378 (2006). 16897754 10.1002/jcp.20744

168. Mercuri E Bönnemann CG Muntoni F Muscular dystrophies Lancet 2019 394 2025 2038 10.1016/S0140-6736(19)32910-1 31789220 Mercuri, E., Bönnemann, C. G. & Muntoni, F. Muscular dystrophies. Lancet 394 , 2025–2038 (2019). 31789220 10.1016/S0140-6736(19)32910-1

169. Mezzell AT Zhang Y Perez AM Vest KE Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics PLoS Genet. 2026 22 e1011743 10.1371/journal.pgen.1011743 41587185 PMC12858073 Mezzell, A. T., Zhang, Y., Perez, A. M. & Vest, K. E. Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics. PLoS Genet. 22 , e1011743 (2026). 41587185 10.1371/journal.pgen.1011743 PMC12858073

170. Bengoechea R Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy Neurobiol. Dis. 2012 46 118 129 10.1016/j.nbd.2011.12.052 22249111 Bengoechea, R. et al. Nuclear speckles are involved in nuclear aggregation of PABPN1 and in the pathophysiology of oculopharyngeal muscular dystrophy. Neurobiol. Dis. 46 , 118–129 (2012). 22249111 10.1016/j.nbd.2011.12.052

171. Banerjee A Vest KE Pavlath GK Corbett AH Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing Nucleic Acids Res. 2017 45 10706 10725 10.1093/nar/gkx786 28977530 PMC5737383 Banerjee, A., Vest, K. E., Pavlath, G. K. & Corbett, A. H. Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing. Nucleic Acids Res. 45 , 10706–10725 (2017). 28977530 10.1093/nar/gkx786 PMC5737383

172. Peng S The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation Cell Death Differ. 2025 32 2111 2125 10.1038/s41418-025-01509-4 40200092 PMC12572152 Peng, S. et al. The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation. Cell Death Differ. 32 , 2111–2125 (2025). 40200092 10.1038/s41418-025-01509-4 PMC12572152

173. Zibold J The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis Brain 2024 147 1768 1783 10.1093/brain/awad410 38079474 PMC11068115 Zibold, J. et al. The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis. Brain 147 , 1768–1783 (2024). 38079474 10.1093/brain/awad410 PMC11068115

174. Lee Y TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations J. Clin. Invest. 2018 128 1164 1177 10.1172/JCI97103 29457785 PMC5824866 Lee, Y. et al. TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J. Clin. Invest. 128 , 1164–1177 (2018). 29457785 10.1172/JCI97103 PMC5824866

175. Kwan HR Nerve-independent formation of membrane infoldings at topologically complex postsynaptic apparatus by caveolin-3 Sci. Adv. 2023 9 eadg0183 10.1126/sciadv.adg0183 37327338 PMC10275590 Kwan, H. R. et al. Nerve-independent formation of membrane infoldings at topologically complex postsynaptic apparatus by caveolin-3. Sci. Adv. 9 , eadg0183 (2023). 37327338 10.1126/sciadv.adg0183 PMC10275590

176. Al-Chalabi A Hardiman O The epidemiology of ALS: a conspiracy of genes, environment and time Nat. Rev. Neurol. 2013 9 617 628 10.1038/nrneurol.2013.203 24126629 Al-Chalabi, A. & Hardiman, O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat. Rev. Neurol. 9 , 617–628 (2013). 24126629 10.1038/nrneurol.2013.203

177. Suk TR Rousseaux MWC The role of TDP-43 mislocalization in amyotrophic lateral sclerosis Mol. Neurodegener. 2020 15 45 10.1186/s13024-020-00397-1 32799899 PMC7429473 Suk, T. R. & Rousseaux, M. W. C. The role of TDP-43 mislocalization in amyotrophic lateral sclerosis. Mol. Neurodegener. 15 , 45 (2020). 32799899 10.1186/s13024-020-00397-1 PMC7429473

