Hijacking the helpers: platelet and neutrophil trafficking in AML and therapeutic exploitation.

Introduction

Acute myeloid leukemia (AML) remains one of the most aggressive and treatment-resistant hematologic malignancies, marked by the clonal expansion of immature myeloid blasts in bone marrow and peripheral blood [ 1 , 2 ]. Despite decades of therapeutic advances, standard chemotherapy and targeted agents are limited by poor marrow penetration, systemic toxicity, and rapid emergence of resistant clones, leaving long-term survival rates low [ 3 , 4 ]. The circulatory and marrow microenvironments actively drive disease progression, immune evasion, and therapy resistance [ 5 – 7 ]. Platelets and neutrophils—traditionally recognized for hemostasis and innate immunity—play key roles in these processes, supporting leukemic niches, immune suppression, and shielding malignant cells from cytotoxic attack [ 7 , 8 ].

Recent insights into platelet–leukocyte interactions, neutrophil trafficking, and extracellular trap biology reveal a largely untapped opportunity for precision intervention [ 9 , 10 ]. Conventional drug delivery systems, including liposomes and nanoparticles, struggle to achieve marrow-specific targeting and effective therapeutic concentration [ 11 , 12 ]. Critically, they fail to harness the intrinsic trafficking and immune-modulatory capabilities of blood cells. This identifies a clear translational gap: strategies that actively exploit endogenous circulatory networks for high-specificity, high-potency therapy are urgently needed.

We propose cellular hitchhiking using patient-derived platelets and neutrophils as a transformative, patient-tailored approach. These carriers combine homing specificity, immune interface modulation, and prolonged circulation to deliver cytotoxic, immunomodulatory, or gene-based therapeutics directly to marrow and sanctuary sites. Using ex vivo priming, biomaterial functionalization, and patient-specific engineering, this strategy maximizes local efficacy while minimizing off-target toxicity, thrombo-inflammatory risk, and systemic side effects.

Designed with the patient in mind, this approach enables personalized therapy, reduces adverse effects, and has the potential to improve remission rates and might reduce relapse in model systems where residual disease is driven by niche-protected cells; translation to human relapse rates is untested. In short, cellular hitchhiking converts circulating blood cells from passive bystanders into programmable therapeutic vehicles. While the concept of cellular hitchhiking represents a novel and biologically rational framework for drug delivery in AML, it remains at a hypothesis-generating stage. The current evidence base derives primarily from preclinical and proof-of-principle studies, and thus any proposed clinical benefit should be regarded as potential rather than proven. Future investigations will be essential to determine whether enhanced marrow drug delivery via platelet or neutrophil carriers can meaningfully improve remission durability or overall survival in AML. Our intention in this review is to synthesize emerging data and conceptual mechanisms rather than to anticipate specific clinical outcomes.

Rethinking targeted therapy in AML

The therapeutic landscape of AML has shifted from a one-size-fits-all cytotoxic paradigm to a mosaic of genotype-directed and mechanism-based treatments that pair targeted small molecules with epigenetic agents and immunotherapies, necessitating a new conceptual framework for both first-line and relapsed disease [ 13 ]. Venetoclax combined with hypomethylating agents has rapidly become a practice-changing backbone for older or unfit patients, demonstrating deep remissions but also exposing convergent and heterogeneous resistance pathways that necessitate rational combinations [ 14 ]. Parallel advances in precision inhibitors against recurring driver mutations—most notably FLT3 and mutant IDH1/2—have converted formerly intractable molecular subsets into targetable disease states, improving response rates while raising new questions about sequencing and cooperative resistance [ 15 , 16 ].

A recent clinical and translational focus on menin inhibitors for KMT2A-rearranged and NPM1-mutant AML illustrates how epigenetic blockade can induce differentiation and deep molecular remissions, and it exemplifies the field’s move toward mutation-selective agents beyond classic kinase inhibitors [ 17 ]. Finally, the rapid emergence of resistance mechanisms to venetoclax, FLT3, and other targeted agents—spanning genetic, metabolic, and microenvironmental routes—underscores that the next frontier in AML therapy will be dynamic, biology-driven combination strategies guided by real-time molecular monitoring and single-cell resolution [ 18 ].

Overview of AML pathology and current treatment limitations

AML is a biologically heterogeneous malignancy of hematopoietic stem/progenitor cells characterized by clonal expansion of immature myeloid blasts, rapid marrow failure, and highly variable clinical behavior driven by complex genetic and epigenetic landscapes [ 1 ]. Advances in genomic profiling have revealed recurrent, targetable lesions (FLT3, IDH1/2, TP53, NPM1, and others) that underpin disease biology and stratify prognosis; yet, this same molecular diversity complicates therapeutic selection and predicts differential responses [ 19 ] (see Fig. 1 ).

Fig. 1 Genetic architecture of AML and functional categories of recurrent mutations. The diagram organizes commonly altered genes into mechanistic modules that map to the boxes in the figure: signaling/proliferation—activating lesions in the FLT3 pathway (ITD or TKD and cooperating nodes) drive mitogenic programs through RAS–RAF–MEK–ERK, PI3K–AKT–mTOR, and JAK–STAT cascades, promoting cell-cycle entry and survival. The TP53 pathway—TP53 mutations, together with the dysregulation of its key regulators (PTEN loss affecting PI3K–AKT restraint and MDM2-mediated p53 degradation)—abrogate the genome’s guardian functions and transcriptional control. DNA-methylation machinery—mutations in DNMT3A and TET2 and neomorphic IDH1/IDH2 variants (via 2-hydroxyglutarate–mediated TET inhibition) reprogram cytosine methylation and gene expression. chromatin modification—lesions in chromatin modifiers such as ASXL1 and EZH2 disrupt Polycomb/PRC2-dependent repression, while KMT2A–MLLT3 fusions redirect histone methylation programs (including DOT1L-dependent H3K79 methylation), reshaping enhancer landscapes. Transcription/differentiation—RUNX1 mutations and the RUNX1–RUNX1T1 fusion impair core-binding factor activity, blocking hematopoietic differentiation and altering lineage-defining transcriptional programs. cohesin complex—mutations in RAD21 and STAG2 compromise cohesin function, perturbing chromosomal segregation, 3D genome organization, and transcriptional regulation. RNA splicing—recurrent lesions in U2AF1, ZRSR2, SF3B1, and SRSF2—deregulate splice-site recognition and isoform usage, with broad downstream effects on hematopoietic gene networks. Nucleophosmin—NPM1 mutations produce aberrant cytoplasmic localization of NPM1 and its binding partners, rewiring transcriptional programs and cooperating with other lesions to drive leukemogenesis. Together, these categories capture the principal genetic circuits—signal transduction, tumor-suppressor control, epigenetic/DNA-methylation, chromatin remodeling, lineage-specifying transcription, cohesin-mediated genome architecture, RNA-processing and nucleolar transport—whose disruption underlies AML pathogenesis, heterogeneity and therapeutic vulnerabilities

In the last decade, multiple targeted agents and combination regimens (FLT3 inhibitors, IDH inhibitors, antibody-drug conjugates, and the venetoclax + hypomethylating agent [HMA] backbone for unfit/older patients) have expanded the armamentarium and improved remission rates in defined subgroups; nevertheless, durable disease control remains elusive for many patients [ 19 , 20 ]. Mechanisms of primary and acquired resistance are multifactorial, including preexisting co-mutations (e.g., TP53, RAS pathway alterations), adaptive metabolic reprogramming, clonal evolution under selective pressure, and microenvironmental protection. These mechanisms limit the long-term benefit of otherwise active agents, such as venetoclax/HMA and FLT3 inhibitors [ 21 , 22 ]. Clinical constraints compound biological challenges: AML predominantly affects older adults who frequently cannot tolerate intensive cytotoxic chemotherapy or allogeneic transplant; comorbidities, treatment toxicity, and access disparities drive early mortality and restrict the applicability of intensive curative strategies [ 1 , 23 ]. In parallel, the incomplete eradication of disease below morphologic detection—measurable residual disease (MRD)—predicts relapse; however, standardization of MRD assays, optimal timepoints, and the best approach to act on MRD remain open questions for both clinical practice and regulatory endpoints [ 24 , 25 ] (see Fig. 2 ).

Fig. 2 AML therapeutic landscape: chemotherapy, targeted therapy, and immunotherapy. This schematic summarizes the diverse therapeutic strategies currently used or under development for AML, organized by their primary mechanisms of action. Conventional chemotherapy remains a backbone, with formulations such as CPX-351 improving pharmacokinetics and outcomes in high-risk subsets. Targeted small molecules have transformed treatment by exploiting specific oncogenic drivers, including FLT3 inhibitors (midostaurin, gilteritinib, quizartinib), IDH1/2 inhibitors (ivosidenib, enasidenib), hedgehog inhibitors (glasdegib), and menin–MLL inhibitors (KO-539, SNDX-5613, revumenib) in patients with mutation-selected tumors. Epigenetic therapies, notably hypomethylating agents (azacitidine, decitabine) and HDAC inhibitors (pracinostat), remain critical for older or unfit patients and serve as partners in combination regimens, often with BCL-2 inhibition. Venetoclax, a selective BCL-2 inhibitor, in combination with HMAs, has become a frontline standard for older/unfit AML by exploiting apoptotic dependency. Antibody-based therapies expand the arsenal, with gemtuzumab ozogamicin (anti-CD33 ADC) integrated into chemotherapy, investigational CD123-directed ADCs, and macrophage checkpoint blockade via anti-CD47 (magrolimab) under evaluation. Immune-based approaches include checkpoint inhibitors (nivolumab, ipilimumab) with modest activity as monotherapy but potential synergy with HMAs, as well as bispecific T-cell engagers (AMG-330, flotetuzumab) and CAR-T/NK-cell therapies targeting CD33, CD123, or NKG2D ligands, which show early promise despite challenges of antigen heterogeneity and hematopoietic toxicity. Collectively, these modalities highlight the shift from non-specific cytotoxic therapy to precision-based, apoptosis-targeting, metabolic, epigenetic, and immune strategies, underscoring the need for rational combinations that address the genetic, metabolic, and microenvironmental complexity of AML to achieve durable responses

Taken together, the current AML landscape is one of meaningful, disease-specific therapeutic progress tempered by persistent limitations: marked heterogeneity that fuels resistance and relapse, a large elderly patient population with limited tolerance for intensive therapy, and gaps in sensitive response assessment and treatment personalization. Addressing these gaps will require integrative strategies that combine precision targeting with approaches to overcome resistance (including metabolic and microenvironmental targeting), more effective MRD-guided treatment algorithms, and broader access to molecular diagnostics and novel agents [ 19 , 20 ].

