Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.

Introduction

Psychiatric and neurological disorders remain a substantial unmet medical need because of their complexity, high prevalence, and limited treatment options. Conditions such as depression, schizophrenia, Alzheimer’s disease (AD), and Parkinson’s disease (PD) are major contributors to global disability, diminish quality of life (QOL), and create significant socioeconomic burden [ 1 – 4 ]. Current therapies are largely symptomatic, with modest efficacy, delayed onset, and adverse effects that can hinder adherence and outcomes. These challenges are compounded by the blood-brain barrier (BBB), which restricts delivery of many therapeutics to the brain and limits the impact of conventional drugs. Consequently, innovative strategies are urgently needed to improve efficacy, enhance safety, and target disease mechanisms to deliver more effective and accessible care [ 5 , 6 ].

Nanoparticles (NPs) offer transformative potential for the central nervous system (CNS), addressing key barriers in diagnosis and therapy. Owing to their unique physicochemical properties, NPs can be engineered to cross the BBB and enable targeted delivery to specific brain regions with greater precision and fewer side effects [ 7 , 8 ]. NPs also expand imaging and tracking capabilities for earlier diagnosis and longitudinal monitoring, and they support gene therapy, neuroprotection, and anti-inflammatory interventions—core elements of personalized medicine [ 6 ]. As research advances, NP platforms may help shift CNS care toward safer, more effective, and potentially disease-modifying treatments that address pressing unmet needs in neuroscience.

In this article, we review the current landscape of NP applications in psychiatric and neurological disorders and outline future perspectives for their clinical translation.

Overview of psychiatric and neurological disorders

Psychiatric (e.g., major depressive disorder, schizophrenia) and neurological disorders (e.g., AD, PD) account for a leading share of global disability [ 1 – 4 , 9 ]. Convergent mechanisms include neuroinflammation with microglial priming, mitochondrial/oxidative stress, proteostasis failure (amyloid-β [Aβ]/tau; α-synuclein), synaptic and circuit dysfunction, and impaired neurovascular/BBB integrity [ 10 – 12 ]. Therapeutic progress is constrained by heterogeneous etiologies, clinical detection that lags molecular onset, and limited CNS exposure of drugs. These cross-cutting challenges motivate delivery technologies that (i) improve brain exposure predictably, (ii) target disease-relevant cell types/pathways, and (iii) enable multimodal intervention [ 13 , 14 ].

Standard agents face low brain bioavailability, off-target toxicity at doses required for CNS effect, poor solubility/stability, and narrow therapeutic windows; disease heterogeneity and comorbidities further complicate dose selection and endpoint sensitivity. NPs can (a) enhance BBB transit (receptor-mediated transcytosis; intranasal), (b) stabilize and solubilize fragile payloads (peptides, siRNA, phytobioactives), (c) provide controlled and stimuli-responsive release aligned to disease chronobiology, and (d) enable multi-target combinations within a single vehicle—properties that directly address these gaps [ 13 – 15 ].

Nanoparticles (NPs)

Structure of nanoparticles

Research on NPs for psychiatric and neurological disorders has rapidly expanded, centering on four primary classes: lipid-based NPs, polymeric NPs, inorganic NPs, and hybrid NPs. Below, we overview these commonly used types (Fig. 1 ).

Lipid-based NPs

Lipid-based NPs are generally spherical nanostructures comprising at least one lipid bilayer surrounding an internal aqueous core. They are broadly classified as liposomes and lipid NPs (LNPs) (Fig. 1A ) [ 13 , 16 ]. Liposomes are vesicles formed from amphiphilic phospholipids with hydrophilic heads and hydrophobic tails, mimicking biological membranes and offering high biocompatibility and biodegradability [ 17 ]. This architecture enables encapsulation of hydrophilic drugs in the core and hydrophobic drugs within the lipid bilayer [ 16 ].

LNPs are a newer generation of lipid carriers composed of a more complex mixture of lipids, including phospholipids, cholesterol, and pegylated lipids [ 18 ]. Phospholipids and cholesterol contribute to stability and facilitate membrane fusion, whereas pegylated lipids reduce nonspecific protein binding, increasing circulation time and drug stability [ 19 ]. Owing to these features, LNPs are widely regarded as ideal nanocarriers for nucleic-acid therapeutics. Their relatively straightforward formulation, high biocompatibility, favorable bioavailability, and low toxicity have made LNPs the most common type of FDA-approved nanomedicine [ 17 , 20 , 21 ].

Polymeric NPs

Polymeric NPs are synthesized from natural polymers (e.g., dextran, chitosan) or synthetic polymers [e.g., poly(lactide-co-glycolic acid) (PLGA), poly(dimethylsiloxane) (PDMS)], enabling diverse compositions and architectures [ 8 , 22 ]. This versatility supports subclasses such as polymeric micelles, polymersomes, and dendrimers (Fig. 1B ) [ 23 – 25 ].

Polymeric micelles are spherical nanostructures with a monolayer shell, featuring a hydrophobic core and hydrophilic corona [ 26 , 27 ]. Polymersomes are vesicles with a bilayer shell of amphiphilic polymers—resembling liposomes—that improve drug stability and retention, thereby enhancing bioavailability [ 28 , 29 ].

Dendrimers are monodisperse, hyperbranched macromolecules bearing numerous surface functional groups, enabling multivalent binding and ligand attachment for targeted CNS delivery [ 30 , 31 ].

In summary, polymeric NPs offer straightforward formulation, facile surface modification, and high biocompatibility, making them promising vehicles for brain drug delivery. Remaining challenges include particle aggregation and potential toxicity, which have limited the number of polymer-based nanomedicines approved for clinical use [ 21 ].

Inorganic NPs

Inorganic NPs are widely used for intracerebral delivery and imaging, including gold NPs, silica NPs, and magnetic NPs (Fig. 1C ). Like polymeric systems, they can be ligand-modified to improve BBB transit [ 17 , 32 ]. Their unique physicochemical, electrical, optical, and magnetic properties permit controlled drug release via external stimuli (e.g., infrared light, ultrasound, magnetic fields). They also enable non-invasive imaging modalities, including MRI and photoacoustic imaging (PAI) [ 25 , 33 ].

Gold NPs (AuNPs), via photothermal effects, are effective for diagnosis and treatment of CNS diseases [ 34 , 35 ]. Mesoporous silica NPs encapsulate drugs with tunable loading and release via pore size and surface modification [ 25 , 36 ]. Magnetic iron-oxide NPs—primarily maghemite (Fe 2 O 3 ) or magnetite (Fe 3 O 4 )—exhibit paramagnetism suited to MRI-guided delivery and tumor imaging [ 37 , 38 ].

Despite these advantages, clinical translation remains limited by issues such as low solubility and potential cytotoxicity associated with certain inorganic materials [ 39 , 40 ].

Hybrid NPs

Hybrid NPs combine two or more nanomaterial types to enhance versatility and physicochemical performance. By integrating complementary strengths, these systems can improve delivery efficiency, targeting precision, and biocompatibility. Common examples include polymer–lipid NPs and lipid–inorganic NPs (Fig. 1D ). Polymer–lipid NPs leverage polymer stability with high lipid drug-loading, enabling sustained release [ 41 ]. Lipid–inorganic NPs combine photothermal or magnetic functionality with lipid biocompatibility, supporting applications in cancer therapy, imaging, and diagnosis [ 42 ].

Although multifunctional designs allow hybrid NPs to meet complex therapeutic needs beyond single-component systems, challenges persist, including preparation complexity, component compatibility, and potential toxicity. Addressing these issues will improve performance and safety and maximize biomedical impact.

Toxicology and long-term fate

Inorganic and hybrid NPs may undergo reticuloendothelial uptake with chronic tissue retention (liver, spleen, lymph nodes, occasionally brain). Dissolution, ion release, and catalytic surface reactions can drive oxidative stress and immunotoxicity [ 43 , 44 ]. We recommend tiered testing: (i) acute/sub-chronic GLP (good laboratory practice) toxicology with dose escalation; (ii) kinetics of organ burden and clearance; (iii) neurobehavioral panels; (iv) immune profiling (complement activation, cytokines); and (v) reproductive/developmental assessments where relevant. Systems toxicology—including transcriptomics and metabolomics—can reveal subclinical liabilities missed by histopathology.

Manufacturing, scalability, and regulatory considerations

Under quality-by-design and CMC (chemistry, manufacturing, and controls) principles, reproducibility hinges on controlling critical quality attributes (CQAs): size/PDI, zeta potential, payload encapsulation, release kinetics, endotoxin level, and residual solvents. Common failure modes include batch-to-batch variability, aggregation during scale-up, and storage-related drift (hydrolysis/oxidation, ligand shedding). Orthogonal analytics and accelerated/real-time stability testing under ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) conditions are essential.

For surface chemistry and ligands, targeting ligands require validated conjugation stoichiometry, serum stability, and retention of affinity post-manufacture [ 45 ]. Regarding the protein corona, in vivo corona composition can redirect biodistribution and mask ligands; pre-coating strategies and zwitterionic/PEGylated surfaces may mitigate these effects, but human plasma testing is necessary to avoid species-specific artifacts [ 46 ]. Finally, for regulatory path, early FDA/EMA engagement on combination-product designation, device dependency (e.g., light/ultrasound), and in vitro–in vivo correlation for release is recommended. Alignment with ICH Q8–Q12 principles supports lifecycle management.

Functions of NPs

Drug delivery

Brain diseases such as depression, schizophrenia, AD, and PD are among the leading causes of disability worldwide [ 2 ]. First-line therapeutics often struggle to cross the BBB, greatly limiting their effectiveness [ 47 ]. Approaches such as temporary BBB opening or local surgical implantation can bypass the barrier but risk introducing toxic molecules into the CNS [ 17 , 48 , 49 ]. By contrast, NP-based delivery systems can transport therapeutic agents into the CNS without compromising BBB integrity (Fig. 2A ) [ 50 ].

Although the BBB excludes many drugs, brain capillary endothelial cells express transporters and receptors that selectively import essential nutrients (e.g., insulin receptor, transferrin receptor, glucose transporter-1) [ 51 ]. NPs functionalized with corresponding ligands or substrates (e.g., insulin, transferrin, glucose) can bind these proteins, triggering receptor- or transporter-mediated uptake and enabling targeted CNS delivery [ 52 ]. Thus, NP-based delivery provides a promising path to more effective treatment of CNS disorders.

Targeted therapy

Molecular markers uniquely expressed in diseased brain cells enable opportunities for diagnosis, prognosis, and prediction of treatment response [ 53 – 55 ], aligning with the rise of precision medicine [ 56 ]. However, the BBB often prevents conventional drugs from reaching target molecules within abnormal brain tissue, limiting therapeutic efficacy [ 47 ]. Dual- and multi-targeted nanomedicines address this challenge: by decorating NP surfaces with ligands that engage both BBB transport (e.g., receptor-mediated transcytosis) and disease-specific markers, these carriers can cross the BBB and deliver payloads precisely to pathological sites (Fig. 2B ) [ 52 , 57 ]. Such site-specific strategies have the potential to substantially enhance efficacy across brain diseases.

Controlled drug release

Over the past decades, NP platforms have enabled not only improved barrier traversal but also precise control over drug release [ 58 , 59 ]. Conventional oral or intravenous drugs are often rapidly metabolized, necessitating frequent dosing to maintain therapeutic concentrations—leading to fluctuating exposure, reduced adherence, and higher risk of toxicity [ 60 , 61 ]. NP-based controlled-release systems mitigate these issues via two principal modes: sustained release and stimuli-responsive release.

Sustained release is achieved by modulating diffusion through an insoluble shell or matrix, or by tuning the degradation rate of biodegradable carriers. Stimuli-responsive systems use materials that react to defined triggers—pH, enzymes, temperature, light, ultrasound, or magnetic/electric fields—to control release in real time and on demand (Fig. 3A ) [ 58 , 62 ]. Selection of a release strategy should reflect disease biology and clinical workflow: chronic neurodegenerative conditions such as AD and PD may benefit from slow, sustained exposure, whereas certain brain tumors with circadian-linked activity may be better suited to stimuli-responsive NPs [ 63 , 64 ].

PK/PD considerations for CNS nanomedicines

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses are essential for widening therapeutic windows, characterizing dose–response, and optimizing release-modulation strategies. Translation requires a quantitative linkage between formulation attributes and effect-site exposure. Key parameters include: (i) release kinetics (burst vs. sustained; zero-order vs. stimuli-responsive), (ii) brain biophase exposure (free payload and intact NP), (iii) the therapeutic window (on-target efficacy vs. neuro/cardiopulmonary toxicity), and (iv) dose–response characterization with hysteresis mapping to detect tolerance or depot effects. Mechanisms of release modulation—diffusion, erosion, desorption, and stimuli (pH, enzymes, light, ultrasound, magnetic fields)—should be matched to disease chronobiology [ 59 , 65 , 66 ].