178. Yan X Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates Cell 2025 188 4123 4140.e18 10.1016/j.cell.2025.04.039 40412392 PMC12303766 Yan, X. et al. Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates. Cell 188 , 4123–4140.e18 (2025). 40412392 10.1016/j.cell.2025.04.039 PMC12303766

179. Sun H Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms Nat. Nanotechnol. 2024 19 1354 1365 10.1038/s41565-024-01683-5 38849544 Sun, H. et al. Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms. Nat. Nanotechnol. 19 , 1354–1365 (2024). 38849544 10.1038/s41565-024-01683-5

180. Gao C Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus Cell Rep. 2022 40 111086 10.1016/j.celrep.2022.111086 35858576 Gao, C. et al. Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus. Cell Rep. 40 , 111086 (2022). 35858576 10.1016/j.celrep.2022.111086

181. Carlozzi NE How different aspects of motor dysfunction influence day-to-day function in Huntington’s disease Mov. Disord. 2019 34 1910 1914 10.1002/mds.27866 31609508 PMC7025393 Carlozzi, N. E. et al. How different aspects of motor dysfunction influence day-to-day function in Huntington’s disease. Mov. Disord. 34 , 1910–1914 (2019). 31609508 10.1002/mds.27866 PMC7025393

182. Yang J Chen X Xu H SQSTM1/p62 droplet -mediated autophagosome formation: insights into Huntington disease Autophagy 2021 17 3256 3259 10.1080/15548627.2021.1953820 34281469 PMC8525954 Yang, J., Chen, X. & Xu, H. SQSTM1/p62 droplet -mediated autophagosome formation: insights into Huntington disease. Autophagy 17 , 3256–3259 (2021). 34281469 10.1080/15548627.2021.1953820 PMC8525954

183. De Virgilio A Parkinson’s disease: autoimmunity and neuroinflammation Autoimmun. Rev. 2016 15 1005 1011 10.1016/j.autrev.2016.07.022 27497913 De Virgilio, A. et al. Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun. Rev. 15 , 1005–1011 (2016). 27497913 10.1016/j.autrev.2016.07.022

184. Stocchi F Bravi D Emmi A Antonini A Parkinson disease therapy: current strategies and future research priorities Nat. Rev. Neurol. 2024 20 695 707 10.1038/s41582-024-01034-x 39496848 Stocchi, F., Bravi, D., Emmi, A. & Antonini, A. Parkinson disease therapy: current strategies and future research priorities. Nat. Rev. Neurol. 20 , 695–707 (2024). 39496848 10.1038/s41582-024-01034-x

185. Dickson, D. W. Neuropathology of Parkinson’s disease and parkinsonism. Cold Spring Harb. Perspect. Med. a041610 (2025). 10.1101/cshperspect.a041610 PMC13532540 40324812

186. Ray S Synuclein aggregation nucleates through liquid-liquid phase separation Nat. Chem. 2020 12 705 716 10.1038/s41557-020-0465-9 32514159 Ray, S. et al. Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem. 12 , 705–716 (2020). 32514159 10.1038/s41557-020-0465-9

187. Ikenoue T De novo peptides that induce the liquid-liquid phase separation of α-synuclein J. Am. Chem. Soc. 2025 147 24113 24126 10.1021/jacs.5c08019 40560766 PMC12257511 Ikenoue, T. et al. De novo peptides that induce the liquid-liquid phase separation of α-synuclein. J. Am. Chem. Soc. 147 , 24113–24126 (2025). 40560766 10.1021/jacs.5c08019 PMC12257511

188. Xu B β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation Cell Rep. 2025 44 115761 10.1016/j.celrep.2025.115761 40440171 Xu, B. et al. β-synuclein blocks α-synuclein condensate fusion to disrupt the maturation of phase separation. Cell Rep. 44 , 115761 (2025). 40440171 10.1016/j.celrep.2025.115761