Systemic nature of AML and therapeutic delivery challenges

AML is not a focal tumor but a systemic, stem-cell-driven disease: malignant hematopoietic clones and therapy-resistant leukemic stem cells (LSCs) circulate and reside within anatomically protected bone-marrow niches and extramedullary reservoirs, creating a distributed disease ecology that underpins minimal residual disease and relapse [ 25 , 26 ]. The bone-marrow microenvironment—stromal cells, endothelial networks, extracellular matrix, hypoxic gradients, and inflammatory signals—actively shelters LSCs through adhesion molecules (VCAM-1, VLA-4), chemokine axes (CXCL12–CXCR4), and metabolic reprogramming; these niche interactions reduce cell cycling, upregulate pro-survival pathways, and blunt cytotoxic and immune-mediated killing [ 27 ]. From a drug-delivery perspective, AML poses three linked challenges: [ 1 ] pharmacokinetic mismatch—systemic agents must reach biologically relevant concentrations inside poorly perfused marrow compartments without intolerable off-target toxicity; [ 2 ] biological escape—dormant LSCs and microenvironment-driven resistance (drug efflux, metabolic shift, protective cytokines) limit intracellular drug action; and [ 3 ] patient factors—older age and comorbidities narrow therapeutic windows for intensive regimens, favoring lower-intensity but often less-curative approaches [ 19 , 28 ]. These obstacles explain growing interest in delivery strategies that exploit endogenous trafficking: neutrophil “hitchhiking” and platelet-based carriers can ferry nanoparticles or drug cargoes across endothelial barriers and toward inflamed or marrow-homing niches, thereby amplifying local payload concentration while reducing systemic exposure—preclinical reports demonstrate enhanced bone-marrow accumulation and target engagement using such cell-mediated routes [ 29 , 30 ].

Rationale for cell-mediated (platelet/neutrophil) targeting

Because AML is a systemic, niche-protected stem-cell disease, delivery platforms that ride endogenous trafficking pathways promise to concentrate payloads in marrow and extramedullary reservoirs while limiting systemic exposure—an attractive complement to molecular inhibitors and immunotherapies that struggle to reach dormant leukemic stem cells [ 31 ]. Platelets are naturally long-circulating, non-nucleated cells that adhere to activated endothelium, exposed subendothelial matrix, and damaged cells; coating nanoparticles with platelet membranes or using intact platelets as carriers prolongs circulation, provides immune camouflage, and leverages platelet tropism for injured vasculature and tumor/lesion sites to increase local drug deposition [ 32 ]. In practice, platelet-membrane-coated nanoparticles (PM@NPs) and platelet-loaded systems have shown improved target accumulation, reduced off-target toxicity, and enhanced efficacy in multiple preclinical cancer models—features that could be repurposed to deliver chemotherapeutics, small molecules, or biologics to leukemic niches [ 33 – 35 ]. Neutrophils offer a complementary route: they rapidly marginate to sites of inflammation, traverse endothelial and marrow barriers, and can carry internalized nanoparticles (the “hitchhiking” concept) to bone marrow or inflamed tumor niches [ 9 , 29 ]. Recent studies demonstrate the rerouting of nanoparticle cargos to the bone marrow by exploiting neutrophil trafficking, which enhances marrow drug levels and therapeutic effect in preclinical models —a particularly relevant capability for AML, where marrow target engagement is essential [ 29 , 36 ]. Beyond tropism, cell-based carriers offer modular engineering advantages: membrane coatings preserve surface-targeting ligands and immune-evasion signals. At the same time, payloads can be tuned for rapid release or intracellular delivery once the carrier reaches its niche [ 37 ]. These features collectively increase the therapeutic index by raising local concentrations at disease sites and lowering systemic peak exposure, which is critical for older AML patients with limited tolerance to cytotoxicity [ 31 , 38 , 39 ]. Nevertheless, translational hurdles remain: manufacturing scale-up, reproducible drug loading and release, potential carrier-mediated pro-thrombotic or pro-inflammatory effects, and regulatory safety assessments must be solved before clinical adoption [ 40 , 41 ].

Leukemia progression and resistance mechanisms

Leukemia progression reflects an evolutionary, multi-step process in which preleukemic clones (often carrying DNMT3A/TET2/ASXL1 mutations) expand, acquire cooperating lesions, and generate hierarchically organized LSCs that seed intratumoral heterogeneity and drive relapse. Single-cell and phylogenetic studies demonstrate that this clonal architecture is frequently branched: minor subclones present at diagnosis can survive therapy and become dominant at relapse, making longitudinal, high-resolution monitoring essential to anticipate disease trajectories [ 42 ]. Resistance to treatment is both genetic and non-genetic. On the genetic side, the selection of preexisting or acquired mutations (e.g., in signaling pathways or drug targets) leads to clear-cut target escape. Equally important are non-genetic mechanisms—epigenetic reprogramming, transcriptional plasticity, and reversible “persister” states—that rewire chromatin, metabolism, and apoptotic thresholds without new driver mutations, enabling rapid, therapy-tolerant adaptation. Functional single-cell and epigenetic profiling have revealed these layers and demonstrated that relapse often exhibits convergent stem-like transcriptional programs, regardless of the mutational route [ 43 , 44 ]. Metabolic and microenvironmental support are central to tolerance. Therapy-resistant blasts and LSCs frequently shift toward mitochondrial oxidative phosphorylation and fatty acid oxidation, utilize niche-derived metabolites, and exploit stromal protection (adhesion, cytokines, altered vascular/adipocyte niches) that reduce drug exposure and apoptotic priming. Targeting these dependencies (metabolic inhibitors, niche-disrupting agents) alongside cytoreduction is therefore a rational strategy now entering clinical testing [ 45 , 46 ] (see Fig. 3 ).

Fig. 3 Molecular and Cellular Mechanisms Underlying Drug Resistance in AML. The schematic integrates four interdependent modules that enable leukemia stem cells (LSCs) and blasts to survive cytotoxic and targeted therapies: the bone marrow niche, genetic/epigenetic drivers, immune escape, and mitochondrial/metabolic remodeling. A Niche interactions (VLA-4/VCAM-1, CD44–hyaluronan, integrins, CXCL12–CXCR4) physically anchor LSCs and activate prosurvival signalling (PI3K–AKT, NF-κB, mTOR), enforce cell-cycle exit (quiescence) and up-regulate anti-apoptotic BCL-2 family proteins; the niche also delivers protective cargo (extracellular vesicles, microRNAs, organelles) that reprogram metabolism and blunt DNA-damage responses, a phenomenon termed cell-adhesion-mediated drug resistance (CAM-DR). B Concurrently, pre-leukemic and driver lesions (DNMT3A, TET2, ASXL1, FLT3-ITD/TKD, RAS, NPM1, CEBPA, mutant IDH1/2) remodel chromatin, signalling and metabolism (e.g., 2-HG), raise DNA-repair and drug-efflux/apoptotic thresholds, and provide substrate for clonal selection under treatment. C AML blasts further evade immune clearance via HLA downregulation, loss/shedding of NKG2D ligands, and upregulation of inhibitory axes (PD-L1→PD-1, Gal-9→TIM-3, CD47→SIRPα, and other checkpoints). At the same time, the microenvironment is skewed toward immunosuppression by Tregs, MDSCs, and tolerogenic macrophages that secrete IDO, arginase-1, IL-10, TGF-β, and ROS, all of which blunt T-cell/NK-cell function and limit immunotherapy efficacy. D Metabolically, resistant cells exhibit mitochondrial plasticity—elevated OXPHOS, FAO, increased mitochondrial mass and mitophagy/autophagy—supported by stromal lipid transfer (CD36), glutamine/TCA flux and enhanced antioxidant capacity, which together preserve ATP, buffer ROS and cooperate with BCL-2/MCL-1/BCL2A1 to prevent apoptosis. Because these modules are tightly interconnected (niche signals sustain mitochondrial fitness; metabolic and epigenetic states influence immune visibility and drug response), overcoming relapse likely requires combinatorial strategies that disrupt niche adhesion/chemotaxis (e.g., CXCR4/VLA-4), target epigenetic or mutation-specific vulnerabilities, reverse immune suppression (checkpoint/CD47 blockade) and inhibit mitochondrial/metabolic dependencies (including BCL-2 family antagonists)

Leukemic stem cells, clonal evolution, and disease progression

Leukemic stem cells (LSCs) are a rare, functionally defined subpopulation that sustains AML by coupling long-term self-renewal with multilineage output; their persistence after therapy is a principal driver of minimal residual disease (MRD), relapse, and poor long-term outcome. Recent reviews synthesize decades of functional, phenotypic, and molecular work showing that LSCs are not a single fixed entity but a spectrum of stem-like states whose frequency and properties vary between patients and over time [ 47 , 48 ]. Many AMLs arise from a preleukemic phase of clonal hematopoiesis (CH), in which mutations in epigenetic regulators (DNMT3A, TET2, ASXL1) expand HSC clones long before the onset of overt disease. These preleukemic clones provide the substrate for later leukemogenic hits: subsequent cooperating mutations or structural events transform a CH clone into frank AML, meaning that the roots of relapse often lie in clones that predate diagnosis. Recognizing and tracking CH-derived clones therefore refines both risk assessment and therapeutic targeting [ 25 , 49 , 50 ]. Clonal evolution in AML is dynamic and frequently branched rather than strictly linear. High-resolution single-cell multi-omic studies now reveal complex evolutionary patterns—monoclonal, linear, and branched polyclonal trajectories—and show that diagnosis, remission, and relapse samples can harbor multiple coexisting subclones with differing mutation sets, karyotypic rearrangements, and transcriptional/epigenetic programs. Importantly, relapse commonly derives either from a rare diagnosis-present LSC that survived therapy or from an evolved subclone that acquired additional adaptive alterations under treatment pressure [ 42 ]. Epigenetic convergence is a recurring theme: relapse often features convergent chromatin and transcriptional programs that reinforce stemness, quiescence, and therapeutic tolerance, even when mutational profiles appear relatively stable. These non-genetic adaptations—chromatin rewiring, enhancer reprogramming, and altered metabolic states—can create drug-tolerant persister states that evade cytotoxic agents and targeted therapies, highlighting why genomic sequencing alone sometimes fails to predict clinical behavior [ 44 , 51 ] (See Fig. 3 b).