Reduced side effects

In treating brain-related diseases, conventional drug delivery systems—typically administered intravenously or orally—remain standard in clinical practice. However, free drugs lack specificity for pathological sites, can damage healthy tissues, and often cause adverse side effects [ 67 ]. Because the BBB restricts entry of many agents, only a small fraction reaches the brain; repeated dosing is often required to achieve therapeutic effects, further increasing toxicity risk [ 47 , 62 , 68 ].

NP-based delivery platforms mitigate these limitations by: (1) preventing rapid degradation or elimination, prolonging plasma half-life; (2) enhancing transport across the BBB to improve bioavailability; (3) enabling targeted delivery to specific cells or tissues, maximizing efficacy while minimizing systemic exposure; and (4) allowing precise control of release rates to stabilize concentrations and reduce dosing frequency and amount [ 58 , 69 ]. Consequently, NP-based systems show strong potential to reduce the side effects associated with traditional drug treatments.

Improved diagnosis and monitoring

As early diagnosis increasingly shapes outcomes and prognosis, many conventional techniques still struggle to detect disease in its earliest stages [ 70 ]. NP-based diagnostics can enhance sensitivity, accuracy, and speed by amplifying detection signals and simplifying workflows, thereby improving biomarker detection for earlier intervention [ 71 , 72 ].

Among NP materials, magnetic NPs, quantum dots (QDs), and gold NPs lead current nanodiagnostics (Fig. 3B ) [ 73 ]. Magnetic NPs can be functionalized with antibodies or probes to capture targets and, under an external magnetic field, enable rapid separation and purification to boost detection rates [ 74 , 75 ]. They can also support brain drug delivery while allowing MRI-based monitoring of treatment response [ 76 ]. QDs offer resistance to photobleaching, broad excitation, and narrow emission spectra—overcoming limitations of traditional dyes and making them well suited to fluorescent labeling [ 77 ]. Gold NPs exhibit distinctive surface plasmon resonance; aggregation-dependent color changes enable rapid, straightforward detection [ 78 ]. Overall, nanodiagnostics is an emerging field that leverages NP properties to improve existing methods and enable new detection technologies [ 79 ].

Novel therapeutic approaches

NP-mediated phototherapy—including photothermal therapy (PTT) and photodynamic therapy (PDT)—offers a targeted approach to brain tumors. Compared with surgery, radiotherapy, and chemotherapy, NP-enabled phototherapy can concentrate action within tumor tissue, reducing collateral damage and addressing some mechanisms of drug resistance [ 80 ]. In PTT, photothermal agents such as gold or iron-oxide NPs absorb near-infrared (NIR) light and convert it to heat to ablate tumor cells; tumor-targeting ligands improve precision and help spare healthy tissue [ 81 ]. In PDT, photosensitizers (PS) activated by specific wavelengths generate reactive oxygen species (ROS) that kill tumor cells; NP loading improves PS solubility and specificity, enabling efficient, selective treatment [ 82 ].

Overcoming drug resistance

Drug resistance—common in refractory disease—arises when pathogens or tumor cells evolve to withstand one or more agents, degrading outcomes [ 83 , 84 ]. Although multidrug regimens can delay resistance, conventional combinations often show limited efficacy and higher toxicity due to uneven distribution and divergent pharmacokinetics [ 85 , 86 ]. NP-based combination strategies address these issues by co-delivering multiple therapeutics with controlled stoichiometry and synchronized pharmacokinetics directly to diseased cells [ 87 ]. Examples include cancer-directed systems that pair chemotherapies with pro-apoptotic agents or combine anti–multidrug-resistance inhibitors with siRNA for targeted effects [ 88 – 90 ].

In summary, NPs provide multifunctional capabilities for CNS applications: as carriers, they improve solubility and stability while enabling targeted, controlled delivery across the BBB via surface modifications; as responsive materials, they leverage endogenous and exogenous stimuli for diagnostics and therapy. Together, these features support enhanced efficacy with reduced side effects in CNS disorders.

Preclinical studies

While the benefits of NPs in diagnosing and treating CNS disorders are widely acknowledged, most nanomedicine research necessarily relies on preclinical models for safety and ethical reasons—an essential step toward clinical translation [ 91 ]. Clinical efficacy in CNS therapy remains limited, largely because the BBB prevents most drug molecules from reaching the brain. The complex, multifactorial pathogenesis of CNS disorders further complicates treatment, as single-target drugs often fail to address multiple neuropathological drivers. In addition, non-specific agents can produce toxic side effects that reduce adherence [ 47 , 67 , 92 ].

Recent advances in nanotechnology offer potential solutions. NPs can encapsulate therapeutics to improve solubility and bioavailability and, via surface modification, enable targeted delivery across the BBB. Crucially, NPs can co-load multiple agents to support multi-target strategies better suited to complex CNS pathologies [ 93 ]. In this section, we highlight recent preclinical studies, focusing on mechanisms and advantages relevant to psychiatric and neurological disorders.

Depression

NP-based delivery systems can cross the BBB and address several limitations of traditional antidepressant therapy [ 94 ]. Pairing NPs with antidepressants is a promising strategy to enhance efficacy by improving BBB penetration, targeted delivery, stability/solubility, and controlled sustained release [ 95 ]. For example, Jin et al. [ 96 ] developed a fluoxetine formulation using black phosphorus nanosheets that, under 808 nm NIR light, exhibits a photothermal effect to enhance BBB penetration, shortening onset and lowering systemic toxicity versus free fluoxetine. In a complementary strategy, fluoxetine-loaded chitosan NPs improved cognition, increased BDNF levels, and reduced hippocampal demyelination in a rat model compared with fluoxetine alone [ 97 ].

Beyond monoaminergic mechanisms, anti-inflammatory and antioxidant pathways are increasingly targeted in depression [ 98 , 99 ]. Because NP surfaces are readily engineered, they enable precise delivery to these pathways. Melatonin, for instance, has anti-inflammatory and antioxidant effects but limited BBB permeability [ 100 ]. Liu et al. [ 101 ] reported a light-responsive melatonin system (CAR-M-UZPM) modified with CTLA-4 to target M1-type microglia via CD86; under 980 nm NIR light, melatonin is released, inhibiting M1 polarization and inflammatory activation (Fig. 4 ), thereby enhancing therapeutic effects.

Some nanomaterials also display intrinsic anti-inflammatory/antioxidant activity. CeO₂@BSA nanoclusters crossed the BBB, scavenged ROS, and alleviated depression-like behaviors in preclinical models [ 102 ]. Polydopamine (PDA) NPs—valued for combined diagnostic and therapeutic potential—harbor phenolic hydroxyl groups that scavenge free radicals and blunt acute inflammation [ 103 , 104 ]; PDA NPs reduced peripheral/central inflammation, repaired synaptic loss, and reversed depression-like behaviors in lipopolysaccharide (LPS)-treated mice [ 105 ]. In addition, PDA NP treatment improved cognitive deficits in LPS-treated mice [ 106 ]. Biochemical analyses further showed that short-term administration increased hippocampal DA, norepinephrine, and tyrosine levels, whereas prolonged treatment markedly elevated acetylcholine levels. This long-term enhancement of cholinergic signaling was mediated by activation of septo-hippocampal projections through DA D 2 receptor signaling in the medial septal nucleus. Taken together, these findings highlight PDA NPs as an effective carrier-free platform for targeted DA delivery that not only restores catecholaminergic tone but also recruits cholinergic circuits to improve cognitive dysfunction [ 106 ].

Ketamine and its enantiomers (esketamine, arketamine) remain important for neuropathic pain and depression [ 107 – 113 ]. To improve exposure and durability, Zhang et al. [ 114 ] created a sustained-release esketamine NP-hydrogel for application at the spinal nerve root, reducing hypersensitivity for ≥14 days after ligation and also alleviating depression-like behaviors in rodents.

Collectively, these studies indicate that NP platforms can (i) traverse the BBB, (ii) enable targeted, multi-pathway modulation (e.g., anti-inflammatory, antioxidant), and (iii) reduce systemic toxicity compared with free drugs. In addition, certain nanomaterials provide inherent bioactivity that may complement payload effects. Confirmation across independent laboratories and head-to-head comparisons versus optimized free drug will be important to guide translation.

Schizophrenia

Current antipsychotics—typical (e.g., haloperidol, chlorpromazine) and atypical (e.g., risperidone, olanzapine, clozapine)—are often limited by slow onset, restricted efficacy, and substantial side effects, including extrapyramidal symptoms and metabolic syndrome [ 115 , 116 ]. Conventional formulations face limited BBB permeability and low oral bioavailability, necessitating higher doses that increase dose-dependent adverse effects. Nanotechnology offers potential solutions: ligand-modified nanomedicines can enhance brain delivery and bioavailability; encapsulation can improve solubility, protect against degradation, and enable sustained release. Accordingly, nanoformulations have been explored for haloperidol, risperidone, paliperidone (the active metabolite of risperidone), olanzapine, and clozapine [ 117 – 119 ].

For example, given haloperidol’s poor solubility, Katare et al. [ 120 ] reported a dendrimer–haloperidol complex with >100-fold higher solubility, yielding increased brain and plasma concentrations. Similarly, Sawant et al. [ 121 ] designed aripiprazole-loaded poly(caprolactone) NPs for intranasal delivery, providing a noninvasive, brain-targeted approach.

Clozapine, effective for treatment-resistant schizophrenia, is constrained by adverse effects (e.g., agranulocytosis, myocarditis, pneumonia, ileus) and low oral bioavailability (<27%) due to first-pass metabolism [ 122 , 123 ]. To improve exposure, a solid-lipid nanoparticle system was reported in 2004 [ 124 ]. Building on this, Patel et al. [ 125 , 126 ] developed clozapine-loaded nanostructured lipid carriers and carbon dots for direct nose-to-brain delivery. Most recently, Funguetto-Ribeiro et al. [ 127 ] investigated clozapine-loaded polymeric nanocapsules functionalized with polysorbate 80, PEG, and chitosan to enhance bioavailability and reduce systemic side effects. These strategies may enable lower dosing and reduced monitoring, though further work is required to confirm the safety and effectiveness of clozapine NP formulations.

Long-acting injectable antipsychotics (LAIs) support schizophrenia management by maintaining therapeutic levels for weeks to months, reducing relapse risk, and improving adherence [ 128 , 129 ]. NP technologies can further refine LAIs via controlled, extended release to sustain exposure while minimizing adverse effects [ 130 ]. FDA-approved long-acting products for aripiprazole and paliperidone, while not strictly “nanomedicines,” employ microspheres/nanotechnology to achieve prolonged release and improved adherence.

In September 2024, the FDA approved KarXT (xanomeline plus trospium chloride) for adult schizophrenia. KarXT is the first antipsychotic to target muscarinic cholinergic receptors rather than dopamine receptors: xanomeline selectively activates M1/M4 receptors, modulating acetylcholine, dopamine, and glutamate pathways implicated in schizophrenia, while peripherally restricted trospium reduces cholinergic adverse effects [ 131 , 132 ]. Clinical studies indicate significant symptom reduction, with cholinergic and anticholinergic side effects observed [ 133 – 135 ]. To mitigate these effects, NP-based intranasal delivery of xanomeline could be explored as a potential alternative.

Overall, NP technologies can enhance antipsychotic therapy by improving brain delivery, enabling controlled release, and reducing systemic exposure—changes that may translate into better quality of life and outcomes for patients with schizophrenia.

Alzheimer’s disease (AD)

AD is characterized by β-amyloid (Aβ) plaques and tau-containing neurofibrillary tangles [ 136 ]. Many current candidates target these pathological mechanisms but are limited by low solubility, poor BBB permeability, and single-mechanism action, yielding at best short-term symptomatic relief without halting progression [ 92 , 137 ]. NPs offer an alternative by enabling delivery of anti-Aβ, anti-inflammatory, and antioxidant agents to multiple AD pathways; such multi-target NP strategies provide new therapeutic potential [ 138 – 141 ].

A key enzyme in AD pathobiology is β-site APP-cleaving enzyme 1 (BACE1), which catalyzes Aβ production [ 142 ]. Intracerebral BACE1 siRNA lowers BACE1 and Aβ and improves cognition in AD model mice [ 143 ]. To achieve noninvasive, neuron-specific BACE1 downregulation, Wang et al. [ 144 ] developed PEGylated poly(2-( N,N -dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) NPs carrying BACE1 siRNA, further modified with CGN (BBB-targeting) and Tet1 (neuron-targeting) peptides. This system delivered BACE1 siRNA to neurons, reduced BACE1 mRNA and amyloid plaques, and improved cognition without evident adverse effects (Fig. 5 ).