189. Han W Wei M Xu F Niu Z Aggregation and phase separation of α-synuclein in Parkinson’s disease Chem. Commun. 2024 60 6581 6590 10.1039/D4CC01591F 38808534 Han, W., Wei, M., Xu, F. & Niu, Z. Aggregation and phase separation of α-synuclein in Parkinson’s disease. Chem. Commun. 60 , 6581–6590 (2024). 10.1039/d4cc01591f 38808534

190. Xu B Distinct effects of familial Parkinson’s disease-associated mutations on α-synuclein phase separation and amyloid aggregation Biomolecules 2023 13 726 10.3390/biom13050726 37238596 PMC10216457 Xu, B. et al. Distinct effects of familial Parkinson’s disease-associated mutations on α-synuclein phase separation and amyloid aggregation. Biomolecules 13 , 726 (2023). 37238596 10.3390/biom13050726 PMC10216457

191. Wang S A novel liquid-liquid phase separation-related gene signature for predicting prognosis in colon cancer Front. Immunol. 2024 15 1514613 10.3389/fimmu.2024.1514613 39749343 PMC11693697 Wang, S. et al. A novel liquid-liquid phase separation-related gene signature for predicting prognosis in colon cancer. Front. Immunol. 15 , 1514613 (2024). 39749343 10.3389/fimmu.2024.1514613 PMC11693697

192. Peng W Liquid-liquid phase separation-related lncRNA prognostic signature and ZNF32-AS2 as a novel biomarker in hepatocellular carcinoma Comput Biol. Med. 2024 169 107975 10.1016/j.compbiomed.2024.107975 38199212 Peng, W. et al. Liquid-liquid phase separation-related lncRNA prognostic signature and ZNF32-AS2 as a novel biomarker in hepatocellular carcinoma. Comput Biol. Med. 169 , 107975 (2024). 38199212 10.1016/j.compbiomed.2024.107975

193. Qiu Y Pan M Chen X A liquid-liquid phase separation-related gene signature as prognostic biomarker for epithelial ovarian cancer Front. Oncol. 2021 11 671892 10.3389/fonc.2021.671892 34168991 PMC8217755 Qiu, Y., Pan, M. & Chen, X. A liquid-liquid phase separation-related gene signature as prognostic biomarker for epithelial ovarian cancer. Front. Oncol. 11 , 671892 (2021). 34168991 10.3389/fonc.2021.671892 PMC8217755

194. Sun L Identification of molecular subtypes based on liquid-liquid phase separation and cross-talk with immunological phenotype in bladder cancer Front. Immunol. 2022 13 1059568 10.3389/fimmu.2022.1059568 36518754 PMC9742536 Sun, L. et al. Identification of molecular subtypes based on liquid-liquid phase separation and cross-talk with immunological phenotype in bladder cancer. Front. Immunol. 13 , 1059568 (2022). 36518754 10.3389/fimmu.2022.1059568 PMC9742536

195. Tao B Wang F Zhu L Liquid-liquid phase separation-related signature predicts prognosis and therapeutic response in esophageal adenocarcinoma Anal. Chim. Acta 2024 1330 343202 10.1016/j.aca.2024.343202 39489946 Tao, B., Wang, F. & Zhu, L. Liquid-liquid phase separation-related signature predicts prognosis and therapeutic response in esophageal adenocarcinoma. Anal. Chim. Acta 1330 , 343202 (2024). 39489946 10.1016/j.aca.2024.343202

196. Xie F Targeting FOXM1 condensates reduces breast tumour growth and metastasis Nature 2025 638 1112 1121 10.1038/s41586-024-08421-w 39814884 Xie, F. et al. Targeting FOXM1 condensates reduces breast tumour growth and metastasis. Nature 638 , 1112–1121 (2025). 39814884 10.1038/s41586-024-08421-w