Remodeling of the bone marrow niche and stromal support

The bone-marrow (BM) niche is actively reprogrammed during leukemogenesis: AML cells co-opt mesenchymal, endothelial, adipocytic, and neural elements to build a pro-leukemic ecosystem that supports blast survival, therapy resistance, and clonal selection. This remodeling is bidirectional—leukemia reshapes stromal composition and function, and the remodeled niche in turn promotes leukemic fitness and relapse [ 46 ]. Mesenchymal stromal cells (MSCs) and osteolineage progenitors are central mediators of niche hijacking. AML-educated MSCs alter their secretome (CXCL12, IL-6, and other trophic factors), extracellular-matrix deposition, and metabolic output to enhance blast adhesion, provide paracrine survival signals, and supply metabolites that blunt chemotherapy efficacy; osteoblastic remodeling can further bias hematopoiesis away from regular HSC support toward leukemia expansion [ 52 ]. The vascular niche and marrow adipocytes also undergo changes that favor disease persistence. Leukemia reshapes endothelial angiocrine signaling and vascular permeability to create protective perivascular “hotspots.” At the same time, bone marrow adipocytes supply fatty acids and lipid fuels that fuel oxidative metabolism in therapy-tolerant blasts, linking niche metabolism to chemoresistance and relapse [ 53 – 55 ]. Neural inputs are an underappreciated axis of remodeling: AML can produce sympathetic neuropathy and alter adrenergic signaling in the marrow, which drives MSC fate shifts, reduces HSC quiescence, and creates microenvironments permissive for leukemic expansion. These neural and inflammatory disruptions connect systemic physiologic states to local niche permissiveness. High-resolution spatial and single-cell studies are now mapping these changes in situ, revealing discrete stromal subpopulations, spatial hubs of immune exclusion, and treatment-induced niche reorganization. Spatial multi-omics in patient samples (including studies before/after therapy or during immunotherapy) provide actionable biomarkers to predict response and to combine niche-directed agents with cytoreductive therapies rationally [ 56 , 57 ]. Therapeutically, the remodeled niche is both a problem and an opportunity: disrupting retention signals (e.g., CXCR4 antagonists), blocking stromal pro-survival pathways, targeting adipocyte–blast metabolic crosstalk (FAO/OXPHOS inhibitors), or restoring healthy neural signaling are all under preclinical and early clinical investigation as strategies to sensitize LSCs and MRD to treatment. Translating these approaches will require integrating spatial/single-cell biomarkers into trials and careful sequencing to avoid collateral hematopoietic toxicity [ 46 , 58 ]. In summary, AML progression reflects not only cancer-cell intrinsic adaptation but also an active, multi-compartmental reprogramming of the BM niche; targeting both the malignant seed and its remodeled environment offers the best path to durable remissions (See Fig. 3 a).

Despite promising preclinical and early clinical signals, attempts to overcome niche-mediated biological escape with microenvironment modulators have frequently been limited by insufficient marrow delivery and a lack of quantitative marrow PK/PD endpoints. CXCR4 antagonists such as plerixafor have been safely combined with chemotherapy and reliably mobilize marrow blasts into blood, but randomized data and robust marrow PK/PD demonstrating durable clinical benefit remain limited [ 59 ]. E-selectin blockade (e.g., uproleselan/GMI-1271) produced encouraging phase-1/2 signals for chemosensitization, yet more recent larger trials have reported mixed results, underscoring the need to separate pharmacodynamic failure from inadequate local exposure [ 60 ].

A recurrent shortcoming across many published studies is the absence of quantitative measures of marrow exposure (e.g., marrow AUC by validated LC-MS/MS), receptor-occupancy/readout assays within the niche, or in-situ functional readouts of adhesion blockade. Without these endpoints it is difficult to determine whether negative or equivocal clinical outcomes reflect true biological ineffectiveness or simply pharmacokinetic under-exposure in protected niche microdomains [ 61 ]. Cell-mediated hitchhiking offers a potential solution to the delivery problem: recent preclinical studies show that neutrophil-guided or platelet-inspired delivery can increase marrow drug concentrations by multiple-fold (reported increases of ~ 5–20× in relevant models), which should substantially improve receptor occupancy and local functional modulation when combined with microenvironment agents [ 61 , 62 ].

Immune evasion strategies of leukemic blasts (checkpoint expression, cytokine crosstalk)

Leukemic blasts deploy a multilayered immune-evasion program that silences both innate and adaptive arms of antitumor immunity, thereby promoting LSC persistence, MRD, and relapse. At the surface level, blasts and LSCs upregulate inhibitory ligands such as PD-L1 and TIM-3: PD-L1 expression is enriched on LSCs in a subset of patients and can be induced by inflammatory and metabolic programs, while TIM-3 acts both as a marker of LSCs and a mediator of T-cell dysfunction—making these checkpoints dual contributors to immune suppression and direct leukemic fitness [ 63 , 64 ]. Innate-immune escape is dominated by “don’t-eat-me” signals and myeloid reprogramming. CD47 overexpression on blasts blocks SIRPα-mediated phagocytosis and shows promising early signals when combined with hypomethylating agents. However, larger randomized studies and recent readouts have tempered initial enthusiasm and highlighted safety/efficacy heterogeneity across patient groups. Concurrently, AML drives expansion and functional skewing of immunosuppressive myeloid cells (MDSCs) and tolerogenic macrophages that blunt antigen presentation and promote tumor tolerance [ 65 , 66 ]. Soluble mediators and antigen visibility further lock the marrow into an immune-cold state. Leukemia-educated stroma and regulatory T cells secrete IL-10, TGF-β, and related factors that suppress effector T cells and dendritic cell function; metabolic byproducts (e.g., lactate) and epigenetic programs additionally downmodulate HLA expression and antigen-presentation machinery, reducing leukemic visibility to cytotoxic T cells and limiting the substrate on which checkpoint blockade can act [ 67 , 68 ] (See Fig. 3 c).

Conventional and emerging therapeutic approaches

Conventional cytotoxic regimens—most notably anthracycline plus cytarabine induction and consolidation with consideration of allogeneic hematopoietic stem-cell transplantation—remain the foundational curative backbone for fit patients, while molecularly targeted agents and apoptosis-directed combinations have broadened effective options and improved outcomes in defined subgroups; for example, adding the FLT3 inhibitor midostaurin to intensive chemotherapy improved survival in FLT3-mutant AML (CALGB 10603/RATIFY), and the BCL-2 inhibitor venetoclax combined with azacitidine established a new standard for older or unfit patients (VIALE-A), with selective second-generation FLT3 inhibitors (e.g., gilteritinib) providing benefit in relapsed/refractory disease [ 69 ] (See Fig. 2 ).

Chemotherapy and radiotherapy: successes and limitations

Chemotherapy and radiotherapy remain foundational tools in the management of AML. Conventional cytotoxic induction—most famously the cytarabine + anthracycline “7 + 3” backbone—produced the first durable remissions and established a reproducible pathway to cure for a subset of patients. Decades of incremental refinements in dosing, supportive care, and consolidation have improved complete remission rates and early survival [ 70 ]. Anthracycline intensification (for example, escalation of daunorubicin dose) is one clear example of how modifying classical regimens produced measurable gains in selected populations: randomized trials demonstrated higher remission rates with higher daunorubicin in younger fit patients, illustrating that careful dose optimization can increase cytoreductive efficacy but also carries age- and comorbidity-dependent toxicity [ 71 ]. Radiotherapy’s role in AML is generally adjunctive and highly situational. Local RT provides reliable control and symptom relief for extramedullary disease (myeloid sarcoma/chloroma) and is a useful palliative tool when systemic therapy fails; total-body irradiation (TBI) remains an essential component of some myeloablative conditioning regimens before allogeneic transplant, where it can contribute to disease control but also adds distinct short- and long-term toxicities that must be balanced against benefit [ 72 ]. Despite these successes, the intrinsic and adaptive limits of chemo-RT are decisive drivers of continuing therapeutic innovation. Relapse after initially successful cytoreduction is common and is most often due to MRD and therapy-resilient leukemic stem cells that survive cytotoxic exposure; MRD dynamics are now recognized as one of the strongest predictors of relapse and guide risk-adapted consolidation and transplant decisions [ 25 , 73 ]. Biological and clinical constraints explain why simple intensification of chemo-RT is not a panacea: systemic cytotoxics damage normal rapidly dividing tissues (myelosuppression, mucositis, cardiotoxicity), older and comorbid patients tolerate intensive regimens poorly, and evolving resistance mechanisms (clonal heterogeneity, niche protection, metabolic and anti-apoptotic rewiring) permit early emergence of tolerant subclones. These realities have driven the field toward rational combinations (for example, hypomethylating agents or targeted drugs paired with venetoclax, or targeted agents added to modified induction) and toward using chemo-RT as a cytoreductive backbone rather than the sole curative modality [ 74 ].

Targeted therapies (TKIs, BCL-2 inhibitors, FLT3 inhibitors)

Targeted therapies have transformed the therapeutic landscape of AML, moving treatment beyond non-selective cytotoxic agents toward those that exploit specific oncogenic dependencies. Small-molecule tyrosine kinase inhibitors (TKIs), inhibitors of anti-apoptotic proteins (notably the BCL-2 inhibitor venetoclax), and an expanding family of FLT3-directed drugs now occupy central roles for molecularly defined patient subsets and for older patients who are unfit for intensive chemotherapy [ 75 ]. Midostaurin—an early multitargeted TKI active against FLT3—was the first to show that adding a FLT3 inhibitor to standard induction/consolidation prolongs survival for newly diagnosed FLT3-mutant AML when combined with “7 + 3” chemotherapy, establishing the paradigm of molecularly guided addition of TKIs to cytotoxic backbones. This trial (CALGB 10603/RATIFY) altered practice for younger, fit patients with FLT3 mutations, illustrating both the promise and limitations of first-generation inhibitors (benefit but incomplete suppression of resistant clones) [ 69 ]. For relapsed/refractory disease, selective second-generation FLT3 inhibitors have produced clinically meaningful improvements. Gilteritinib, a potent FLT3 inhibitor with activity against both ITD and many TKD mutants, demonstrated superior remission rates and overall survival compared with salvage chemotherapy in the phase 3 ADMIRAL study, earning regulatory approval and becoming a standard option in FLT3-mutant R/R AML. Other FLT3 agents—including quizartinib—have also shown benefit in R/R settings and are being developed in earlier-line and combination regimens, though their toxicity profiles (for example, QT prolongation with some drugs) and the emergence of resistant FLT3-mutant alleles remain challenges [ 76 , 77 ]. The arrival of venetoclax—an oral BCL-2 inhibitor—has been especially practice-changing for older or unfit patients. In the pivotal VIALE-A phase 3 trial, venetoclax combined with azacitidine produced higher complete remission rates and a meaningful overall survival benefit compared to azacitidine alone in newly diagnosed patients ineligible for intensive chemotherapy, rapidly becoming a new standard of care and prompting a broad investigation of venetoclax combinations across molecular subgroups. Long-term follow-up confirms durable improvement for many patients, though resistance (via MCL-1 upregulation, metabolic rewiring, or TP53-linked biology) is a key translational problem [ 78 ].