Molybdenum disulfide (MoS₂) NPs possess intrinsic anti-inflammatory/antioxidant properties and can facilitate photothermal ablation of amyloid plaques under NIR irradiation [ 145 , 146 ]. Building on this, Qi et al. [ 147 ] created MoS₂ quantum dots cloaked with macrophage membranes (MoS₂ QDs/MM) for inflammation-targeted delivery; with NIR photothermal assistance, the platform crossed the BBB, inhibited Aβ 1-42 deposition, reduced ROS, and improved learning and memory in AD mice.

Additional NP strategies include L- and D-glutathione-stabilized gold NPs that cross the BBB and prevent Aβ 1-42 aggregation; the D-isomer showed higher Aβ 1-42 binding affinity, greater brain biodistribution, and stronger anti-fibrillation effects with cognitive benefit in models [ 148 ]. Intranasal lithium chloride NPs also show promise—suppressing neuroinflammatory pyroptosis and improving memory and mood in AD models [ 149 ]—and intranasal NP delivery is being further explored for AD therapy [ 150 , 151 ].

In summary, NP platforms enable targeted delivery across the BBB and address key AD pathologies (Aβ, oxidative stress, neuroinflammation). Through precise targeting, controlled release, and potentially reduced toxicity, NPs improve cognitive outcomes in AD models and may help slow disease progression and improve quality of life for patients.

Parkinson’s disease (PD)

PD is the second most common neurodegenerative disorder, marked by degeneration of dopaminergic neurons in the substantia nigra, dopamine (DA) deficiency, and motor symptoms such as rigidity, bradykinesia, and tremor. Pathology includes intracellular α-synuclein aggregates (Lewy bodies), with mitochondrial dysfunction, oxidative stress, and neuroinflammation contributing to disease progression [ 152 ]. Standard therapy relies on DA replacement with levodopa or DA receptor agonists; however, these approaches are symptomatic only, lose effectiveness over time, and can lead to “on–off” phenomena and end-of-dose deterioration [ 153 , 154 ].

NP-based delivery systems offer advantages for PD, including payload protection, efficient BBB transit, controlled intraparenchymal release, and improved cell-type targeting [ 155 ]. Encapsulating levodopa can prevent premature peripheral conversion to DA and enhance bioavailability, while BBB-targeting surface ligands or antibodies further increase brain exposure, improving efficacy and reducing systemic adverse effects [ 156 ].

Beyond DA replacement, immunotherapy against α-synuclein aggregation is a promising strategy, especially monoclonal antibodies directed at extracellular α-synuclein [ 157 ]. Conventional antibodies, however, poorly access intracellular targets, where pathogenic α-synuclein accumulates [ 158 , 159 ]. Nanobodies offer smaller size, enhanced brain penetration, stability, and suitability for intracellular targeting [ 160 , 161 ]. Chatterjee et al. [ 162 ] developed a proteasome-targeted anti-α-synuclein nanobody (VH14*PEST) that reduced intracellular accumulation, promoted proteasomal clearance, elevated brain DA, and improved motor function in PD models. To avoid interference with physiological monomers, Butler et al. [ 163 ] identified PFFNB2, a nanobody selective for α-synuclein aggregates, positioning it as a targeted candidate therapy.

In summary, NP technologies can enhance PD management by enabling BBB crossing, controlled and localized release, and precise targeting. Protecting levodopa from premature degradation and increasing its brain delivery may improve symptomatic control, while intracellularly active nanobody strategies could address disease drivers—together supporting better outcomes and the potential to slow progression.

NPs with neurotrophic and growth factors

Neurotrophic factors such as BDNF, and growth factors including glial cell–derived neurotrophic factor (GDNF) and transforming growth factor-β1 (TGF-β1), are essential for neuronal survival, growth, and plasticity, supporting overall brain health [ 164 – 171 ]. Altered levels of these factors are linked to multiple psychiatric and neurological disorders, including depression, schizophrenia, AD, and PD [ 172 – 178 ]. As therapeutic targets, they offer opportunities to restore neuroplasticity and mitigate neuroinflammatory damage.

NPs can address the poor brain permeability and limited stability that constrain neurotrophic and growth factor therapeutics. By leveraging receptor-mediated transcytosis, NPs can be engineered to cross the BBB and deliver cargo to neural tissues. For instance, Mahanta et al. [ 179 ] developed mannose-conjugated, chitosan-coated PLGA (CHTMAN-PLGA) NPs that co-deliver cannabidiol and BDNF; in vitro, CHTMAN-PLGA-CBD/pBDNF achieved a fourfold increase in BDNF expression versus naked BDNF. Likewise, PEGylated NPs formed via electrostatic interactions among human serum albumin, neurotrophin-3 (NT3), and BDNF provided gradual release in the mouse vitreous for 28 days, stabilizing neurotrophins in vivo [ 180 ]. In another study, a single injection of GDNF (pDNA)–loaded LNPs sustained expression for seven days, indicating therapeutic potential for PD [ 181 ].

Therapeutic proteins and peptides for CNS disorders span neurotrophic/growth factors (e.g., BDNF, GDNF, TGF-β1), anti-aggregation peptides targeting Aβ or α-synuclein, metabolic peptides (e.g., insulin, GLP-1 analogs with neurotrophic/anti-inflammatory actions), and enzyme/protease modulators (e.g., BACE1-directed siRNA or peptides) [ 144 , 182 , 183 ]. NP delivery can protect these biologics from enzymatic degradation, enable receptor-mediated BBB transport, provide controlled or stimuli-responsive release, support co-delivery of adjuvant small molecules, and allow cell-type–specific targeting (neurons vs. microglia/astrocytes) via surface ligands [ 184 , 185 ].

In summary, NPs create a protective microenvironment that shields neurotrophic and growth factors from degradation and improves bioavailability. Functionalization with targeting ligands further enhances uptake by neurons or glia, enabling precise regional delivery. These features increase the therapeutic potential of neurotrophic factor–based strategies for psychiatric and neurological disorders. In addition, intranasal administration of NP-loaded factors offers a practical route for treating CNS conditions.

In vivo evidence

Representative in vivo studies illustrate the promise of nanomedicine across CNS indications. Black-phosphorus fluoxetine nanosheets activated by near-infrared light accelerated antidepressant onset with reduced systemic toxicity versus free drug [ 96 ]; CeO₂@BSA nanoclusters crossed the BBB, scavenged ROS, and produced antidepressant-like effect [ 102 ]; PDA NPs dampened neuroinflammation, rescued synapses, and reversed behavioral deficits [ 105 ]; MoS₂ quantum dots cloaked with macrophage membranes used NIR-assisted transit to the brain, lowering Aβ and oxidative stress while improving cognition in AD mice [ 146 ]; and intranasal lithium NPs attenuated neuroinflammatory pyroptosis and enhanced memory and mood in AD models [ 149 ]. Together, these examples demonstrate controllable delivery, disease-relevant target engagement, and meaningful functional benefits in rodents, while underscoring the need for human exposure–response studies to guide translation.

Bridging preclinical signals to clinical outcomes

Despite robust preclinical signals, clinical translation of CNS nanomedicines has been inconsistent. Differences in BBB integrity and immune tone between rodent models and humans, species-specific protein-corona composition, and exposure mismatches (brain C_max/AUC) often contribute to non-replication [ 11 , 14 ]. In addition, many animal studies optimize disease-stage timing and administration routes (e.g., intrathecal, intra-tumoral) that are impractical clinically. Reported “target engagement” rarely quantifies payload concentrations in human brain interstitial fluid. Conflicting safety/efficacy reports frequently map to variation in NP size distribution, surface charge, ligand density, and storage-related aggregation. To enhance predictiveness, we recommend: (i) harmonized PK/PD reporting across plasma↔CSF↔brain tissue; (ii) human-relevant endpoints with blinded quantification; (iii) early incorporation of human in-vitro BBB/immune-competent co-culture systems; and (iv) pre-registered protocols with disclosure of negative findings [ 186 , 187 ].

Clinical studies

Nanomedicines have gained traction in clinical care owing to their small size, customizable surfaces, and high drug-loading capacity, which together can improve diagnosis and therapy—especially in oncology. Doxil (liposomal doxorubicin), the first FDA-approved nanodrug (1995), is used for multiple myeloma, ovarian cancer, and AIDS-related Kaposi’s sarcoma; its liposomal formulation enhances tumor delivery and reduces off-target toxicity, including cardiotoxicity [ 188 ]. Other nanoformulated anticancer agents, such as Abraxane and Onivyde, have likewise received FDA approval for specific indications [ 189 , 190 ].

Despite the promise of nanomedicines for CNS disorders, most candidates remain in preclinical or clinical-trial stages. Only a limited number have been approved for clinical use or diagnostic applications in psychiatric and neurological disorders. The sections below summarize currently approved systems relevant to CNS applications and reference data from fda.gov and clinicaltrials.gov.

Clinical maturation of CNS nanomedicines

We summarize ongoing and completed CNS nanomedicine trials with an emphasis on design, endpoints, and reported outcomes where available (Table 1 ). Common patterns include an early-phase focus on safety and PK, reliance on surrogate imaging/biochemical endpoints, and heterogeneity in functional outcomes. Cross-trial comparisons are challenging due to differences in indication, payload, and delivery route, underscoring the need for shared core outcome sets.

Depression, anxiety, and schizophrenia

A search of ClinicalTrials.gov did not identify clinical studies using nanomedicines for diagnosing or treating depression or schizophrenia. Three trials registered on the Iranian Clinical Trials Registry (IRCT20131125015536N8; IRCT20140413017254N5; IRCT20120314009297N5) have evaluated nanocurcumin in related contexts. Reported findings suggest reductions in anxiety and depression among patients with diabetic peripheral neuropathy and coronary slow flow phenomenon, and improvements in negative symptoms in schizophrenia. However, larger, well-controlled studies are needed before recommending broad clinical application [ 191 – 193 ].

AD

No nanomedicines for AD have yet received approval, and most candidates remain in preclinical development. A few—such as NanoLithium ® NP03 (Medesis Pharma SA, France) and APH-1105 (Aphios Corporation, USA)—have progressed to clinical testing (Table 1 ). NanoLithium ® NP03 is a lipid NP–based lithium formulation designed to enhance BBB permeability of lithium ions and exert anti-inflammatory and antioxidant effects. APH-1105 uses liposomes to improve in vivo stability and targeting, with the goal of reducing Aβ plaque formation by modulating α-secretase. Ongoing trials are assessing safety, tolerability, and preliminary efficacy, but results are pending and require continued follow-up [ 194 – 196 ].

PD

Nanotechnology applications in PD are largely experimental, with a small number of candidates in clinical trials, including CNM-Au8 (Clene Nanomedicine, USA) and Nano-PSO (Distribuidora Biolife SA de CV, Mexico) (Table 1 ). CNM-Au8, a gold NP–based therapeutic designed to bolster neuronal energy metabolism and reduce oxidative stress, has been evaluated across several studies. In the Phase 2 REPAIR PD trial, CNM-Au8 was associated with increases in NAD + /NADH ratio, β-ATP, and phosphorylation potential in PD and multiple sclerosis brains [ 197 ]; further trials are needed to establish clinical benefit in PD. CNM-Au8 is also under study in amyotrophic lateral sclerosis [ 198 – 200 ].

Nano-PSO consists of nanodroplets derived from pomegranate seed oil (PSO), rich in unsaturated fatty acids and polyphenols, with putative anti-inflammatory and antioxidant activity. The nanodroplet format is intended to enhance BBB transit and cerebral delivery. Trials are underway in PD and age-related cognitive impairment; outcomes have not yet been reported [ 201 ].

Nanomaterial-based diagnostics are also being explored. One trial ( NCT01246336 ) tested a breath sensor combining organically functionalized carbon nanotubes and gold NPs to detect PD-associated volatile organic compounds, enabling potential early diagnosis and risk screening [ 202 ].

Matrix metalloproteinases (MMPs) in neurodegenerative disorders

Matrix metalloproteinase (MMP)-2/9 regulate extracellular-matrix remodeling at the neurovascular unit and are upregulated in neuroinflammatory states. Excess MMP activity disrupts tight junctions, increases BBB permeability, exposes neurons to peripheral mediators, and alters synaptic plasticity; interactions with Aβ/tau may further propagate pathology [ 203 ]. Nanomedicine strategies include brain-targeted or stimuli-responsive delivery of MMP inhibitors, RNAi/ASO approaches against pathogenic MMP isoforms, and imaging nanoparticles to monitor MMP activity for dose guidance.