197. Liu J Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma Nat. Commun. 2021 12 1022 10.1038/s41467-021-21386-y 33589584 PMC7884723 Liu, J. et al. Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma. Nat. Commun. 12 , 1022 (2021). 33589584 10.1038/s41467-021-21386-y PMC7884723

198. Chen Y Xiang H Li X Chen Y Zhang J Near-infrared laser-switching DNA phase separation nanoinducer for glioma therapy ACS Nano 2024 18 24426 24440 10.1021/acsnano.4c07514 39171897 Chen, Y., Xiang, H., Li, X., Chen, Y. & Zhang, J. Near-infrared laser-switching DNA phase separation nanoinducer for glioma therapy. ACS Nano 18 , 24426–24440 (2024). 39171897 10.1021/acsnano.4c07514

199. Chen H Cell surface engineering by phase-separated coacervates for antibody display and targeted cancer cell therapy Angew. Chem. Int. Ed. Engl. 2024 63 e202410566 10.1002/anie.202410566 39103291 Chen, H. et al. Cell surface engineering by phase-separated coacervates for antibody display and targeted cancer cell therapy. Angew. Chem. Int. Ed. Engl. 63 , e202410566 (2024). 39103291 10.1002/anie.202410566

200. Nakamura T Phase separation of FSP1 promotes ferroptosis Nature 2023 619 371 377 10.1038/s41586-023-06255-6 37380771 PMC10338336 Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619 , 371–377 (2023). 37380771 10.1038/s41586-023-06255-6 PMC10338336

201. Doll S FSP1 is a glutathione-independent ferroptosis suppressor Nature 2019 575 693 698 10.1038/s41586-019-1707-0 31634899 Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575 , 693–698 (2019). 31634899 10.1038/s41586-019-1707-0

202. Li M BiFC and FACS-based CRISPR screening revealed that QKI promotes PABPN1 LLPS in colorectal cancer cells Protein Cell 2025 16 557 574 10.1093/procel/pwaf022 40052530 PMC12275093 Li, M. et al. BiFC and FACS-based CRISPR screening revealed that QKI promotes PABPN1 LLPS in colorectal cancer cells. Protein Cell 16 , 557–574 (2025). 40052530 10.1093/procel/pwaf022 PMC12275093

203. Wen P Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals Nat. Chem. 2025 17 279 288 10.1038/s41557-024-01705-8 39806140 Wen, P. et al. Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals. Nat. Chem. 17 , 279–288 (2025). 39806140 10.1038/s41557-024-01705-8

204. Sun Y Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics Nat. Chem. 2022 14 274 283 10.1038/s41557-021-00854-4 35115657 Sun, Y. et al. Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics. Nat. Chem. 14 , 274–283 (2022). 35115657 10.1038/s41557-021-00854-4

205. Sun Y Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules Nat. Commun. 2024 15 10094 10.1038/s41467-024-54463-z 39572548 PMC11582321 Sun, Y. et al. Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules. Nat. Commun. 15 , 10094 (2024). 39572548 10.1038/s41467-024-54463-z PMC11582321

206. Bao Y Photo-responsive phase-separating fluorescent molecules for intracellular protein delivery Angew. Chem. Int Ed. Engl. 2023 62 e202307045 10.1002/anie.202307045 37648812 Bao, Y. et al. Photo-responsive phase-separating fluorescent molecules for intracellular protein delivery. Angew. Chem. Int Ed. Engl. 62 , e202307045 (2023). 37648812 10.1002/anie.202307045

207. Duan G Drug molecule recruitment empowered by phase separation on cell membranes in vivo JACS Au 2025 5 2567 2579 10.1021/jacsau.5c00197 40575317 PMC12188389 Duan, G. et al. Drug molecule recruitment empowered by phase separation on cell membranes in vivo. JACS Au 5 , 2567–2579 (2025). 40575317 10.1021/jacsau.5c00197 PMC12188389