Immunotherapies reshaping leukemia care (CAR-T, bispecific antibodies, checkpoint blockade)

Immunotherapy has reshaped expectations for many cancers, and in AML, a diverse suite of immune strategies—CAR-T cells, T–cell–engaging bispecific antibodies, and checkpoint blockade combinations—are being actively developed to convert short remissions into durable cures. Progress has been steady but uneven: unlike B-cell malignancies, AML presents unique biological barriers (antigen overlap with normal hematopoiesis, profound immune suppression in the marrow, and antigenic heterogeneity), so clinical impact to date has been more incremental than transformative [ 79 ].

CAR-T cell therapy

CAR-T approaches in AML have focused on myeloid antigens such as CD33, CD123, and CLL-1 (CLEC12A), and on engineering strategies that try to minimize myeloablation (dual targeting, transient expression, safety switches). Early-phase studies and recent reviews show that CAR-T can induce remissions. Still, durable, broadly reproducible responses are limited by (i) on-target/off-tumor toxicity against normal HSCs, (ii) antigen loss or heterogeneity, and (iii) an immunosuppressive marrow niche that impairs CAR persistence. Newer designs, including combinatorial (AND/OR) targeting, armored CARs, and approaches that spare normal hematopoiesis, are entering trials and improving the therapeutic index in preclinical and small clinical series [ 80 , 81 ].

Bispecific T-cell engagers and antibody constructs

Bispecific antibodies (CD3×myeloid antigen) such as AMG-330 (CD33×CD3) and flotetuzumab (CD123×CD3) recruit endogenous T cells to kill blasts and have generated meaningful responses in relapsed/refractory AML, including durable remissions in subsets of patients. Advantages include immediate off-the-shelf availability and the ability to titrate exposure to manage cytokine release; limits include the need for an intact effector T-cell compartment (which may be dysfunctional after heavy therapy) and the potential for rapid T-cell exhaustion. Preclinical combinations (for example, adding innate immune agonists such as STING activators) can potentiate bispecific efficacy and are under active investigation [ 82 , 83 ].

Checkpoint blockade and immune-restorative combinations

Single-agent PD-1/PD-L1 blockade has produced modest activity in AML, likely due to the fact that antigen presentation and effector function are often impaired, and because multiple inhibitory pathways coexist. More promising signals arise when checkpoint inhibitors are combined with hypomethylating agents or other modulators that enhance tumor immunogenicity; however, randomized data are mixed, and increased immune-related toxicity is a recurring concern. Targeting alternative myeloid-relevant checkpoints, such as TIM-3 (e.g., sabatolimab), is a significant area of focus because TIM-3 is expressed on both exhausted T cells and LSCs, offering a dual immune-restorative and direct antileukemic opportunity. Early TIM-3 combinations show encouraging activity in subsets but require confirmation in larger trials [ 84 ].

Platelets in AML: natural carriers and modulators

Platelets in AML are more than bystanders: they act as dynamic modulators of leukemic biology and—because of their innate cargo-handling and homing properties—represent both a natural vehicle for disease propagation and a promising platform for targeted delivery. Recent studies of extracellular vesicle (EV) signatures in AML patients, mechanistic work on platelet–cell adhesion, and advances in biomimetic nanotechnology together define a dual role for platelets in AML pathophysiology and therapy [ 85 , 86 ]. Platelet–blast aggregates form via selectins and integrins, enabling platelets to physically “cloak” circulating blasts and reduce recognition by innate cytotoxic cells (notably NK cells), a phenomenon well characterized in circulating tumor cell biology and increasingly reported in hematologic contexts. At the same time, activated platelets release dense- and α-granule mediators (e.g., TGF-β, PF4) that reshape local immune responsiveness and can blunt cytotoxic lymphocyte or NK activity [ 87 , 88 ]. Extracellular vesicles—both those released by blasts and platelet-derived EVs (PEVs)—are central effectors. AML patient plasma contains abundant disease-associated EVs with cargoes that promote blast survival, metabolic rewiring, angiogenesis, and chemoresistance; PEVs similarly transfer miRNAs, proteins, and lipids that reprogram myeloid and stromal cells and can reinforce a pro-leukemic niche. Profiling studies that combine single-cell and circulating EV signatures show correlations between specific vesicle populations and poor clinical features, supporting a model in which vesicle exchange is an active axis of AML progression [ 85 , 86 ].

Therapeutic and translational implications fall into two linked categories: (1) disrupting platelet-mediated support for blasts, and (2) exploiting platelets/PEVs as delivery vectors. Targeting the P-selectin/PSGL-1 adhesion axis and selectin-mediated trafficking disrupts platelet–blast tethering and leukocyte recruitment in preclinical models, with clinical precedent in non-malignant diseases (proof-of-concept biologics), suggesting a plausible route to reduce immune shielding or marrow retention of blasts [ 89 , 90 ]. Concurrently, platelet membranes and PEVs have been repurposed to create biomimetic carriers: platelet membrane-coated nanoparticles and engineered platelet constructs prolong circulation, present native adhesion ligands for homing, and can be loaded with small molecules, nucleic acids, or immunomodulators. Several preclinical studies, including membrane-wrapped nanoparticle work specifically applied to AML models, demonstrate enhanced delivery to marrow or tumor sites and an improved therapeutic index in animal experiments, positioning platelet platforms as attractive adjuncts to conventional chemotherapy or targeted agents [ 30 ].

Key challenges must be addressed before clinical translation in AML. These include rigorous demonstration that platelet-based carriers do not inadvertently enhance blast survival or dissemination, establishing scalable GMP workflows for PEV/isolate production and loading, profiling immunogenicity and off-target organ accumulation (spleen, liver, lung), and balancing antileukemic efficacy with thrombo-inflammatory risk. Mechanistic human studies linking platelet/EV biomarkers to response endpoints will be essential to define which patient subgroups might benefit [ 41 , 91 ] (see Fig. 4 ).

Fig. 4 Platelets in acute myeloid leukemia (AML): a dual role as endogenous modulators and biomimetic delivery platforms. A Platelets form stable aggregates with circulating leukemic blasts through selectin‑ and integrin‑mediated adhesion (notably P‑selectin/PSGL‑1 and αIIbβ3‑fibrinogen bridges). These platelet–blast conjugates physically shield blasts from innate immune effectors (e.g., NK cells) and locally deliver α‑granule mediators (TGF‑β, PF4) that suppress cytotoxic responses and promote blast survival. B Reciprocal extracellular vesicle (EV) exchange—involving platelet-derived EVs (PEVs) and blast-derived vesicles—transfers regulatory miRNA, proteins, and lipids to stromal and immune cells, driving metabolic reprogramming, angiogenesis, and chemoresistance within marrow and peripheral niches. Correlative single‑cell and circulating EV profiling link specific vesicle signatures to adverse clinical phenotypes. C Translational strategies follow a two-pronged logic: the interruption of platelet-mediated support (e.g., P-selectin/PSGL-1 blockade, integrin inhibition, or modulation of platelet activation) and the repurposing of platelet membranes/PEVs as biomimetic carriers for the targeted delivery of cytotoxics, nucleic acids, or immunomodulators to marrow and leukemic niches. D Critical safety and translational considerations include thrombo-inflammatory risk, innate immune activation (complement, cytokines, NETosis), and off-target biodistribution; therefore, comprehensive preclinical profiling (coagulation assays, complement and cytokine panels, NET biomarkers, biodistribution imaging) and GMP-grade manufacturing workflows are prerequisites for clinical translation. Collectively, these panels synthesize mechanistic insights and propose actionable intervention points to both dismantle platelet‑mediated leukemic niches and harness platelet biology for targeted AML therapies

Platelet–blast interactions and their role in disease progression

Platelets engage in bidirectional crosstalk with leukemic blasts that extends beyond hemostasis to actively shape disease biology. Leukemia-driven platelet abnormalities (quantitative and qualitative) are well documented, and platelets in turn modulate blast survival, proliferation, and chemoresistance through direct contact, secretion of growth factors and cytokines (e.g., TGF-β), and transfer of platelet-derived extracellular vesicles and microRNAs that reprogram blast behavior [ 92 , 93 ]. Mechanistically, platelets can physically “cloak” circulating blasts, limiting recognition and killing by innate immune effectors (notably NK cells) and thereby promoting immune evasion—an axis first characterized in solid-tumor metastasis that has growing evidence in hematologic malignancies. Platelet granule contents (α-granule proteins, TGF-β) and surface adhesion receptors (P-selectin, integrins) facilitate the formation of stable platelet–blast aggregates, creating a local immunosuppressive niche that favors blast persistence. Concurrently, platelet–blast interactions can alter the marrow and systemic tumor microenvironment (cytokine milieu, myeloid cell programming), which supports leukemic stem cell survival and may blunt responses to cytotoxic therapy [ 93 ]. Clinically, combined measures of platelet indices and peripheral blast counts carry prognostic information: dynamic platelet trajectories during induction and baseline platelet counts have been associated with treatment response and survival in acute leukemias, suggesting that platelet–blast biology influences—and may be reflected in—simple laboratory readouts. These observations suggest that targeting platelet–blast interfaces (by blocking platelet adhesion receptors, modulating platelet activation, or intercepting platelet-derived vesicle signaling) could enhance anti-leukemic therapy or reduce the risk of relapse [ 94 , 95 ]. In summary, platelet–blast interactions are multifaceted contributors to leukemia progression, providing physical protection, paracrine pro-survival signaling, and microenvironmental remodeling. Translating mechanistic insights into targeted interventions and validating platelet-based biomarkers remain priority areas for future preclinical and clinical investigation [ 92 , 96 ].

P-selectin/PSGL-1 axis as a therapeutic target

The P-selectin/PSGL-1 interaction is a central adhesion and signaling node that links activated platelets and endothelium to leukocytes and tumor cells, rapidly forming multicellular aggregates that shape inflammation, thrombosis, and the tumor/leukemia microenvironment. Mechanistically, P-selectin translocates to the platelet surface or endothelial Weibel–Palade bodies upon activation and binds to sialofucosylated PSGL-1 on leukocytes and tumor cells, triggering adhesive tethering, outside-in signaling, and the local release of immunomodulatory mediators that promote cell survival and trafficking [ 89 ]. Because this axis both mediates harmful cell–cell shielding (e.g., platelet cloaking of circulating tumor or blast cells) and amplifies inflammatory circuits (including NET formation), it has attracted therapeutic interest across disciplines—from vaso-occlusive disease to oncology and thrombosis. Preclinical work shows that blocking P-selectin/PSGL-1 disrupts platelet–leukocyte aggregates, reduces leukocyte recruitment and NETosis, and can sensitize tumors in models to immune or cytotoxic therapies [ 89 , 97 ]. Clinical translation has already begun: crizanlizumab, a humanized anti–P–selectin antibody approved for sickle cell disease, provides proof of principle that P-selectin blockade can reduce pathologic cell adhesion and clinical events in humans. Ongoing studies continue to refine safety, patient selection, and combinatory uses. At the same time, newer strategies are emerging beyond ligand blockade—including PSGL-1–directed antibodies that reverse immune suppression and enhance the antitumor activity of macrophages or T cells, and selectin-based targeted delivery systems that exploit this axis for drug or imaging payload delivery [ 98 , 99 ].