Phytobioactive-loaded NPs for neurological/psychiatric disorders

Phytobioactive‐loaded NPs—curcumin, resveratrol, quercetin, berberine, and related polyphenols/terpenoids in PLGA or other polymers, solid-lipid nanoparticles, liposomes, chitosan shells, and hybrids—consistently improve brain delivery, stability, and controlled release of otherwise labile, poorly bioavailable agents [ 204 – 206 ]. In AD/PD and mood-related rodent models (oral or intranasal, sometimes with BBB-shuttle ligands), they reduce Aβ and α-synuclein burden, dampen microglial activation/oxidative stress (e.g., Nrf2/SIRT1; ROS scavenging), restore mitochondrial function, promote autophagy and synaptic plasticity (↑BDNF/PSD-95), and improve cognition and motor/affective behaviors versus free compounds. Design “knobs” (size/PDI, surface charge, ligand density, stimuli-responsive matrices) tune therapeutic windows by aligning local exposure to disease chronobiology while limiting off-target toxicity. Key translational hurdles persist—batch variability, long-term safety of inorganic/hybrid cores, protein-corona effects, and the need for harmonized PK/PD (free vs. encapsulated drug in CSF/ISF) and head-to-head comparators. Overall, phytobioactive NPs offer a practical route to multi-pathway neuroprotection and potential disease modification, especially when combined with gut- or intranasal-first delivery, BBB targeting, and quantitative exposure–response frameworks.

Trial design and implementation

Clinical translation must explicitly address patient-to-patient variability. Age, sex, genetic background, and comorbidities (metabolic, cardiovascular, immunological) can alter NP PK/PD and thereby efficacy and safety; pediatric and geriatric populations differ in organ function, immune responses, and BBB permeability, and immunocompromised individuals may exhibit atypical nano–immune interactions [ 207 ]. Embedding exposure–response analyses (population PK/PD) alongside fluid (plasma/CSF) and imaging biomarkers supports dose optimization and early go/no-go decisions [ 208 ]. Implementation should align with existing care pathways (e.g., clinic infusion vs. at-home oral dosing; MRI/ultrasound availability for stimuli-responsive systems). Economic viability depends on scalable CMC, cold-chain/stability, chair time, and monitoring burden; these should be planned prospectively and aligned with quality/risk-management expectations for products containing nanomaterials [ 209 ].

Patient-specific considerations and safety challenges

BBB integrity varies across individuals and diseases (e.g., AD, stroke, multiple sclerosis), altering NP penetration and distribution and motivating stratified trial designs with personalized dosing. Key hazards include immunogenicity (complement activation, cytokine release) and off-target accumulation, necessitating rational surface engineering and testing in immune-competent preclinical models [ 210 , 211 ]. Long-term safety programs should track biodistribution, clearance kinetics, and delayed toxicities from first-in-human through post-marketing, aligned with regulatory expectations [ 212 ]. Addressing these factors systematically is essential to move CNS nanomedicines from promise to clinical practice.

Beyond the brain: gut-brain axis

NP-based approaches using the gut-brain axis

Although traditionally brain-centric, psychiatric and neurological disorders also involve the gut–brain axis and gut microbiota dysbiosis [ 213 – 230 ]. Diet, aging, antibiotics, stress, infection, metabolic disease, and circadian disruption reshape microbial diversity and metabolites (SCFAs [short-chain fatty acids], bile acids, tryptophan derivatives) [ 231 ]. In mood disorders and AD/PD, reports describe reduced SCFA producers ( Faecalibacterium , Roseburia ), more pathobionts ( Enterobacteriaceae ), elevated LPS/secondary bile acids, altered indole/tryptamine pathways, and barrier dysfunction with endotoxemia, linking to microglial activation, BBB permeability, vagal signaling, and neuroinflammation [ 219 ].

NPs can precisely deliver drugs, probiotics, and bioactives (small molecules, antibiotics, antibodies, microbial metabolites, siRNA) to gut regions to modulate microbiota, quell inflammation, and restore signaling (Fig. 6 ) [ 232 – 235 ]. For example, glucosylated, cationic polymeric NPs improved proximal–small-intestine uptake of oral antibiotics, enhancing bioavailability while limiting microbiota exposure and dysbiosis in mice [ 236 ]. Targeted antimicrobial peptides (STAMPs) engineered via ML/phage display self-assembled into NPs and, with a gut-targeted EPV carrier, protected against colonic infection, reduced inflammation, and aided microbiota recovery [ 237 ]. Additional studies show neural trafficking of gut-delivered silver nanomaterials via vagal/spinal routes [ 238 ], antidepressant-like effects from an N-doped carbon-dot nanoenzyme through microbiome modulation [ 239 ], and oral chiral Au NPs improving cognition and AD pathology by altering gut microbiota [ 240 ].

Constipation—linked to dysbiosis—is a potential early risk factor for AD/PD and may precede clinical symptoms; early gut-targeted NP interventions could be preventative [ 241 – 243 ]. Overall, NP strategies (e.g., probiotic/bioactive encapsulation) may prevent dysbiosis and attenuate neurodegeneration, and NP tools to interface with the vagus nerve merit development. Early gut-focused nanomedicine could slow disease progression, pending confirmation of long-term safety/efficacy in humans (Fig. 6 ).

Safety, variability, and regulatory considerations

Microbiome-directed nanotherapies must accommodate wide inter- and population-level variability in taxa, diet, and antibiotic exposure [ 244 ]. Synthetic carriers for antimicrobials/probiotics/metabolites should demonstrate containment, minimal horizontal gene transfer risk, and reversibility [ 245 ]. Regulatory pathways for live biotherapeutics and engineered microbes intersect drug–biologic–device guidance and often require environmental risk assessments and traceability. For NP-enabled delivery of live/engineered agents, CMC should document biological stability, containment, and kill-switch performance, and trials should include stool/metabolome monitoring, infection surveillance, and stopping rules for dysbiosis-related events [ 246 ].

Gut–brain axis nanomedicine: opportunities and challenges

NP-mediated modulation of the gut–brain axis is promising but early. While preclinical data support NP delivery of probiotics, antimicrobials, and gene modulators, risks include disruption of community stability, metabolite networks, and immune activation; broad microbiome variability further limits reproducibility and generalizability [ 247 ]. Regulatory complexity—especially with live agents, GMOs, or hybrid bio–synthetic platforms—demands rigorous ecological/safety assessment, containment, and long-term monitoring [ 248 , 249 ]. Progress will require cautious interpretation, harmonized trial designs, and careful regulatory navigation.

Conclusion and future perspectives

NP technologies are reshaping therapeutic and diagnostic strategies for psychiatric and neurological disorders by enabling targeted delivery, improved bioavailability, controlled and stimuli-responsive release, and multimodal payloads. Across preclinical models of depression, schizophrenia, AD, and PD, NPs have shown disease-relevant target engagement and functional benefit, including anti-inflammatory, antioxidant, and anti-aggregative effects, as well as enhancements in imaging and biomarker readouts. Yet despite these advances, clinically approved CNS nanoformulations remain limited, underscoring the gap between laboratory promise and durable patient benefit.

Bridging this gap requires a model-informed translational playbook. Formulation attributes should be quantitatively linked to effect-site exposure using harmonized PK/PD readouts across plasma, CSF, and brain interstitial fluid, together with exposure–response modeling and human-relevant BBB/immune co-culture systems. Early-phase trials should prospectively embed these tools to enable rational dose selection, adaptive decision-making, and go/no-go criteria. In parallel, Quality-by-Design and rigorous CMC programs must define and control critical quality attributes, employ orthogonal analytics, and establish stability under ICH conditions—while planning for scale-up, cold chain, and any device dependencies (e.g., light/ultrasound).

Clinical development must also center patient variability and safety by design. Age, sex hormones, genetics, comorbidities, and disease-related BBB heterogeneity shape NP PK/PD, efficacy, and risk; trials should prespecify subgroups, adopt estimand-aligned adaptive designs, and use sparse sampling to characterize population PK across strata. Proactive safety monitoring is essential—including infusion reactions, anti-PEG/anti-ligand antibodies, complement activation–related pseudoallergy, and off-target accumulation via MRI/PET/SPECT where applicable—coupled with long-term registries (≥2–5 years) to detect delayed toxicities and durability of effect. Standardized outcome sets (clinical, functional, imaging, and fluid biomarkers), preregistration (including negative findings), and interoperable data standards will enable cross-trial synthesis and accelerate learning.

Beyond brain-directed strategies, NP platforms targeting the gut–brain axis open complementary therapeutic avenues by modulating microbiota, metabolites, and neuroimmune signaling. These approaches remain early and must navigate substantial variability in human microbiomes, as well as containment and gene-transfer risks for live or engineered agents. Stepwise clinical advancement with predefined safety gates, environmental risk assessments, and stool/metabolome monitoring will be important, alongside careful evaluation of real-world feasibility (e.g., access to MRI/ultrasound for stimuli-responsive systems, chair time, and monitoring burden). Pairing trials with digital biomarkers and remote monitoring can improve resolution on treatment dynamics and support scalable, equitable implementation.

Taken together, the near-term agenda for CNS nanomedicine is clear: couple mechanistic PK/PD rigor with manufacturability, standardize outcomes and data practices, stratify thoughtfully for patient heterogeneity, and steward long-term safety. With coordinated efforts across academia, industry, and regulators—and measured exploration of gut–brain axis opportunities—NP-enabled interventions can progress from promising prototypes to reproducible, accessible, and clinically meaningful therapies for patients with psychiatric and neurological disorders.

Acknowledgements

This study was supported by the project funded by the National Natural Science Foundation of China (Grant No. 82171189 and No. 81971020 to JJY), the Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (Grant No. ZYCXTD2023012). We used AI-tool ChatGPT to enhance the readability in the text.

Author contributions

TTZ, PML, KH, and JJY conceived, drafted and approved the final version of this work.

Competing interest

Dr. Hashimoto is one of the editorial board members of this journal. Dr. Hashimoto is the inventor of filed patent applications on “The use of R -Ketamine in the treatment of psychiatric diseases”, “( S )-norketamine and salt thereof as pharmaceutical”, “ R -Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, and “ R -Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder” by the Chiba University. Dr. Hashimoto has also received research support from Otsuka. The other authors have no conflict of interest.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Kenji Hashimoto, Email: hashimoto@faculty.chiba-u.jp.

Jian-jun Yang, Email: yjyangjj@126.com.

References

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.

2. GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16:877–97.

3. Muntaner C, Eaton WW, Miech R, O’Campo P. Socioeconomic position and major mental disorders. Epidemiol Rev. 2004;26:53–62. 10.1093/epirev/mxh001

4. Carroll WM. The global burden of neurological disorders. Lancet Neurol. 2019;18:418–9. 10.1016/S1474-4422(19)30029-8

5. Bommersbach TJ, McKean AJ, Olfson M, Rhee TG. National trends in mental health-related emergency department visits among youth, 2011-20. JAMA. 2023;329:1469–77. 10.1001/jama.2023.4809

6. Hampel H, Gao P, Cummings J, Toschi N, Thompson PM, Hu Y, et al. The foundation and architecture of precision medicine in neurology and psychiatry. Trends Neurosci. 2023;46:176–98. 10.1016/j.tins.2022.12.004

7. Gao H. Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm Sin B. 2016;6:268–86. 10.1016/j.apsb.2016.05.013

8. Raman S, Mahmood S, Hilles AR, Javed MN, Azmana M, Al-Japairai KAS. Polymeric nanoparticles for brain drug delivery - A review. Curr Drug Metab. 2020;21:649–60. 10.2174/1389200221666200508074348

9. Murayama R, Cai Y, Nakamura H, Hashimoto K. Demyelination in psychiatric and neurological disorders: Mechanisms, clinical impact, and novel therapeutic strategies. Neurosci Biobehav Rev. 2025;174:106209 10.1016/j.neubiorev.2025.106209

10. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. 10.1016/S1474-4422(15)70016-5

11. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50. 10.1038/nrneurol.2017.188

12. Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci. 2018;21:1332–40. 10.1038/s41593-018-0235-9

13. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20:101–24. 10.1038/s41573-020-0090-8

14. Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Target Ther. 2023;8:217 10.1038/s41392-023-01481-w

15. Pardridge WM. A historical review of brain drug delivery. Pharmaceutics. 2022;14:1283 10.3390/pharmaceutics14061283

16. Tenchov R, Bird R, Curtze AE, Zhou Q. Lipid nanoparticles ─ From liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 2021;15:16982–7015. 10.1021/acsnano.1c04996

17. Zhou Z, Sun T, Jiang C. Recent advances on drug delivery nanocarriers for cerebral disorders. Biomed Mater. 2021;16:024104 10.1088/1748-605X/abdc97

18. Kulkarni JA, Witzigmann D, Leung J, Tam YYC, Cullis PR. On the role of helper lipids in lipid nanoparticle formulations of siRNA. Nanoscale. 2019;11:21733–9. 10.1039/c9nr09347h

19. Cheng X, Lee RJ. The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv Drug Deliv Rev. 2016;99:129–37. 10.1016/j.addr.2016.01.022

20. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and challenges of liposome assisted dug delivery. Front Pharmacol. 2015;6:286 10.3389/fphar.2015.00286

21. Anselmo AC, Mitragotri S. Nanoparticles in the clinic: An update. Bioeng Transl Med. 2019;4:e10143 10.1002/btm2.10143

22. Mogoşanu GD, Grumezescu AM, Bejenaru C, Bejenaru LE. Polymeric protective agents for nanoparticles in drug delivery and targeting. Int J Pharm. 2016;510:419–29. 10.1016/j.ijpharm.2016.03.014

23. Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, et al. Polymeric nanoparticles: Production, characterization, toxicology and ecotoxicology. Molecules. 2020;25:3731 10.3390/molecules25163731

24. Tang Z, He C, Tian H, Ding J, Hsiao BS, Chu B, et al. Polymeric nanostructured materials for biomedical applications. Prog Polymer Sci. 2016;60:86–128.