208. Guo RC In vivo self-assembly induced cell membrane phase separation for improved peptide drug internalization Angew. Chem. Int. Ed. Engl. 2021 60 25128 25134 10.1002/anie.202111839 34549872 Guo, R. C. et al. In vivo self-assembly induced cell membrane phase separation for improved peptide drug internalization. Angew. Chem. Int. Ed. Engl. 60 , 25128–25134 (2021). 34549872 10.1002/anie.202111839

209. Fortin AG Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence Acta Biomater. 2025 200 313 325 10.1016/j.actbio.2025.05.031 40349899 PMC12539274 Fortin, A. G. et al. Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence. Acta Biomater. 200 , 313–325 (2025). 40349899 10.1016/j.actbio.2025.05.031 PMC12539274

210. Huang K Cartilage-penetrating framework nucleic acid nanoparticles ameliorate osteoarthritis by promoting drug delivery and chondrocyte uptake Adv. Sci. 2025 12 e2502661 10.1002/advs.202502661 PMC12245130 40192172 Huang, K. et al. Cartilage-penetrating framework nucleic acid nanoparticles ameliorate osteoarthritis by promoting drug delivery and chondrocyte uptake. Adv. Sci. 12 , e2502661 (2025). 10.1002/advs.202502661 PMC12245130 40192172

211. Zhou Z Programmed drug delivering Janus hydrogel adapted to the spatio-temporal therapeutic window for Achilles tendon repair Acta Biomater. 2025 201 139 155 10.1016/j.actbio.2025.05.052 40412506 Zhou, Z. et al. Programmed drug delivering Janus hydrogel adapted to the spatio-temporal therapeutic window for Achilles tendon repair. Acta Biomater. 201 , 139–155 (2025). 40412506 10.1016/j.actbio.2025.05.052

212. Torrino S Mechano-dependent sorbitol accumulation supports biomolecular condensate Cell 2025 188 447 464.e20 10.1016/j.cell.2024.10.048 39591966 PMC11761381 Torrino, S. et al. Mechano-dependent sorbitol accumulation supports biomolecular condensate. Cell 188 , 447–464.e20 (2025). 39591966 10.1016/j.cell.2024.10.048 PMC11761381

213. Dupont S Role of YAP/TAZ in mechanotransduction Nature 2011 474 179 183 10.1038/nature10137 21654799 Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474 , 179–183 (2011). 21654799 10.1038/nature10137

214. Zhu F Cell-reprogramming-inspired dynamically responsive hydrogel boosts the induction of pluripotency via phase-separated biomolecular condensates Adv. Mater. 2024 36 e2211609 10.1002/adma.202211609 36989141 Zhu, F. et al. Cell-reprogramming-inspired dynamically responsive hydrogel boosts the induction of pluripotency via phase-separated biomolecular condensates. Adv. Mater. 36 , e2211609 (2024). 36989141 10.1002/adma.202211609

215. Tan K Elastic modulus of hydrogel regulates osteogenic differentiation via liquid-liquid phase separation of YAP J. Biomed. Mater. Res. A 2023 111 1781 1797 10.1002/jbm.a.37590 37494632 Tan, K. et al. Elastic modulus of hydrogel regulates osteogenic differentiation via liquid-liquid phase separation of YAP. J. Biomed. Mater. Res. A 111 , 1781–1797 (2023). 37494632 10.1002/jbm.a.37590

216. Sun X Biomolecular condensates decipher molecular codes of cell fate: from biophysical fundamentals to therapeutic practices Int. J. Mol. Sci. 2024 25 4127 10.3390/ijms25074127 38612940 PMC11012904 Sun, X. et al. Biomolecular condensates decipher molecular codes of cell fate: from biophysical fundamentals to therapeutic practices. Int. J. Mol. Sci. 25 , 4127 (2024). 38612940 10.3390/ijms25074127 PMC11012904