A recent advance in hematologic malignancies has identified PSGL-1 as an immune checkpoint-like regulator of phagocytosis and T-cell function. Antibody or genetic disruption of PSGL-1 in preclinical models enhanced macrophage-mediated clearance and improved responses to chemotherapy and checkpoint combinations, positioning PSGL-1 blockade as both an anti-adhesive and an immunotherapeutic strategy. These data suggest dual opportunities: [ 1 ] interrupt adhesion-mediated protection of malignant cells and [ 2 ] reprogram immune checkpoints to restore antitumor immunity [ 100 , 101 ].

Platelets as immune modulators and drug carriers

Platelets are no longer viewed solely as cellular mediators of hemostasis—they are dynamic immune sentinels that actively shape innate and adaptive responses, modulate inflammation, and remodel tissue microenvironments. Platelets sense vascular and pathogen-associated signals through surface receptors (P-selectin, GPIb, integrins, CLEC-2), rapidly secrete a broad spectrum of cytokines/chemokines (e.g., PF4, TGF-β), and release abundant platelet-derived extracellular vesicles (pEVs) that carry proteins, lipids, and regulatory RNAs—together, these mechanisms place platelets at the intersection of thrombosis, immunity, and tissue repair [ 102 , 103 ].

Mechanistically, three complementary modalities explain how platelets reprogram immune responses. First, direct adhesive contacts and receptor-mediated signaling (P-selectin–PSGL-1, integrin interactions) rapidly recruit and modulate leukocytes, altering trafficking and activation thresholds. Second, dense- and α-granule cargoes deliver soluble immunomodulators locally (for example, TGF-β that suppresses cytotoxic lymphocytes). Third, pEVs act as potent intercellular messengers, transferring miRNAs, signaling proteins, and even mitochondrial components to recipient cells, thereby reprogramming myeloid phenotypes, affecting dendritic cell function, and influencing T-cell and NK-cell responses. The net effect can be either immunostimulatory (host defense, wound healing) or immunosuppressive (tumor and blast immune evasion), context dependent [ 104 ]. In cancer and hematologic malignancies, the “platelet cloak” model has robust experimental support: platelets adhere to circulating tumor or blast cells, transfer adhesive and immune-modulatory molecules, and physically mask malignant cells from NK- and T-cell recognition—a mechanism tied to enhanced survival in circulation and to metastatic seeding. These platelet–tumor (or platelet–blast) aggregates also deposit pro-survival factors and EVs that promote resistance to apoptosis and chemotherapeutics, making platelets active facilitators of disease progression rather than passive bystanders [ 105 ].

Conversely, the same biological traits that enable platelets to shield and modulate cells have inspired their repurposing as delivery platforms. Native pEVs and engineered platelet membrane vesicles can be loaded with small molecules, nucleic acids, or immunomodulators and exploit inherent targeting motifs to home to injured endothelium, thrombi, or tumor vasculature—improving local drug concentration while reducing systemic exposure. Parallel biomimetic strategies coat synthetic nanoparticles with platelet membranes (or hybrid platelet/erythrocyte membranes) to confer immune evasion, prolonged circulation, and specific adhesion properties; several preclinical reports show enhanced tumor or plaque targeting and therapeutic benefit in mouse models [ 106 , 107 ]. Despite promising proof-of-principle, translation faces practical and safety hurdles, including the need for scalable and reproducible isolation and loading of pEVs, batch-to-batch membrane quality control, potential prothrombotic or immunosuppressive side effects, and the careful balancing of carrier targeting versus unintended facilitation of malignant dissemination. Addressing manufacturability (good manufacturing practice pipelines), rigorously profiling immunogenicity, and pairing delivery platforms with mechanism-based patient selection (for example, vascular-targeted therapy in highly platelet-interactive tumors) are essential next steps [ 108 , 109 ]. While these preclinical data are encouraging , it is important to emphasize that conventional animal models have recognized limitations that can impede clinical translation—including interspecies differences in immune biology and pharmacokinetics , limited fidelity of xenografts to the human leukemic niche , and variable engraftment of primary AML samples [ 110 ].

In conclusion, platelets embody a dual translational opportunity: as critical endogenous regulators of immunity, they reveal mechanisms of disease progression that can be therapeutically interrupted, and as biomimetic carriers, they offer a biocompatible route to targeted delivery. The coming years should prioritize mechanistic human studies that link platelet biomarkers to treatment response, controlled preclinical safety studies of platelet-derived carriers, and early clinical trials that test whether intercepting platelet–immune interfaces improves outcomes when combined with chemotherapy or immunotherapy [ 91 , 111 ].

Neutrophils in AML: beyond innate immunity

Neutrophil dysfunction in AML and implications for therapy

AML profoundly remodels granulopoiesis and neutrophil function, producing a spectrum of defects that go beyond simple neutropenia to include arrested maturation, altered functional competence, skewed neutrophil phenotypes, and dysregulated neutrophil extracellular trap (NET) biology—all of which have direct clinical consequences for infection risk, thrombosis, immune surveillance, and responses to therapy [ 112 ]. AML blasts and the leukemic marrow microenvironment suppress normal hematopoietic differentiation and frequently induce emergency granulopoiesis programs that release immature neutrophil forms into the circulation. Single-cell transcriptomic and functional studies now document that many neutrophils exposed to the AML milieu are incompletely matured (transcriptionally immature, with abnormal granule enzyme profiles and impaired degranulation), which both reduces antimicrobial competence and alters intercellular signaling in the tumor microenvironment. These immature/low-density granulocyte (LDG) populations can exhibit immunoregulatory properties distinct from those of mature neutrophils [ 112 , 113 ]. Several integrated multi-omics analyses report that NET formation is frequently impaired in patients with AML. This deficit helps explain the high rates of life-threatening infection seen during disease and treatment. At the same time, NETs (when formed) have been implicated in promoting thrombosis, protecting malignant cells from immune clearance, and modulating tumor metabolism in other malignancies—producing a duality in which deficient NETosis increases infectious vulnerability while aberrant or focal NET activity may fuel complications (thrombosis, therapy resistance) in selected settings. Thus, NET biology in AML is heterogeneous and must be interpreted in patient- and context-specific terms [ 114 , 115 ]. Molecular drivers and biomarkers, including transcriptional programs (such as those driven by oncogenic mutations like IDH1, which can repress neutrophil maturation) and altered cytokine signaling in the marrow niche, as well as AML-derived extracellular vesicles, combine to rewire neutrophil development and function. Bioinformatic and gene-signature studies show that NET- and neutrophil-related gene sets correlate with prognosis and immune landscape features in AML cohorts, suggesting both mechanistic links and possible biomarker utility for risk stratification [ 116 ].

Translational and practical challenges: moving from concept to clinic requires (i) robust, standardized assays of neutrophil function, maturation and NET activity (to permit patient selection and on-treatment monitoring), (ii) careful safety evaluation because neutrophil suppression can increase infections, (iii) GMP-grade reagents for NET-modifying therapies and clear stopping rules, and (iv) mechanistic human studies linking neutrophil phenotypes to clinical endpoints (infection, thrombosis, remission/relapse) to avoid unintended harms [ 112 , 115 ].

Potential for neutrophil-mediated drug delivery to bone marrow

Neutrophils are emerging as attractive cellular “shuttles” for delivering therapeutics to the bone marrow because of two biologic facts: (1) neutrophils naturally traffic between blood and marrow (and aged/“senescent” neutrophils preferentially return to marrow under CXCL12/CXCR4 guidance), and (2) neutrophils avidly take up particulate cargos or can be used to carry membrane-coated/biomimetic nanoparticles that preserve targeting motifs. These properties have been deliberately exploited in recent preclinical work to reroute small molecules and nanoparticle payloads across the marrow–blood barrier and concentrate them inside bone marrow niches [ 29 , 117 ]. Strategies fall into three technical categories that have appeared in the literature: (A) cellular hitchhiking—incubating drug-loaded nanoparticles with autologous neutrophils (or with neutrophils aged in vitro) so the cells internalize or adsorb particles and then naturally home to marrow where particles are released; (B) membrane camouflaging / neutrophil-coated nanoparticles—wrapping synthetic nanoparticles with neutrophil plasma membranes to inherit adhesion molecules and chemokine receptors that direct vascular margination and marrow access; and (C) EV-based approaches—using neutrophil-derived extracellular vesicles (or engineering EVs) as intrinsically biocompatible carriers that can penetrate marrow microenvironments. Each approach leverages neutrophil trafficking cues (notably CXCR4–CXCL12 gradients, changes in L-selectin/CD62L, and integrin display with cell age/activation) to bias delivery to the marrow compartment [ 29 , 40 ]. Multiple groups have shown robust marrow enrichment of therapeutics using neutrophil hitchhiking or neutrophil-inspired coatings. Notable demonstrations include the adoptive transfer of nanoparticle-loaded (aged) neutrophils to deliver chemotherapeutics or bone-anabolic drugs to the marrow in mouse models, and neutrophil-membrane-camouflaged nanoparticles that preferentially accumulate at marrow and inflamed bone sites, with improved efficacy compared to free drug. These studies report increased drug concentration in marrow, improved control of bone metastasis or enhanced osteogenic responses, and reduced systemic exposure in preclinical models [ 29 , 118 ]. Therefore, in addition to orthotopic and systemic rodent studies, we recommend orthogonal validation using patient-derived xenografts, humanized models, and relevant ex vivo human stromal co-culture systems to better assess efficacy and safety prior to clinical translation, and to reduce the well-documented attrition between animal studies and human trials [ 119 ].

Therapeutic opportunities are particularly relevant to hematology/oncology and bone disease. Neutrophil-mediated delivery could (a) increase the marrow bioavailability of chemotherapeutics for marrow-resident malignancies (e.g., AML, myeloma) while lowering systemic toxicity; (b) concentrate bone-active agents (anabolics, antiresorptives, radiopharmaceuticals) for osteoporosis or bone metastasis; and (c) serve as a means to deliver immunomodulators or gene vectors into niche stromal or malignant cell populations that are otherwise difficult to reach. Early preclinical results suggest proof of concept across these use cases [ 29 ]. Neutrophil platforms combine (1) natural homing (no need for synthetic targeting ligands) (2), biocompatibility (autologous cells or cell-derived membranes/EVs), and (3) the capacity to cross physiological barriers (the marrow sinusoidal endothelium) that limit many nanoparticles. Membrane-coated particles also inherit “self” signals that can reduce rapid clearance and prolong circulation, further promoting marrow delivery [ 40 , 118 ].