25. Furtado D, Björnmalm M, Ayton S, Bush AI, Kempe K, Caruso F. Overcoming the blood-brain barrier: The role of nanomaterials in treating neurological diseases. Adv Mater. 2018;30:e1801362 10.1002/adma.201801362

26. Croy SR, Kwon GS. Polymeric micelles for drug delivery. Curr Pharm Des. 2006;12:4669–84. 10.2174/138161206779026245

27. Kuperkar K, Patel D, Atanase LI, Bahadur P. Amphiphilic block copolymers: their structures, and self-assembly to polymeric micelles and polymersomes as drug delivery vehicles. Polymers (Basel). 2022;14:4702 10.3390/polym14214702

28. Leong J, Teo JY, Aakalu VK, Yang YY, Kong H. Engineering polymersomes for diagnostics and therapy. Adv Healthc Mater. 2018;7:e1701276 10.1002/adhm.201701276

29. Rideau E, Dimova R, Schwille P, Wurm FR, Landfester K. Liposomes and polymersomes: a comparative review towards cell mimicking. Chem Soc Rev. 2018;47:8572–610. 10.1039/c8cs00162f

30. Xu L, Zhang H, Wu Y. Dendrimer advances for the central nervous system delivery of therapeutics. ACS Chem Neurosci. 2014;5:2–13. 10.1021/cn400182z

31. Palmerston Mendes L, Pan J, Torchilin VP. Dendrimers as nanocarriers for nucleic acid and drug delivery in cancer therapy. Molecules. 2017;22:1401 10.3390/molecules22091401

32. Sekhon BS, Kamboj SR. Inorganic nanomedicine-part 2. Nanomedicine. 2010;6:612–8.

33. Luo M, Lee LKC, Peng B, Choi CHJ, Tong WY, Voelcker NH. Delivering the promise of gene therapy with nanomedicines in treating central nervous system diseases. Adv Sci (Weinh). 2022;9:e2201740 10.1016/j.nano.2010.04.003

34. Wang J, Potocny AM, Rosenthal J, Day ES. Gold nanoshell-linear tetrapyrrole conjugates for near infrared-activated dual photodynamic and photothermal therapies. ACS Omega. 2019;5:926–40. 10.1021/acsomega.9b04150

35. Dheyab MA, Aziz AA, Khaniabadi PM, Jameel MS, Oladzadabbasabadi N, Rahman AA, et al. Gold nanoparticles-based photothermal therapy for breast cancer. Photodiagnosis Photodyn Ther. 2023;42:103312 10.1016/j.pdpdt.2023.103312

36. Croissant JG, Fatieiev Y, Almalik A, Khashab NM. Mesoporous silica and organosilica nanoparticles: physical chemistry, biosafety, delivery strategies, and biomedical applications. Adv Healthc Mater. 2018;7:1700831 10.1002/adhm.201700831.

37. Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29:487–96. 10.1016/j.biomaterials.2007.08.050

38. Wang C, Lin G, Luan Y, Ding J, Li PC, Zhao Z, et al. HIF-prolyl hydroxylase 2 silencing using siRNA delivered by MRI-visible nanoparticles improves therapy efficacy of transplanted EPCs for ischemic stroke. Biomaterials. 2019;197:229–43. 10.1016/j.biomaterials.2018.05.053

39. Arias LS, Pessan JP, Vieira APM, Lima TMT, Delbem ACB, Monteiro DR. Iron oxide nanoparticles for biomedical applications: A perspective on synthesis, drugs, antimicrobial activity, and toxicity. Antibiotics (Basel). 2018;7:46 10.3390/antibiotics7020046

40. Manshian BB, Jiménez J, Himmelreich U, Soenen SJ. Personalized medicine and follow-up of therapeutic delivery through exploitation of quantum dot toxicity. Biomaterials. 2017;127:1–12. 10.1016/j.biomaterials.2017.02.039

41. Mohanty A, Uthaman S, Park IK. Utilization of polymer-lipid hybrid nanoparticles for targeted anti-cancer therapy. Molecules. 2020;25:4377 10.3390/molecules25194377

42. Yanar F, Carugo D, Zhang X. Hybrid nanoplatforms comprising organic nanocompartments encapsulating inorganic nanoparticles for enhanced drug delivery and bioimaging applications. Molecules. 2023;28:5694 10.3390/molecules28155694

43. Dobrovolskaia MA. Lessons learned from immunological characterization of nanomaterials at the nanotechnology characterization laboratory. Front Immunol. 2022;13:984252 10.3389/fimmu.2022.984252

44. Saker R, Regdon G, Sovány T. Pharmacokinetics and toxicity of inorganic nanoparticles and the physicochemical properties/factors affecting them. J Drug Deliv Sci Technol. 2024;99:105979 10.1016/j.jddst.2024.105979

45. Camacho Vieira C, Peltonen L, Karttunen AP, Ribeiro AJ. Is it advantageous to use quality by design (QbD) to develop nanoparticle-based dosage forms for parenteral drug administration? Int J Pharm. 2024;657:124163 10.1016/j.ijpharm.2024.124163

46. Monopoli MP, Aberg C, Salvati A, Dawson KA. Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol. 2012;7:779–86. 10.1038/nnano.2012.207

47. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2:3–14. 10.1602/neurorx.2.1.3

48. Aryal M, Arvanitis CD, Alexander PM, McDannold N. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system. Adv Drug Deliv Rev. 2014;72:94–109. 10.1016/j.addr.2014.01.008

49. Omata D, Hagiwara F, Munakata L, Shima T, Kageyama S, Suzuki Y, et al. Characterization of brain-targeted drug delivery enhanced by a combination of lipid-based microbubbles and non-focused ultrasound. J Pharm Sci. 2020;109:2827–35. 10.1016/j.xphs.2020.06.008

50. Ljubimova JY, Sun T, Mashouf L, Ljubimov AV, Israel LL, Ljubimov VA, et al. Covalent nano delivery systems for selective imaging and treatment of brain tumors. Adv Drug Deliv Rev. 2017;113:177–200. 10.1016/j.addr.2017.06.002

51. Xie J, Shen Z, Anraku Y, Kataoka K, Chen X. Nanomaterial-based blood-brain-barrier (BBB) crossing strategies. Biomaterials. 2019;224:119491 10.1016/j.biomaterials.2019.119491

52. Luo Y, Yang H, Zhou YF, Hu B. Dual and multi-targeted nanoparticles for site-specific brain drug delivery. J Control Release. 2020;317:195–215. 10.1016/j.jconrel.2019.11.037

53. Henley SM, Bates GP, Tabrizi SJ. Biomarkers for neurodegenerative diseases. Curr Opin Neurol. 2005;18:698–705. 10.1097/01.wco.0000186842.51129.cb

54. Iqbal J, Weisenburger DD, Greiner TC, Vose JM, McKeithan T, Kucuk C, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;115:1026–36. 10.1182/blood-2009-06-227579

55. Bonomo R, Cavaletti G, Skene DJ. Metabolomics markers in Neurology: current knowledge and future perspectives for therapeutic targeting. Expert Rev Neurother. 2020;20:725–38. 10.1080/14737175.2020.1782746

56. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–5. 10.1056/NEJMp1500523

57. Gao H, Qian J, Cao S, Yang Z, Pang Z, Pan S, et al. Precise glioma targeting of and penetration by aptamer and peptide dual-functioned nanoparticles. Biomaterials. 2012;33:5115–23. 10.1016/j.biomaterials.2012.03.058

58. Sun T, Zhang YS, Pang B, Hyun DC, Yang M, Xia Y. Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed Engl. 2014;53:12320–64. 10.1002/anie.201403036

59. Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016;116:2602–63. 10.1021/acs.chemrev.5b00346

60. Gillette JR. Factors affecting drug metabolism. Ann N Y Acad Sci. 1971;179:43–66. 10.1111/j.1749-6632.1971.tb46890.x

61. Ekins S, Ring BJ, Grace J, McRobie-Belle DJ, Wrighton SA. Present and future in vitro approaches for drug metabolism. J Pharmacol Toxicol Methods. 2000;44:313–24. 10.1016/s1056-8719(00)00110-6

62. Adepu S, Ramakrishna S. Controlled drug delivery systems: current status and future directions. Molecules. 2021;26:5905 10.3390/molecules26195905

63. Ballance WC, Qin EC, Chung HJ, Gillette MU, Kong H. Reactive oxygen species-responsive drug delivery systems for the treatment of neurodegenerative diseases. Biomaterials. 2019;217:119292 10.1016/j.biomaterials.2019.119292

64. Diamantopoulou Z, Castro-Giner F, Schwab FD, Foerster C, Saini M, Budinjas S, et al. The metastatic spread of breast cancer accelerates during sleep. Nature. 2022;607:156–62. 10.1038/s41586-022-04875-y

65. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12:991–1003. 10.1038/nmat3776

66. Loryan I, Reichel A, Feng B, Bundgaard C, Shaffer C, Kalvass C, et al. Unbound brain-to-plasma partition coefficient, K p,uu,brain -a game changing parameter for CNS drug discovery and development. Pharm Res. 2022;39:1321–41. 10.1007/s11095-022-03246-6

67. Akyüz E, Köklü B, Ozenen C, Arulsamy A, Shaikh MF. Elucidating the potential side effects of current anti-seizure drugs for epilepsy. Curr Neuropharmacol. 2021;19:1865–83. 10.2174/1570159X19666210826125341

68. Loryan I, Hammarlund-Udenaes M, Syvänen S. Brain distribution of drugs: pharmacokinetic considerations. Handb Exp Pharmacol. 2022;273:121–50. 10.1007/164_2020_405

69. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17:20–37. 10.1038/nrc.2016.108

70. Bhujbal SS, Kad MM, Patole VC. Recent diagnostic techniques for the detection of Alzheimer’s disease: a short review. Ir J Med Sci. 2023;192:2417–26. 10.1007/s11845-022-03244-y

71. Xu H, Li S, Liu YS. Nanoparticles in the diagnosis and treatment of vascular aging and related diseases. Signal Transduct Target Ther. 2022;7:231 10.1038/s41392-022-01082-z

72. Alharbi KK, Al-Sheikh YA. Role and implications of nanodiagnostics in the changing trends of clinical diagnosis. Saudi J Biol Sci. 2014;21:109–17. 10.1016/j.sjbs.2013.11.001

73. Baptista PV, Doria G, Quaresma P, Cavadas M, Neves CS, Gomes I, et al. Nanoparticles in molecular diagnostics. Prog Mol Biol Transl Sci. 2011;104:427–88. 10.1016/B978-0-12-416020-0.00011-5

74. Vedarethinam V, Jeevanandam J, Acquah C, Danquah MK. Magnetic nanoparticles for protein separation and purification. Methods Mol Biol. 2023;2699:125–59. 10.1007/978-1-0716-3362-5_8

75. Le TD, Suttikhana I, Ashaolu TJ. State of the art on the separation and purification of proteins by magnetic nanoparticles. J Nanobiotechnology. 2023;21:363 10.1186/s12951-023-02123-7

76. Israel LL, Galstyan A, Holler E, Ljubimova JY. Magnetic iron oxide nanoparticles for imaging, targeting and treatment of primary and metastatic tumors of the brain. J Control Release. 2020;320:45–62. 10.1016/j.jconrel.2020.01.009

77. Yao J, Li P, Li L, Yang M. Biochemistry and biomedicine of quantum dots: from biodetection to bioimaging, drug discovery, diagnostics, and therapy. Acta Biomater. 2018;74:36–55. 10.1016/j.actbio.2018.05.004