Significant translational challenges and safety considerations

Neutrophil-based delivery strategies face several intrinsic translational hurdles, beginning with the short lifespan of circulating neutrophils. These cells persist in the bloodstream only for hours to days, necessitating careful timing for ex vivo manipulations or consideration of aged/subset neutrophils with predictable marrow tropism to ensure effective delivery [ 120 ].

A second key consideration is the balance between loading efficiency and cell functionality. High payloads can compromise neutrophil viability, chemotactic responsiveness, or barrier-crossing ability, making it essential to optimize particle loading while preserving core cellular functions [ 29 ]. Closely linked is the risk of inadvertent neutrophil activation, which can trigger degranulation, NETosis, or vascular occlusion. Engineered carriers must therefore be carefully designed to avoid pro-thromboinflammatory responses that could exacerbate patient risk [ 40 ]. Analogous risk-mitigation frameworks from other advanced therapeutic platforms offer instructive precedents. For example, in chimeric antigen receptor (CAR)-T cell therapy, the early recognition of cytokine-release-associated coagulopathy led to implementation of proactive monitoring algorithms and pre-emptive intervention protocols—such as early interleukin-6 blockade and thrombo-inflammatory biomarker tracking—which have markedly reduced severe coagulopathic events in clinical practice [ 121 , 122 ]. Similarly, the thrombotic and complement-activation risks observed with liposomal or platelet-mimetic nanoparticle carriers have been mitigated through surface-charge tuning, PEGylation, and antiplatelet co-formulations, approaches that have now advanced to Phase I–II evaluation with favorable safety readouts [ 123 , 124 ].

Neutrophil-mediated delivery also carries context-dependent tumor-promoting risks. In certain microenvironments, neutrophils may support malignant cell survival, dissemination, or immune evasion, necessitating rigorous preclinical evaluation to ensure that therapeutic carriage does not inadvertently enhance disease progression [ 125 ]. In parallel, early clinical translation is shaped by significant manufacturing and regulatory challenges. Handling autologous cells, producing extracellular vesicles or membrane-coated particles under GMP conditions, and ensuring sterility and batch consistency represent substantial operational barriers [ 40 ].

To address these challenges, near-term study designs should incorporate several key strategies. First, functional readouts of neutrophil chemotaxis, viability, and marrow homing should be rigorously assessed when optimizing payload load and incubation conditions. Second, comparative evaluation of autologous cell hitchhiking versus acellular membrane-coating approaches can help determine the most suitable platform for a given therapeutic payload and indication. Third, safety endpoints—including thrombosis, systemic inflammation, and effects on tumor biology—must be integrated into preclinical oncology models. Finally, pharmacodynamic measurements within marrow (e.g., local drug concentration, target engagement, and effects on malignant or stromal cells) should complement traditional biodistribution studies to provide actionable translational insights. Several recent methodological studies provide detailed protocols and comparative data to guide these experimental designs [ 29 , 40 ] (see Fig. 5 ).

Fig. 5 Pathogenic and Therapeutic Roles of Neutrophils in AML: NETs, Thrombosis and Delivery Strategies. A In AML, leukemic blasts and a rewired bone-marrow niche (e.g., IDH1/2 mutations, altered cytokine milieus, AML-derived extracellular vesicles) disrupt granulopoiesis, producing arrested-maturation neutrophils and low-density granulocytes (LDGs) with altered granule composition and transcriptional immaturity. B These AML-exposed neutrophils show reduced maturation markers (CD10/CD16), abnormal granule enzyme distribution (MPO/NE), impaired degranulation and oxidative burst, and context-dependent NET biology—diminished stimulus-induced NETosis in immature cells (increasing infection risk) versus focal or dysregulated NETs in marrow/vascular niches that are prothrombotic, immune-shielding and metabolically active—clinically associating with infection, thrombosis and variable therapy response. C Translational opportunities exploit neutrophil trafficking to target the marrow by: (i) cellular “hitchhiking” with autologous neutrophils loaded ex vivo with drugs/NPs, (ii) EV-based carriers for cargo transfer, and (iii) neutrophil-membrane-camouflaged or neutrophil-coated nanoparticles that confer homing/“self” markers—each approach requiring preservation of chemotaxis (CXCR4/CXCL12), viability and function and head-to-head comparison with free drug. D Key translational challenges are short neutrophil lifespan, loading-vs-function trade-offs, NETosis/thrombosis and context-dependent tumor risks, and manufacturing/regulatory hurdles; we therefore recommend a staged workflow—particle/carrier physicochemical QC, in-vitro loading optimization with standardized functional panels (maturation markers, chemotaxis, phagocytosis, ROS), comprehensive NET/thrombosis testing (CitH3, MPO–DNA, microscopy, platelet activation/thrombin assays), in-vivo biodistribution and marrow PD, predefined safety endpoints/stopping rules, and GMP-grade manufacture with prospective mechanistic human correlative studies linking neutrophil phenotype to infection, thrombosis and clinical outcomes

Harnessing neutrophil homing and trafficking pathways

Neutrophil trafficking is governed by a concise set of conserved molecular cues—chemokine receptors, selectins, and integrins—that collectively control release from the bone marrow, vascular margination, tissue entry, and programmed return to the marrow for clearance. The CXCL12 (SDF-1)/CXCR4 axis is the dominant signal that retains and re-recruits senescent neutrophils into the bone marrow, while CXCR1/CXCR2 and their ELR⁺ CXC ligands (CXCL1/2/5/8) direct emergency mobilization and tissue recruitment; selectin-dependent rolling and integrin activation control the early adhesive steps and transendothelial migration. Understanding and manipulating these nodes provides both (a) levers to alter neutrophil distribution for therapeutic benefit and (b) biologic routes to use neutrophils themselves as delivery vectors [ 117 , 126 ]. Antagonizing CXCR4 (e.g., plerixafor) rapidly mobilizes marrow-resident leukocytes and stem/progenitor cells by disrupting the retention mediated by CXCL12. Conversely, transient CXCR4 upregulation on aged neutrophils serves as the physiologic cue for marrow homing and can be exploited to route cargo-loaded cells back to marrow niches. CXCR2 antagonists inhibit neutrophil influx into tumors and inflamed tissues, and are being investigated as modulators of tumor-associated neutrophil biology. Importantly, CXCR2 and CXCR4 often act antagonistically to regulate neutrophil egress versus return, so combining selective modulation can tune net trafficking [ 117 ]. L-selectin (CD62L) shedding, endothelial E- and P-selectin engagement, and subsequent integrin activation determine whether a circulating neutrophil will roll, arrest, and extravasate. Therapeutic strategies include the temporary blockade of selectin interactions to reduce pathologic infiltration (or to prevent off-target capture of neutrophil-carried payloads) and engineering nanoparticle surfaces to mimic or avoid selectin/integrin ligands, depending on whether one wants to capture at inflamed endothelium or preserve circulation for marrow homing. Mechanistic studies of selectin-mediated signaling show that altering L-selectin dynamics can profoundly change transmigration and tissue targeting [ 127 ]. Two complementary translational strategies exploit trafficking for therapy: (1) route neutrophils as carriers (hitchhiking/membrane-camouflage) and (2) remodel neutrophil distribution or activity to change disease biology. The first approach utilizes either (A) ex vivo loading of autologous neutrophils with drug nanoparticles (or adsorbing particles onto neutrophil surfaces) that then home back to the marrow or inflamed tissues, or (B) neutrophil-membrane-coated nanoparticles that inherit chemokine and adhesion receptors to achieve the desired margination/homing. Convincing preclinical demonstrations—most notably the “neutrophil hitchhiking” studies—show markedly increased drug concentration in bone marrow and therapeutic benefit in bone and marrow disease models [ 9 , 29 ].

The second approach targets neutrophil trafficking to alter pathology: CXCR2 inhibitors (and CXCR1 blockers) are being trialed to limit protumor neutrophil infiltration or to reduce neutrophil-driven immunosuppression; transient CXCR4 modulation can be used either to mobilize cells (improving accessibility to therapies) or to enhance marrow homing (for targeted delivery). Early clinical and translational studies suggest that modulating chemokine receptors can alter the intratumoral myeloid composition and improve the sensitivity of tumors to other treatments; however, these interventions require careful timing and biomarker-guided patient selection, as neutrophils are also crucial for host defense [ 128 , 129 ].

While recruitment of neutrophils to the bone-marrow niche may enhance delivery and local efficacy of hitchhiking approaches, it also raises the risk of promoting immunosuppressive neutrophil phenotypes (e.g., N2-like TANs or PMN-MDSC) that can inhibit T-cell responses and facilitate leukemic persistence. Studies of neutrophil plasticity and tumor-associated neutrophils document this duality and show that microenvironmental cues can rapidly shift neutrophil function toward immunosuppression [ 130 ]. Therefore, translational strategies should explicitly balance transient recruitment (to deliver payloads) with mechanisms to avoid sustained infiltration or functional reprogramming—for example by (i) timing delivery to minimize prolonged marrow retention, (ii) co-monitoring neutrophil phenotype in marrow and blood (surface markers, PD-L1, low-density neutrophil/MDSC signatures), and (iii) measuring functional immune readouts (ex vivo T-cell proliferation assays, cytokine panels) as safety/pharmacodynamic endpoints. These readouts have been used to detect immunosuppressive neutrophil populations in cancer and AML and should be incorporated into preclinical and early-phase clinical evaluations of neutrophil-based delivery [ 131 – 133 ].

Practical translation demands attention to timing (neutrophil half-life and circadian trafficking), payload burden (overloading impairs chemotaxis and viability), activation status (avoid triggers of degranulation/NETosis that cause off-target inflammation or thrombosis), and infection risk (trafficking suppression can increase susceptibility). For carrier approaches, compare living-cell hitchhiking versus acellular membrane/EV platforms: living cells can actively home and release cargo, but are short-lived and more brutal to standardize; membrane-coated particles are more controllable, yet may lose active transcellular transport behaviors. GMP workflows, functional quality-control assays (chemotaxis, CXCR4/CXCR2 responsiveness, and L-selectin expression), and early safety endpoints (thrombosis, pulmonary sequestration, and systemic inflammation) should be integrated into preclinical-to-first-in-human pipelines [ 9 , 134 ].

Concept of cellular hitchhiking in hematologic malignancies

Definition and principles of platelet/neutrophil hitchhiking

Platelet–neutrophil hitchhiking describes a set of biological and bioengineering phenomena in which therapeutic cargos (nanoparticles, drugs, imaging agents) or even other cells piggyback on endogenous platelet–neutrophil interactions or on neutrophils/platelets themselves to travel from the blood to specific tissues. In the biomedical-engineering sense, “hitchhiking” can be achieved in two main ways: (1) adsorption-mediated hitchhiking, where particles bind to the outer membrane of circulating cells (platelets, neutrophils, erythrocytes) and are carried passively until they detach at the target site; and (2) internalization-mediated hitchhiking, where cargos are taken up into leukocytes (often neutrophils or monocytes) and are actively transported as the cell migrates to inflamed or tissue-specific niches. Both approaches utilize the natural trafficking and effector functions of blood cells to enhance delivery efficiency and minimize rapid clearance [ 135 , 136 ]. Platelets and neutrophils form intimate physical and functional units in circulation—platelet P-selectin binding to neutrophil PSGL-1, platelet integrin/ICAM interactions, and chemokine gradients (CXCR2/CXCR4 axes) drive platelet–neutrophil aggregate formation, neutrophil activation, and directed extravasation to inflamed tissues. These same receptor–ligand pairs and chemotactic cues that recruit neutrophils to sites of injury or specific organs are what engineers aim to exploit: either by decorating nanoparticles with ligands that preferentially bind to activated platelets or neutrophils, or by designing particle properties that favor adsorption to the cell membrane under flow conditions. In physiological settings, platelets can also act as “bridges,” concentrating neutrophils at vascular walls and catalyzing NET formation; in hitchhiking systems, this association may be harnessed to steer cargo-bearing cells into tissues [ 137 , 138 ].

Physical and engineering principles that determine success. Key parameters include particle size, shape, surface chemistry (ligands, charge, stealth coatings), and the mechanical shear environment: (a) small, flexible particles or those with biomimetic membranes more readily remain attached to cell membranes under shear; (b) multivalent ligand presentations (heteromultivalency) increase selective binding to activated platelet–neutrophil complexes; and (c) internalization versus surface-attachment balances retention (internalization protects cargo but risks intracellular degradation) against fast release (surface-attached cargo can detach at the target). Computational and in vitro shear-flow studies demonstrate that higher shear rates favor desorption unless adhesion strength or multivalent interactions are engineered accordingly, making the vascular geometry and injection site essential design considerations [ 135 , 136 ].

Recent high-impact demonstrations include neutrophil-mediated rerouting of nanoparticles to the bone marrow [ 9 , 29 ], neutrophil-assisted delivery across restrictive barriers such as the inflamed CNS and lung [ 139 , 140 ], and multiple examples of platelet-inspired or platelet-membrane-coated particles that concentrate therapeutic payloads at vascular lesions via P-selectin/PSGL-1 and related adhesion pathways [ 141 , 142 ]. These studies demonstrate improved tissue accumulation and functional benefits in disease models (e.g., bone metastasis, ischemia-reperfusion, sepsis), as well as the feasibility of both ex-situ cell engineering (loading cells and then re-infusing them) and in-situ approaches (injecting NPs that selectively bind to endogenous neutrophils/platelets) [ 29 , 143 ]. Hitchhiking leverages endogenous homing to reduce off-target clearance and increase the effective dose at disease sites, while avoiding some of the manufacturing burdens associated with fully engineered cell therapies. But there are important caveats: binding to active neutrophils or platelets can inadvertently trigger cell activation, NETosis, or thrombosis; intracellular carriage risks cargo degradation; and heterogeneity of cell activation between patients complicates predictability. Additional translational hurdles include the immunogenicity of nanoparticle coronas, scale-up reproducibility, and the need to precisely balance adhesion strength so that cargo release occurs at the desired tissue rather than prematurely or at non-target vascular beds. Several recent reviews outline these trade-offs and propose standardized in vivo screening strategies to assess safety and biodistribution [ 144 ].

Comparative considerations: platelet- versus neutrophil-based hitchhiking for marrow delivery in AML

Although both platelet- and neutrophil-based hitchhiking strategies share the goal of amplifying intra-marrow drug exposure, they differ in targeting biology, practical constraints, and predictable safety trade-offs that determine their suitability for particular AML contexts. Mechanistically, neutrophil-based platforms exploit a physiologic CXCL12–CXCR4 trafficking axis by which senescent/CXCR4 hi neutrophils re-enter the bone marrow; several recent preclinical studies demonstrate that neutrophils (or neutrophil-inspired coatings) can ferry internalized or adsorbed nanoparticles across the marrow–blood barrier and markedly increase marrow drug concentration (proof-of-principle increases in marrow AUC of several-fold have been reported) [ 145 ]. By contrast, platelet-based carriers (intact platelets, platelet-derived EVs, or platelet-membrane-coated nanoparticles) localize through adhesive interactions with activated endothelium and platelet–blast aggregates; platelet membranes additionally confer immune-camouflage and typically prolong systemic circulation, which can be advantageous when sustained exposure or adhesion to blast–endothelial interfaces is desired [ 146 ].

Host hematologic status strongly conditions platform performance. AML-associated thrombocytopenia and qualitative platelet defects may reduce the yield and functional competence of autologous platelet carriers, whereas neutropenia or dysfunctional granulopoiesis after induction or during cytotoxic therapy can limit neutrophil availability and alter trafficking behavior; these disease-dependent variables argue that carrier selection should be matched to the clinical setting (e.g., newly diagnosed versus post-induction, candidate for autologous versus allogeneic/acellular approaches) [ 147 ]. Safety profiles differ in predictable ways. Platelet carriers raise concern for activation-dependent procoagulant events and thrombo-inflammation if platelets are inadvertently activated during processing or in vivo; neutrophil carriers carry risks of NETosis, immunosuppressive myeloid reprogramming, and immunothrombosis if recruitment or activation is excessive. Both approaches therefore require standardized preclinical panels for coagulation, platelet activation and NET biomarkers prior to translation [ 148 ].

From a translational standpoint, platelet-membrane or PEV-based approaches are generally more amenable to same-day, minimal-manipulation autologous workflows, whereas living-cell neutrophil strategies confront the short neutrophil half-life and sensitive handling requirements that demand rapid processing or alternative acellular solutions (membrane-coated nanoparticles or engineered EVs) to ease logistics and GMP implementation [ 146 ]. Finally, direct head-to-head efficacy and safety data in AML-specific in vivo models (matched PDX or syngeneic AML systems) remain sparse. We therefore recommend standardized comparative preclinical studies that measure identical PK/PD endpoints (bone-marrow C_max and AUC by validated LC-MS/MS), cellular efficacy (blast reduction, remission rates, relapse incidence), biodistribution, and comprehensive safety panels (coagulation, platelet activation, NET markers, cytokines). Until such data are available, carrier choice should be guided by disease biology, host hematologic reserve, payload kinetics, and rigorous preclinical safety testing.

Lessons from solid tumor applications

Platelet- and neutrophil-hitchhiking have moved from proofs-of-concept to sophisticated preclinical tumor models. Reviews indicate enhanced tumor delivery, immune modulation, and an improved therapeutic index; however, recurring technical and biological hurdles limit consistent performance [ 149 , 150 ]. First successful tumor targeting with platelet-based systems typically exploits biologic cues that are consistently exposed in many solid tumors—endothelial disruption, exposed subendothelial collagen, and local coagulation—so platelet-derived coatings or platelet-conjugated payloads can accumulate by homing to these features rather than relying solely on enhanced permeability. Similarly, neutrophil-based approaches rely on inflammation cues (chemokine gradients, surgical or therapy-induced sterile inflammation) to recruit carrier cells into tumor beds; engineering must therefore match the carrier strategy to the tumor’s biology (e.g., immune-hot vs. immune-cold, post-surgical residual disease). Representative platelet-conjugate systems and reviews describe both membrane-coated nanoparticles and platelet-conjugated prodrugs as two viable mechanistic routes [ 150 , 151 ].

Second, cargo handling and release kinetics are critical trade-offs. Surface-adsorbed cargo (ex vivo platelets “decorated” with drug or nanoparticle) benefits from easy loading and rapid target exposure, but risks premature shedding in high shear or during nonspecific adhesion. Internalization (loading into neutrophils or other leukocytes) protects payloads during circulation but raises concerns about intracellular degradation, delayed release, and possible functional impairment of the carrier cell. Recent reports with neutrophil-carried nanocrystals and engineered CAR-neutrophils show promising tumor penetration and efficacy in models (including brain tumors). Still, they also emphasize careful selection of carrier loading methods (nanocrystal vs. encapsulated drug) to preserve both carrier viability and timely release [ 36 , 152 ]. Third, the tumor microenvironment (TME) both enables and limits hitchhiking. Tumor heterogeneity in vascular integrity, stromal density, and chemokine expression results in significant inter-tumor and intra-tumor variation in carrier recruitment. Platelet-hitchhiking platforms that leverage coagulation or collagen exposure can self-amplify at sites of vascular disruption, thereby improving local retention. However, tumors with dense stroma or poor perfusion may still resist adequate carrier infiltration. Several studies, therefore, pair hitchhiking with local priming strategies—mild vascular disrupting agents, low-dose irradiation, or surgery—to increase carrier recruitment [ 151 , 153 ]. Fourth, safety signals cannot be an afterthought. Binding or activating platelets and neutrophils can inadvertently trigger thrombosis, platelet degranulation, NET formation, or systemic inflammation—outcomes that are particularly dangerous in cancer patients who are already prone to thrombo-inflammatory conditions. Recent preclinical work explicitly addresses NET formation as both a potential mechanism of tumor targeting and a risk factor, and some designs incorporate NET-inhibitory elements or tuned adhesion strengths to avoid pathological activation. These safety trade-offs are a recurring theme in reviews and targeted studies. They must be assessed in robust coagulation and inflammation panels before moving to large animal or human studies [ 154 , 155 ]. Fifth, manufacturing and regulatory translation require standardization of biological inputs. Platelet-membrane coatings and autologous cell carriers introduce donor variability (activation state, surface proteome, storage stability) that complicates reproducibility. Reviews of biomimetic nanoparticles emphasize the importance of standardized isolation, characterization (including surface markers and protein corona analysis), and functional assays (such as adhesion under shear and release kinetics) to meet regulatory expectations and ensure batch-to-batch comparability. Parallel efforts in scalable membrane-coating and GMP-compatible loading methods are emerging, but remain a bottleneck for clinical translation [ 150 , 156 ].