78. Yang J, Wang X, Sun Y, Chen B, Hu F, Guo C, et al. Recent advances in colorimetric sensors based on gold nanoparticles for pathogen detection. Biosensors (Basel). 2022;13:29 10.3390/bios13010029

79. Park SM, Aalipour A, Vermesh O, Yu JH, Gambhir SS. Towards clinically translatable in vivo nanodiagnostics. Nat Rev Mater. 2017;2:17014 10.1038/natrevmats.2017.14

80. Kadkhoda J, Tarighatnia A, Barar J, Aghanejad A, Davaran S. Recent advances and trends in nanoparticles based photothermal and photodynamic therapy. Photodiagnosis Photodyn Ther. 2022;37:102697 10.1016/j.pdpdt.2021.102697

81. Wang Y, Luo S, Wu Y, Tang P, Liu J, Liu Z, et al. Highly penetrable and on-demand oxygen release with tumor activity composite nanosystem for photothermal/photodynamic synergetic therapy. ACS Nano. 2020;14:17046–62. 10.1021/acsnano.0c06415

82. Chen L, Huang J, Li X, Huang M, Zeng S, Zheng J, et al. Progress of nanomaterials in photodynamic therapy against tumor. Front Bioeng Biotechnol. 2022;10:920162 10.3389/fbioe.2022.920162

83. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6:1769–92. 10.3390/cancers6031769

84. Gabaldón T. Nothing makes sense in drug resistance except in the light of evolution. Curr Opin Microbiol. 2023;75:102350 10.1016/j.mib.2023.102350

85. Güvenç Paltun B, Kaski S, Mamitsuka H. Machine learning approaches for drug combination therapies. Brief Bioinform. 2021;22:bbab293 10.1093/bib/bbab293

86. Di Maio M, Chiodini P, Georgoulias V, Hatzidaki D, Takeda K, Wachters FM, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:1836–43. 10.1200/JCO.2008.17.5844

87. Hu CM, Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol. 2012;83:1104–11. 10.1016/j.bcp.2012.01.008

88. Shim MK, Moon Y, Yang S, Kim J, Cho H, Lim S, et al. Cancer-specific drug-drug nanoparticles of pro-apoptotic and cathepsin B-cleavable peptide-conjugated doxorubicin for drug-resistant cancer therapy. Biomaterials. 2020;261:120347 10.1016/j.biomaterials.2020.120347

89. Khan MM, Torchilin VP. Recent trends in nanomedicine-based strategies to overcome multidrug resistance in tumors. Cancers (Basel). 2022;14:4123 10.3390/cancers14174123

90. Yalamarty SSK, Filipczak N, Li X, Pathrikar TV, Cotter C, Torchilin VP. Co-delivery of siRNA and chemotherapeutic drug using 2C5 antibody-targeted dendrimer-based mixed micelles for multidrug resistant cancers. Pharmaceutics. 2022;14:1470 10.3390/pharmaceutics14071470

91. Najahi-Missaoui W, Arnold RD, Cummings BS. Safe nanoparticles: are we there yet? Int J Mol Sci. 2020;22:385 10.3390/ijms22010385

92. Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener. 2018;7:2 10.1186/s40035-018-0107-y

93. Altinoglu G, Adali T. Alzheimer’s disease targeted nano-based drug delivery systems. Curr Drug Targets. 2020;21:628–46. 10.2174/1389450120666191118123151

94. Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018;16:71 10.1186/s12951-018-0392-8

95. Mutingwende FP, Kondiah PPD, Ubanako P, Marimuthu T, Choonara YE. Advances in nano-enabled platforms for the treatment of depression. Polymers (Basel). 2021;13:1431 10.3390/polym13091431

96. Jin L, Hu P, Wang Y, Wu L, Qin K, Cheng H, et al. Fast-acting black-phosphorus-assisted depression therapy with low toxicity. Adv Mater. 2020;32:e1906050 10.1002/adma.201906050

97. Dadkhah M, Afshari S, Samizadegan T, Shirmard LR, Barin S. Pegylated chitosan nanoparticles of fluoxetine enhance cognitive performance and hippocampal brain derived neurotrophic factor levels in a rat model of local demyelination. Exp Gerontol. 2024;195:112533 10.1016/j.exger.2024.112533

98. Suneson K, Lindahl J, Chamli Hårsmar S, Söderberg G, Lindqvist D. Inflammatory depression-mechanisms and non-pharmacological interventions. Int J Mol Sci. 2021;22:1640 10.3390/ijms22041640

99. Bhatt S, Nagappa AN, Patil CR. Role of oxidative stress in depression. Drug Discov Today. 2020;25:1270–6. 10.1016/j.drudis.2020.05.001

100. Mannino G, Caradonna F, Cruciata I, Lauria A, Perrone A, Gentile C. Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin-1β. J Pineal Res. 2019;67:e12598 10.1111/jpi.12598

101. Liu Y, Hu P, Zheng Z, Zhong D, Xie W, Tang Z, et al. Photoresponsive vaccine-like CAR-M system with high-efficiency central immune regulation for inflammation-related depression. Adv Mater. 2022;34:e2108525 10.1002/adma.202108525

102. Fu S, Chen H, Yang W, Xia X, Zhao S, Xu X, et al. ROS-targeted depression therapy via BSA-incubated ceria nanoclusters. Nano Lett. 2022;22:4519–27.

103. Liu F, He X, Zhang J, Chen H, Zhang H, Wang Z. Controllable synthesis of polydopamine nanoparticles in microemulsions with pH-activatable properties for cancer detection and treatment. J Mater Chem B. 2015;3:6731–9. 10.1039/c5tb01159k

104. Ball V. Polydopamine nanomaterials: Recent advances in synthesis methods and applications. Front Bioeng Biotechnol. 2018;6:109 10.3389/fbioe.2018.00109

105. Zhu TT, Wang H, Gu HW, Ju LS, Wu XM, Pan WT, et al. Melanin-like polydopamine nanoparticles mediating anti-inflammatory and rescuing synaptic loss for inflammatory depression therapy. J Nanobiotechnology. 2023;21:52 10.1186/s12951-023-01807-4

106. Liu PM, Wang YG, Zhu TT, Zhang JC, Gu HW, Li HJ, et al. Polydopamine nanoparticles restore cognition via targeted dopamine delivery and septo-hippocampal cholinergic activation. Theranostics. 2026;16:3616–33. 10.7150/thno.121735

107. Wei Y, Chang L, Hashimoto K. Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor. Mol Psychiatry. 2022;27:559–73. 10.1038/s41380-021-01121-1

108. Hashimoto K. Ketamine: anesthetic, psychotomimetic, antidepressant, or anthelmintic? Mol Psychiatry. 2022;27:3116–8. 10.1038/s41380-022-01587-7

109. Wang X, Yang J, Hashimoto K. R)-ketamine as prophylactic and therapeutic drug for neurological disorders: Beyond depression. Neurosci Biobehav Rev. 2022;139:104762 10.1016/j.neubiorev.2022.104762

110. Hashimoto K, Zhao M, Zhu T, Wang X, Yang J. Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions. J Anes Transl Med. 2024;3:65–75. 10.1016/j.jatmed.2024.07.001

111. Hashimoto K. Extending ketamine’s antidepressant effects. Science. 2025;388:589–90. 10.1126/science.adx4559

112. He L, Wang X, Luo S, Jiang N, Yan Y, Xie M, et al. Microglial BDNF modulates arketamine’s antidepressant-like effects through cortico-accumbal pathways. Sci Adv. 2025;11:eadv5986 10.1126/sciadv.adv5986

113. Zhao MM, Yang JJ, Hashimoto K. Ketamine and its enantiomers in treatment-resistant depression: promise, pitfalls, and personalized psychiatry. Eur Arch Psychiatry Clin Neurosci. 2025;275:1267–9. 10.1007/s00406-025-02066-0

114. Zhang H, Zhou P, Jiang Y, Li L, Ju F, Cheng Q, et al. Sustained-release esketamine based nanoparticle-hydrogel delivery system for neuropathic pain management. Int J Nanomedicine. 2023;18:1131–43. 10.2147/IJN.S400798

115. Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull. 2015;114:169–79. 10.1093/bmb/ldv017

116. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394:939–51. 10.1016/S0140-6736(19)31135-3

117. Sun Y, Kang C, Liu F, Song L. Delivery of antipsychotics with nanoparticles. Drug Dev Res. 2016;77:393–9. 10.1002/ddr.21331

118. Annu RS, Md S, Baboota S, Ali J. Analyzing nanotheraputics-based approaches for the management of psychotic disorders. J Pharm Sci. 2019;108:3757–68. 10.1016/j.xphs.2019.08.027

119. Muthu MS, Agrawal P, Singh RP. Antipsychotic nanomedicine: a successful platform for clinical use. Nanomedicine (Lond). 2014;9:2071–4. 10.2217/nnm.14.164

120. Katare YK, Daya RP, Sookram Gray C, Luckham RE, Bhandari J, Chauhan AS, et al. Brain targeting of a water insoluble antipsychotic drug haloperidol via the intranasal route using PAMAM dendrimer. Mol Pharm. 2015;12:3380–8. 10.1021/acs.molpharmaceut.5b00402

121. Sawant K, Pandey A, Patel S. Aripiprazole loaded poly(caprolactone) nanoparticles: Optimization and in vivo pharmacokinetics. Mater Sci Eng C Mater Biol Appl. 2016;66:230–43. 10.1016/j.msec.2016.04.089

122. Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209:385–92. 10.1192/bjp.bp.115.177261

123. Hashimoto K. Host microbiota in clozapine-induced ileus and pneumonia among people with schizophrenia. Br J Psychiatry. 2025;227:574–5. 10.1192/bjp.2024.255

124. Venkateswarlu V, Manjunath K. Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J Control Release. 2004;95:627–38. 10.1016/j.jconrel.2004.01.005

125. Patel HP, Gandhi P, Chaudhari PS, Desai BV, Desai DT, Dedhiya PP, et al. Clozapine loaded nanostructured lipid carriers engineered for brain targeting via nose-to-brain delivery: Optimization and in vivo pharmacokinetic studies. J Drug Deliv Sci Technol. 2021;64:102533 10.1016/j.jddst.2021.102533

126. Patel HP, Desai PH, Patel RV, Lodha SN, Gore AH, Patil PO, et al. Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo, and in vivo studies. Colloids Surf B Biointerfaces. 2024;237:113862 10.1016/j.colsurfb.2024.113862

127. Funguetto-Ribeiro AC, Maciel TR, Lunardi AG, Gomes DB, Ibarra M, Haas SE. Clozapine-loaded nanocapsules improve antipsychotic activity in rats: building a sequential PopPK/PD model to discriminate nanocarriers in the preformulation step. Pharm Res. 2023;40:1751–63. 10.1007/s11095-023-03551-8

128. Brissos S, Veguilla MR, Taylor D, Balanzá-Martinez V. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol. 2014;4:198–219. 10.1177/2045125314540297

129. Correll CU, Citrome L, Haddad PM, Lauriello J, Olfson M, Calloway SM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77:1–24. 10.4088/JCP.15032su1

130. Ferreira MD, Duarte J, Veiga F, Paiva-Santos AC, Pires PC. Nanosystems for brain targeting of antipsychotic drugs: An update on the most promising nanocarriers for increased bioavailability and therapeutic efficacy. Pharmaceutics. 2023;15:678 10.3390/pharmaceutics15020678

131. Mirza NR, Peters D, Sparks RG. Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev. 2003;9:159–86. 10.1111/j.1527-3458.2003.tb00247.x

132. Paul SM, Yohn SE, Brannan SK, Neugebauer NM, Breier A. Muscarinic receptor activators as novel treatments for schizophrenia. Biol Psychiatry. 2024;96:627–37. 10.1016/j.biopsych.2024.03.014

133. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384:717–26. 10.1056/NEJMoa2017015

134. Kaul I, Sawchak S, Correll CU, Kakar R, Breier A, Zhu H, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403:160–70. 10.1016/S0140-6736(23)02190-6

135. Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: A randomized clinical trial. JAMA Psychiatry. 2024;81:749–56. 10.1001/jamapsychiatry.2024.0785

136. Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7:33 10.1038/s41572-021-00269-y

137. Srivastava S, Ahmad R, Khare SK. Alzheimer’s disease and its treatment by different approaches: A review. Eur J Med Chem. 2021;216:113320 10.1016/j.ejmech.2021.113320

138. Sahni JK, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C. Neurotherapeutic applications of nanoparticles in Alzheimer’s disease. J Control Release. 2011;152:208–31. 10.1016/j.jconrel.2010.11.033

139. Gupta J, Fatima MT, Islam Z, Khan RH, Uversky VN, Salahuddin P. Nanoparticle formulations in the diagnosis and therapy of Alzheimer’s disease. Int J Biol Macromol. 2019;130:515–26. 10.1016/j.ijbiomac.2019.02.156

140. Bi X, Cao N, He J. Recent advances in nanoenzymes for Alzheimer’s disease treatment. Colloids Surf B Biointerfaces. 2024;244:114139 10.1016/j.colsurfb.2024.114139

141. Menendez-Gonzalez M. Intrathecal immunoselective nanopheresis for Alzheimer’s disease: what and how? why and when? Int J Mol Sci. 2024;25:10632 10.3390/ijms251910632

142. Zhao J, Liu X, Xia W, Zhang Y, Wang C. Targeting amyloidogenic processing of APP in Alzheimer’s disease. Front Mol Neurosci. 2020;13:137 10.3389/fnmol.2020.00137

143. Singer O, Marr RA, Rockenstein E, Crews L, Coufal NG, Gage FH, et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci. 2005;8:1343–9. 10.1038/nn1531

144. Wang P, Zheng X, Guo Q, Yang P, Pang X, Qian K, et al. Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer’s disease. J Control Release. 2018;279:220–33. 10.1016/j.jconrel.2018.04.034

145. Ren C, Li D, Zhou Q, Hu X. Mitochondria-targeted TPP-MoS2 with dual enzyme activity provides efficient neuroprotection through M1/M2 microglial polarization in an Alzheimer’s disease model. Biomaterials. 2020;232:119752 10.1016/j.biomaterials.2019.119752

146. Ye P, Li L, Qi X, Chi M, Liu J, Xie M. Macrophage membrane-encapsulated nitrogen-doped carbon quantum dot nanosystem for targeted treatment of Alzheimer’s disease: Regulating metal ion homeostasis and photothermal removal of β-amyloid. J Colloid Interface Sci. 2023;650:1749–61. 10.1016/j.jcis.2023.07.132

147. Qi X, Li L, Ye P, Xie M. Macrophage membrane-modified MoS2 quantum dots as a nanodrug for combined multi-targeting of Alzheimer’s disease. Adv Healthc Mater. 2023;13:e2303211 10.1002/adhm.202303211

148. Hou K, Zhao J, Wang H, Li B, Li K, Shi X, et al. Chiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer’s disease. Nat Commun. 2020;11:4790 10.1038/s41467-020-18525-2

149. Bhuiyan P, Zhang W, Liang G, Jiang B, Vera R, Chae R, et al. Intranasal lithium chloride nanoparticles inhibit inflammatory pyroptosis in brains and ameliorate memory loss and depression behavior in 5xFAD mice. bioRxiv. 2024. 10.1101/2024.09.18.613794. [Preprint]2024.09.18.61379439651126

150. Yang W, Shi Y, Zhang Y, Yang Y, Du Y, Yang Z, et al. Intranasal carrier-free nanomodulator addresses both symptomatology and etiology of Alzheimer’s disease by restoring neuron plasticity and reprogramming lesion microenvironment. ACS Nano. 2024;18:29779–93. 10.1021/acsnano.4c09449

151. Hu Y, Cui J, Sun J, Liu X, Gao S, Mei X, et al. A novel biomimetic nanovesicle containing caffeic acid-coupled carbon quantum dots for the the treatment of Alzheimer’s disease via nasal administration. J Nanobiotechnology. 2024;22:642 10.1186/s12951-024-02912-8

152. Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med. 2020;36:1–12. 10.1016/j.cger.2019.08.002

153. Lees AJ. The on-off phenomenon. J Neurol Neurosurg Psychiatry. 1989;52:29–37. 10.1136/jnnp.52.suppl.29

154. Chou KL, Stacy M, Simuni T, Miyasaki J, Oertel WH, Sethi K, et al. The spectrum of “off” in Parkinson’s disease: what have we learned over 40 years? Parkinsonism Relat Disord. 2018;51:9–16. 10.1016/j.parkreldis.2018.02.001

155. Baskin J, Jeon JE, Lewis SJG. Nanoparticles for drug delivery in Parkinson’s disease. J Neurol. 2021;268:1981–94. 10.1007/s00415-020-10291-x

156. van Vliet EF, Knol MJ, Schiffelers RM, Caiazzo M, Fens MHAM. Levodopa-loaded nanoparticles for the treatment of Parkinson’s disease. J Control Release. 2023;360:212–24. 10.1016/j.jconrel.2023.06.026

157. Vaikath NN, Hmila I, Gupta V, Erskine D, Ingelsson M, El-Agnaf OMA. Antibodies against alpha-synuclein: tools and therapies. J Neurochem. 2019;150:612–25. 10.1111/jnc.14713

158. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, et al. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32:13454–69. 10.1523/JNEUROSCI.1292-12.2012

159. Slastnikova TA, Ulasov AV, Rosenkranz AA, Sobolev AS. Targeted intracellular delivery of antibodies: The state of the art. Front Pharmacol. 2018;9:1208 10.3389/fphar.2018.01208

160. Dong JX, Lee Y, Kirmiz M, Palacio S, Dumitras C, Moreno CM, et al. A toolbox of nanobodies developed and validated for use as intrabodies and nanoscale immunolabels in mammalian brain neurons. eLife. 2019;8:e48750 10.7554/eLife.48750

161. Silva-Pilipich N, Smerdou C, Vanrell L. A small virus to deliver small antibodies: new targeted therapies based on AAV delivery of nanobodies. Microorganisms. 2021;9:1956 10.3390/microorganisms9091956

162. Chatterjee D, Bhatt M, Butler D, De Genst E, Dobson CM, Messer A, et al. Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model. NPJ Parkinsons Dis. 2018;4:25 10.1038/s41531-018-0062-4

163. Butler YR, Liu Y, Kumbhar R, Zhao P, Gadhave K, Wang N, et al. α-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice. Nat Commun. 2022;13:4060 10.1038/s41467-022-31787-2

164. Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev. 2004;45:104–14. 10.1016/j.brainresrev.2004.02.003

165. Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010;64:341–57. 10.1111/j.1440-1819.2010.02113.x

166. Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol. 2010;70:289–97. 10.1002/dneu.20758

167. Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell. 2022;185:62–76. 10.1016/j.cell.2021.12.003

168. Wei Y, Chang L, Hashimoto K. Intranasal administration of transforming growth factor-β1 elicits rapid-acting antidepressant-like effects in a chronic social defeat stress model: A role of TrkB signaling. Eur Neuropsychopharmacol. 2021;50:55–63. 10.1016/j.euroneuro.2021.04.010

169. Xu D, Liu G, Zhao M, Wan X, Qu Y, Murayama R, et al. Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-β1. J Affect Disord. 2024;367:745–55. 10.1016/j.jad.2024.08.222

170. Zhao MM, Zhu TT, Xu D, Wan X, Liu G, Murayama R, et al. Transforming growth factor-β1 mediates the beneficial effects of arketamine on demyelination and remyelination in the brains of cuprizone-treated mice. Eur J Pharmacol. 2024;985:177096 10.1016/j.ejphar.2024.177096

171. Zhu TT, Zhao MM, Xu D, Cai Y, Liu G, Murayama R, et al. Arketamine alleviates cognitive impairments and demyelination in mice with postoperative cognitive dysfunction via TGF-β1 activation. Prog Neuropsychopharmacol Biol Psychiatry. 2025;136:111228 10.1016/j.pnpbp.2024.111228

172. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54:70–5. 10.1016/s0006-3223(03)00181-1

173. Lee KM, Kim YK. The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder. Int Immunopharmacol. 2006;6:1298–304. 10.1016/j.intimp.2006.03.015

174. Yang B, Ren Q, Zhang JC, Chen QX, Hashimoto K. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis. Transl Psychiatry. 2017;7:e1128 10.1038/tp.2017.95

175. Niitsu T, Ishima T, Yoshida T, Hashimoto T, Matsuzawa D, Shirayama Y, et al. A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia. Psychiatry Res. 2014;215:268–73. 10.1016/j.psychres.2013.12.009

176. Niitsu T, Shirayama Y, Matsuzawa D, Shimizu E, Hashimoto K, Iyo M. Association between serum levels of glial cell-line derived neurotrophic factor and attention deficits in schizophrenia. Neurosci Lett. 2014;575:37–41. 10.1016/j.neulet.2014.05.034

177. Idemoto K, Niitsu T, Hata T, Ishima T, Yoshida S, Hattori K, et al. Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response. Psychiatry Res. 2021;301:113967 10.1016/j.psychres.2021.113967

178. Hock C, Heese K, Hulette C, Rosenberg C, Otten U. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol. 2000;57:846–51. 10.1001/archneur.57.6.846

179. Mahanta AK, Chaulagain B, Trivedi R, Singh J. Mannose-functionalized chitosan-coated PLGA nanoparticles for brain-targeted codelivery of CBD and BDNF for the treatment of Alzheimer’s disease. ACS Chem Neurosci. 2024;15:4021–32. 10.1021/acschemneuro.4c00392

180. Dąbkowska M, Stukan I, Kosiorowska A, Szatanik A, Łuczkowska K, Machalińska A, et al. In vitro and in vivo characterization of human serum albumin-based PEGylated nanoparticles for BDNF and NT3 codelivery. Int J Biol Macromol. 2024;265:130726 10.1016/j.ijbiomac.2024.130726

181. Yang C, Mwangi SM, Balasubramaniam A, Li G, Merlin-Zhang O, Liu Y, et al. Treatment of obesity through glial cell-derived neurotrophic factor lipid nanoparticle delivery in mice. Gastro Hep Adv. 2024;3:38–47. 10.1016/j.gastha.2023.08.012

182. Reich N, Hölscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Front Neurosci. 2022;16:970925 10.3389/fnins.2022.970925

183. Sehra N, Parmar R, Jain R. Peptide-based amyloid-beta aggregation inhibitors. RSC Med Chem. 2025;16:1083–104. 10.1039/d4md00729h

184. Xia M, Zhao T, Wang X, Li Y, Li Y, Zheng T, et al. Brain-derived neurotrophic factor and its applications through nanosystem delivery. Iran J Pharm Res. 2021;20:137–51. 10.22037/ijpr.2021.115705.15484

185. Hersh AM, Alomari S, Tyler BM. Crossing the blood-brain barrier: advances in nanoparticle technology for drug delivery in neuro-oncology. Int J Mol Sci. 2022;23:4153 10.3390/ijms23084153

186. Ioannidis JPA, Kim BYS, Trounson A. How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation. Nat Biomed Eng. 2018;2:797–809. 10.1038/s41551-018-0314-y

187. Joyce P, Allen CJ, Alonso MJ, Ashford M, Bradbury MS, Germain M, et al. A translational framework to DELIVER nanomedicines to the clinic. Nat Nanotechnol. 2024;19:1597–611. 10.1038/s41565-024-01754-7

188. Barenholz Y. Doxil ® -the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160:117–34. 10.1016/j.jconrel.2012.03.020

189. Harries M, Ellis P, Harper P. Nanoparticle albumin-bound paclitaxel for metastatic breast cancer. J Clin Oncol. 2005;23:7768–71. 10.1200/JCO.2005.08.002

190. Yang W, Yang Z, Liu J, Liu D, Wang Y. Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation. Asian J Pharm Sci. 2019;14:687–97. 10.1016/j.ajps.2018.08.003

191. Asadi S, Gholami MS, Siassi F, Qorbani M, Sotoudeh G. Beneficial effects of nano-curcumin supplement on depression and anxiety in diabetic patients with peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2020;34:896–903. 10.1002/ptr.6571

192. Soltani M, Hosseinzadeh-Attar MJ, Rezaei M, Alipoor E, Vasheghani-Farahani A, Yaseri M, et al. Effect of nano-curcumin supplementation on cardiometabolic risk factors, physical and psychological quality of life, and depression in patients with coronary slow flow phenomenon: a randomized double-blind clinical trial. Trials. 2024;25:515 10.1186/s13063-024-08354-9

193. Hosseininasab M, Zarghami M, Mazhari S, Salehifar E, Moosazadeh M, Fariborzifar A, et al. Nanocurcumin as an add-on to antipsychotic drugs for treatment of negative symptoms in patients with chronic schizophrenia: A randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2021;41:25–30. 10.1097/JCP.0000000000001324

194. Guilliot S, Wilson EN, Touchon J, Soto ME. Nanolithium, a new treatment approach to Alzheimer’s disease: A review of existing evidence and clinical perspectives. J Prev Alzheimers Dis. 2024;11:428–34. 10.14283/jpad.2024.26

195. Taléns-Visconti R, de Julián-Ortiz JV, Vila-Busó O, Diez-Sales O, Nácher A. Intranasal drug administration in Alzheimer-type dementia: towards clinical applications. Pharmaceutics. 2023;15:1399 10.3390/pharmaceutics15051399

196. Aphios. Safety, tolerability and efficacy assessment of intranasal nanoparticles of APH-1105, a novel alpha secretase modulator for mild to moderate cognitive impairment due to Alzheimer’s disease (AD). clinicaltrials.gov; Report No.: NCT03806478 . 2021

197. Ren J, Dewey RB III, Rynders A, Evan J, Evan J, Ligozio S, et al. Evidence of brain target engagement in Parkinson’s disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials. J Nanobiotechnology. 2023;21:478 10.1186/s12951-023-02236-z

198. Vucic S, Kiernan MC. Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS. Expert Opin Investig Drugs. 2023;32:783–5. 10.1080/13543784.2023.2263368

199. Vucic S, Menon P, Huynh W, Mahoney C, Ho KS, Hartford A, et al. Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension. EClinicalMedicine. 2023;60:102036 10.1016/j.eclinm.2023.102036

200. Bireley JD, Morren JA. CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS). Expert Opin Investig Drugs. 2023;32:677–83. 10.1080/13543784.2023.2252738

201. Qubty D, Frid K, Har-Even M, Rubovitch V, Gabizon R, Pick CG. Nano-PSO administration attenuates cognitive and neuronal deficits resulting from traumatic brain injury. Molecules. 2022;27:2725 10.3390/molecules27092725

202. Tisch U, Schlesinger I, Ionescu R, Nassar M, Axelrod N, Robertman D, et al. Detection of Alzheimer’s and Parkinson’s disease from exhaled breath using nanomaterial-based sensors. Nanomedicine (Lond). 2013;8:43–56. 10.2217/nnm.12.105

203. Ganguly K, Adhikary K, Acharjee A, Acharjee P, Trigun SK, Mutlaq AS, et al. Biological significance and pathophysiological role of matrix metalloproteinases in the central nervous system. Int J Biol Macromol. 2024;280:135967 10.1016/j.ijbiomac.2024.135967

204. Ashique S, Afzal O, Yasmin S, Hussain A, Altamimi MA, Webster TJ, et al. Strategic nanocarriers to control neurodegenerative disorders: concept, challenges, and future perspective. Int J Pharm. 2023;633:122614 10.1016/j.ijpharm.2023.122614

205. Ashique S, Kumar N, Mishra N, Muthu S, Rajendran RL, Chandrasekaran B, et al. Unveiling the role of exosomes as cellular messengers in neurodegenerative diseases and their potential therapeutic implications. Pathol Res Pract. 2024;260:155451 10.1016/j.prp.2024.155451

206. Albadrani HM, Chauhan P, Ashique S, Babu MA, Iqbal D, Almutary AG, et al. Mechanistic insights into the potential role of dietary polyphenols and their nanoformulation in the management of Alzheimer’s disease. Biomed Pharmacother. 2024;174:116376 10.1016/j.biopha.2024.116376

207. Kaizer AM, Belli HM, Ma Z, Nicklawsky AG, Roberts SC, Wild J, et al. Recent innovations in adaptive trial designs: A review of design opportunities in translational research. J Clin Transl Sci. 2023;7:e125 10.1017/cts.2023.537

208. Ruiz-Garcia A, Baverel P, Bottino D, Dolton M, Feng Y, González-García I, et al. A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development. J Pharmacokinet Pharmacodyn. 2023;50:147–72. 10.1007/s10928-023-09850-2

209. Clogston JD, Foss W, Harris D, Oberoi H, Pan J, Pu E, et al. Current state of nanomedicine drug products: an industry perspective. J Pharm Sci. 2024;113:3395–405. 10.1016/j.xphs.2024.09.005

210. Knox EG, Aburto MR, Clarke G, Cryan JF, O’Driscoll CM. The blood-brain barrier in aging and neurodegeneration. Mol Psychiatry. 2022;27:2659–73. 10.1038/s41380-022-01511-z

211. La-Beck NM, Islam MR, Markiewski MM. Nanoparticle-induced complement activation: implications for cancer nanomedicine. Front Immunol. 2021;11:603039 10.3389/fimmu.2020.603039

212. Fan T, Yan L, He S, Hong Q, Ai F, He S, et al. Biodistribution, degradability and clearance of 2D materials for their biomedical applications. Chem Soc Rev. 2022;51:7732–51. 10.1039/d1cs01070k

213. Nemani K, Hosseini Ghomi R, McCormick B, Fan X. Schizophrenia and the gut-brain axis. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:155–60. 10.1016/j.pnpbp.2014.08.018

214. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96. 10.1038/mp.2016.44

215. Yang J, Zheng P, Li Y, Wu J, Tan X, Zhou J, et al. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Sci Adv. 2020;6:eaba8555 10.1126/sciadv.aba8555

216. Zhu F, Guo R, Wang W, Ju Y, Wang Q, Ma Q, et al. Transplantation of microbiota from drug-free patients with schizophrenia causes schizophrenia-like abnormal behaviors and dysregulated kynurenine metabolism in mice. Mol Psychiatry. 2020;25:2905–18. 10.1038/s41380-019-0475-4

217. Chang L, Wei Y, Hashimoto K. Brain-gut-microbiota axis in depression: A historical overview and future directions. Brain Res Bull. 2022;182:44–56. 10.1016/j.brainresbull.2022.02.004

218. Wei Y, Wang T, Liao L, Fan X, Chang L, Hashimoto K. Brain-spleen axis in health and diseases: A review and future perspective. Brain Res Bull. 2022;182:130–40. 10.1016/j.brainresbull.2022.02.008

219. McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O’Hely M, et al. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry. 2022;27:1920–35. 10.1038/s41380-022-01456-3

220. Liu L, Wang H, Chen X, Zhang Y, Zhang H, Xie P. Gut microbiota and its metabolites in depression: from pathogenesis to treatment. EBioMedicine. 2023;90:104527 10.1016/j.ebiom.2023.104527

221. Hashimoto K. Emerging role of the host microbiome in neuropsychiatric disorders: overview and future directions. Mol Psychiatry. 2023;28:3625–37. 10.1038/s41380-023-02287-6

222. Hashimoto K. Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein-Barr virus and the gut-brain axis. Mol Psychiatry. 2023;28:4968–76. 10.1038/s41380-023-02161-5

223. Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil. 2019;25:48–60. 10.5056/jnm18087

224. Tan AH, Lim SY, Lang AE. The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic. Nat Rev Neurol. 2022;18:476–95. 10.1038/s41582-022-00681-2

225. Ashique S, De Rubis G, Sirohi E, Mishra N, Rihan M, Garg A, et al. Short chain fatty acids: fundamental mediators of the gut-lung axis and their involvement in pulmonary diseases. Chem Biol Interact. 2022;368:110231 10.1016/j.cbi.2022.110231

226. Ashique S, Mohanto S, Ahmed MG, Mishra N, Garg A, Chellappan DK, et al. Gut-brain axis: A cutting-edge approach to target neurological disorders and potential synbiotic application. Heliyon. 2024;10:e34092 10.1016/j.heliyon.2024.e34092

227. Wang D, Gui S, Pu J, Zhong X, Yan L, Li Z, et al. PsycGM: a comprehensive database for associations between gut microbiota and psychiatric disorders. Mol Psychiatry. 2025;30:4222–33. 10.1038/s41380-025-03000-5

228. Feng X, Jia M, Cai M, Zhu T, Hashimoto K, Yang JJ. Central-peripheral neuroimmune dynamics in psychological stress and depression: insights from current research. Mol Psychiatry. 2025;30:4881–98. 10.1038/s41380-025-03085-y

229. Liu L, Wang H, Guo S, Liu S, Du Y, Wang L, et al. The emerging role of the gut microbiome in depression: implications for precision medicine. Mol Psychiatry. 2025;30:5901–13. 10.1038/s41380-025-03191-x

230. Ma L, Wang HB, Hashimoto K. The vagus nerve: an old but new player in brain-body communication. Brain Behav Immun. 2025;124:28–39. 10.1016/j.bbi.2024.11.023

231. Loh JS, Mak WQ, Tan LKS, Ng CX, Chan HH, Yeow SH, et al. Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. 2024;9:37 10.1038/s41392-024-01743-1

232. Ejazi SA, Louisthelmy R, Maisel K. Mechanisms of nanoparticle transport across intestinal tissue: An oral delivery perspective. ACS Nano. 2023;17:13044–61. 10.1021/acsnano.3c02403

233. Pandey RP, Gunjan, Himanshu, Mukherjee R, Chang CM. Nanocarrier-mediated probiotic delivery: a systematic meta-analysis assessing the biological effects. Sci Rep. 2024;14:631 10.1038/s41598-023-50972-x

234. He H, Qin Q, Xu F, Chen Y, Rao S, Wang C, et al. Oral polyphenol-armored nanomedicine for targeted modulation of gut microbiota-brain interactions in colitis. Sci Adv. 2023;9:eadf3887 10.1126/sciadv.adf3887

235. Wu H, Shi C, Li Q, Wang L, Wang R, Chen F, et al. Oral administration of bioactive nanoparticulates for inflammatory bowel disease therapy by mitigating oxidative stress and restoring intestinal microbiota homeostasis. Mol Pharm. 2024;21:6193–205. 10.1021/acs.molpharmaceut.4c00499

236. Zhang G, Wang Q, Tao W, Jiang W, Elinav E, Wang Y, et al. Glucosylated nanoparticles for the oral delivery of antibiotics to the proximal small intestine protect mice from gut dysbiosis. Nat Biomed Eng. 2022;6:867–81. 10.1038/s41551-022-00903-4

237. Xu B, Shaoyong W, Wang L, Yang C, Chen T, Jiang X, et al. Gut-targeted nanoparticles deliver specifically targeted antimicrobial peptides against Clostridium perfringens infections. Sci Adv. 2023;9:eadf8782 10.1126/sciadv.adf8782

238. Wang X, Cui X, Wu J, Bao L, Tan Z, Chen C. Peripheral nerves directly mediate the transneuronal translocation of silver nanomaterials from the gut to central nervous system. Sci Adv. 2023;9:eadg2252 10.1126/sciadv.adg2252

239. Jia H, Gong J, Hu Z, Wen T, Li C, Chen Y, et al. Antioxidant carbon dots nanozymes alleviate stress-induced depression by modulating gut microbiota. Langmuir. 2024;40:19739–50. 10.1021/acs.langmuir.4c02481

240. Guo X, Li C, Zhang J, Sun M, Xu J, Xu C, et al. Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis. Nat Aging. 2023;3:1415–29. 10.1038/s43587-023-00516-9

241. Yu QJ, Yu SY, Zuo LJ, Lian TH, Hu Y, Wang RD, et al. Parkinson disease with constipation: clinical features and relevant factors. Sci Rep. 2018;8:567 10.1038/s41598-017-16790-8

242. Nedelec T, Couvy-Duchesne B, Monnet F, Daly T, Ansart M, Gantzer L, et al. Identifying health conditions associated with Alzheimer’s disease up to 15 years before diagnosis: an agnostic study of French and British health records. Lancet Digit Health. 2022;4:e169–e178. 10.1016/S2589-7500(21)00275-2

243. Feng C, Gao G, Wu K, Weng X. Causal relationship between gut microbiota and constipation: a bidirectional Mendelian randomization study. Front Microbiol. 2024;15:1438778 10.3389/fmicb.2024.1438778

244. Procházková N, Laursen MF, La Barbera G, Tsekitsidi E, Jørgensen MS, Rasmussen MA, et al. Gut physiology and environment explain variations in human gut microbiome composition and metabolism. Nat Microbiol. 2024;9:3210–25. 10.1038/s41564-024-01856-x

245. Charbonneau MR, Isabella VM, Li N, Kurtz CB. Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun. 2020;11:1738 10.1038/s41467-020-15508-1

246. Gonzales-Luna AJ, Carlson TJ, Garey KW. Review Article: Safety of live biotherapeutic products used for the prevention of Clostridioides difficile infection recurrence. Clin Infect Dis. 2023;77:S487–S496. 10.1093/cid/ciad642

247. Valles-Colomer M, Blanco-Míguez A, Manghi P, Asnicar F, Dubois L, Golzato D, et al. The person-to-person transmission landscape of the gut and oral microbiomes. Nature. 2023;614:125–35. 10.1038/s41586-022-05620-1

248. Peng G, Sinkko HM, Alenius H, Lozano N, Kostarelos K, Bräutigam L, et al. Graphene oxide elicits microbiome-dependent type 2 immune responses via the aryl hydrocarbon receptor. Nat Nanotechnol. 2023;18:42–48. 10.1038/s41565-022-01260-8

249. Rodriguez J, Cordaillat-Simmons M, Pot B, Druart C. The regulatory framework for microbiome-based therapies: insights into European regulatory developments. NPJ Biofilms Microbiomes. 2025;11:53 10.1038/s41522-025-00683-0