From these observations, several practical recommendations emerge for groups translating hitchhiking to solid tumors: (1) select the hitchhiking axis (platelet vs. neutrophil) that aligns with the tumor’s dominant biological cues; (2) design cargo-carrier interfaces to balance retention versus timely release under physiological shear; (3) incorporate inflammation- or coagulation-priming strategies only when supported by safety data; (4) build standardized in-vitro shear and ex-vivo human blood assays early in development; and (5) actively measure pro-thrombotic/NETosis biomarkers in efficacy studies. Consolidated methodological and review articles illustrate these points, providing protocols and comparative data to operationalize them [ 151 ] (See Table 1 ).

Table 1 Design parameters & QC for Marrow-Targeted Platelet/Neutrophil platforms Parameter/Design element Target/options Matters Recommended QC / assay Safety risks & mitigations Carrier choice Platelet, Neutrophil, Membrane-coated NP, EV Sets tropism, lifespan, and active versus passive delivery. Viability; membrane proteome; circulation T½. Platelets→thrombosis; Neutrophils→NETosis/infection. Minimize activation. Loading mode Surface adsorption versus internalization Controls protection versus release timing and carrier function. Imaging (localization); release kinetics; lysosomal degradation. Surface→shedding; Internal→impaired chemotaxis. Limit load. Size/mechanics Diameter, shape, deformability (e.g., 50–200 nm; soft) Affects attachment under shear, margination, and extravasation. DLS/NTA; AFM; flow margination assays. Too large/rigid→detachment or emboli. Limit size. Surface chemistry/stealth PEG, zwitterions Extends circulation, reduces clearance & immunogenicity. serum stability; complement (C3a, CH50). Incomplete stealth→rapid clearance, complement activation. Ligand identity & density P-selectin/PSGL-1 mimics, CXCR4 ligands, aptamers, Abs Tunes adhesion strength and selectivity. Ligand quantification; SPR/BLI; shear-flow adhesion. High density→activation/aggregation; low→desorption. Dynamic linkers/triggers Shear-sensitive, enzyme-cleavable, pH/ROS responsive Enables niche-specific release; reduces off-target release. Shear rupture; enzyme cleavage; conditional release assays. Poor tuning→premature or no release. Use multi-cue linkers. Receptor / chemotactic compatibility Preserve CXCR4/CXCR2/L-selectin; avoid blocking Maintains homing and migration capacity. Flow cytometry for receptors; chemotaxis assays. Receptor perturbation→loss of homing, infection risk. Payload chemistry & stability Small molecule, prodrug, siRNA, EV, NP core Determines intracellular fate and PD in marrow. Stability in lysate; intracellular release; target engagement PD. Labile payloads lost; toxic payloads harm the carrier/host. Use prodrugs/controlled release. Shear & vascular geometry Design for arterial→capillary→sinusoidal shear profile Shear affects desorption and activation; marrow sinusoids have low shear. Microfluidic shear profiles; ex vivo blood perfusion. Ignoring shear→premature shedding or emboli. Optimize injection route. Dose & payload per cell Minimal effective load; define max per cell/particle Overload impairs function and increases the risk of activation. Dose–response for chemotaxis, viability, activation, and NETosis. Excess →NETosis, thrombosis, impaired trafficking. Manufacturing & donor variability (GMP) Standardize isolation, coating, storage; document donor state Donor heterogeneity causes batch variability. Batch QC: activation index, marker panel, sterility, endotoxin. Variability →inconsistent safety/efficacy. Set acceptance criteria. Preclinical safety panel Thrombosis, NET markers, cytokines, coagulation, and organ histology Detect thrombo-inflammatory or sequestration risks preclinically. Thrombin gen.; aggregation; D-dimer; MPO-DNA (NET); IL-6/TNF; histology. Positive signals →redesign (reduce ligand, change linker, add inhibitors). Patient selection & timing Screen coagulopathy, infection, cytopenias; schedule versus chemo/mobilizers AML comorbidities affect safety and homing. Baseline CBC, coag panel, infection markers; plan timing. High-risk patients may be excluded or use non-cell platforms.

In conclusion, solid-tumor applications have demonstrated that cell-hitchhiking is not a single plug-and-play trick, but rather a platform family that must be tailored to match tumor biology, cargo chemistry, and safety constraints. The most compelling recent papers—ranging from platelet-conjugated tumor-targeting prodrugs to neutrophil-carried nanocrystals and engineered CAR-neutrophils—demonstrate both strong therapeutic potential and specific failure modes that inform rational design choices for clinical translation. Continued cross-disciplinary work (tumor biology, hemostasis, materials engineering, and translational medicine), guided by standardized assays and early safety readouts, will determine whether hitchhiking matures into a clinically robust approach for solid-tumor therapy [ 40 , 157 ].

Adaptation to systemic, blood-based malignancies

Translating platelet- and neutrophil-hitchhiking strategies from solid tumors to hematologic malignancies requires re-envisioning both the therapeutic target and the carrier system to accommodate the unique dynamics of the circulatory and marrow niches. Unlike solid tumors, hematologic cancers are already intravascular or bone-marrow–resident and depend heavily on circulatory trafficking, chemokine-guided homing, and intimate interactions with platelets, neutrophils, and the endothelium. This biological context both simplifies specific delivery objectives (no need to extravasate across a dense stromal barrier) and creates unique challenges (high background of malignant cells, risk of off-target activation, and altered host immune/coagulation status). Several recent reviews and primary studies summarize these opportunities and constraints, pointing toward feasible engineering solutions [ 158 ].

Several biological features of hematologic malignancies—including conserved chemokine and adhesion axes— provide a clear rationale for repurposing hitchhiking platforms to steer therapeutics toward bone marrow and lymphoid niches. Hematologic malignancies often exploit the same adhesion and chemokine axes that mediate neutrophil and platelet trafficking, most notably the CXCR4–CXCL12 (SDF-1) signaling axis for marrow homing, selectin-mediated rolling, and integrin-dependent firm adhesion in marrow niches. Because malignant blasts and diseased marrow niches present these conserved cues, hitchhiking platforms can be repurposed to steer therapeutics toward bone marrow, splenic white pulp, or lymph nodes rather than solid parenchymal lesions. In practice, this can mean (1) designing particles that preferentially adsorb to circulating leukocytes that are already recruited to marrow (2), transiently decorating platelets or neutrophils ex vivo and re-infusing them so they home with high affinity to marrow niches, or (3) in-situ strategies that inject ligands/particles that selectively attach to endogenous cells trafficking to hematopoietic organs. Reviews in nanomedicine and hematology highlight how these homing axes make marrow a tractable target for cell-mediated delivery [ 158 , 159 ]. Distinct engineering trade-offs for systemic disease. In solid tumors, the problem is tissue entry; in blood cancers, the key challenges are specificity and safety . Specificity is difficult because therapeutic cargo carried on platelets or neutrophils will encounter a significant fraction of malignant cells in circulation—proper for disseminated killing but risking systemic cytokine release or collateral damage to normal hematopoietic cells. Safety concerns are amplified in patients with hematologic malignancies who frequently have baseline cytopenias, coagulopathies, or prothrombotic states. Platforms that trigger platelet activation, neutrophil degranulation, or NETosis can precipitate thrombosis, bleeding, or systemic inflammation. Therefore, designs for blood cancers must prioritize controlled, tunable adhesion (shear- and enzyme-sensitive linkers), minimal activation cues on carrier surfaces, and thorough coagulation/NETosis readouts in preclinical studies. Recent experimental and review literature highlights these safety trade-offs and proposes the use of standardized panels for preclinical safety testing [ 155 , 160 ].

By exploiting the natural migratory and homing programs of leukocytes, therapeutic carriers can be guided into the bone marrow and immune-privileged sanctuary sites where residual disease often persists. Several promising tactics have emerged in the last 2–3 years. One approach utilizes neutrophils’ innate chemotaxis to inflammation and marrow homing. Drug-loaded nanocrystals or membrane-coated particles are phagocytosed or surface-adsorbed by neutrophils, thereby facilitating their entry into the marrow or inflamed lymphoid tissue, where the cargo is released once the carrier reaches its niche. Another approach is to exploit platelet interactions with leukemic blasts: platelets bind to blasts. They can shield them from immune recognition—a process that can be reversed by using platelet-membrane-coated nanoparticles or platelet-conjugated prodrugs that selectively bind to blast-platelet aggregates and locally release cytotoxic agents or immune modulators. Reviews and proof-of-concept papers demonstrate marrow targeting via neutrophil carriers and platelet-inspired coatings in cancer models and discuss mechanisms that can be taken to hematologic settings [ 36 , 161 ].

Systemic malignancies offer distinct opportunities for hitchhiking-based therapeutics, where the shared vascular microenvironment between malignant and immune cells enables direct cellular targeting and controlled drug deposition. Because malignant cells circulate, hitchhiking strategies can be designed for two complementary goals: (A) systemic purge —deliver broad, circulation-wide cytotoxic or immunomodulatory payloads by exploiting the very circulation that sustains disease; and (B) microenvironment reprogramming —deliver agents that modify marrow niches (e.g., CXCR4 antagonists, stromal modulators, or immune-activating cytokines) to make them less permissive for malignant survival. The relative ease of accessing circulating cells also enables ex vivo carrier loading (isolating a patient’s neutrophils or platelets, loading them under controlled conditions, and reinfusing), a translational advantage for personalized medicine. Nanomedicine reviews and engineering papers discuss both systemic and niche-directed payload strategies [ 159 , 162 ] (see Table 2 ).

Table 2 Key distinctions between solid tumors and acute myeloid leukemia (AML) that affect the design and translation of cell-/platelet-based hitchhiking delivery strategies Feature (relevance to hitchhiking) Solid tumors AML (blood / bone-marrow resident) Microenvironmental architecture Dense, desmoplastic stroma and abnormal vasculature → requires penetration and extravasation strategies (ECM degradation, size/shape tuning). Predominantly intravascular and marrow-resident niches with intimate stromal and endosteal interactions → requires efficient marrow homing/retention and interaction with niche cells rather than deep tissue penetration. Primary delivery barrier Interstitial pressure, dense ECM and heterogeneous perfusion hinder nanoparticle/ cell extravasation. Access is largely vascular but dependent on homing to marrow sinusoids and retention in hematopoietic niches; trafficking/retention signals (CXCR4/CXCL12, VLA-4) are key. Target localization & retention strategy Promote extravasation, proteolytic activity, or tumor-penetrating ligands; long residence in interstitium desirable. Promote marrow homing/adhesion and local retention (targeting niche receptors, timed mobilization), or leverage intravascular interaction dynamics. Immune contexture & safety concerns Tumor immune suppression, presence of CAFs and immunosuppressive myeloid cells → immunomodulation often required; thrombosis risk depends on local endothelial activation. Systemic proinflammatory/hemorrhagical alterations, infection risk, and marrow suppression (e.g., neutropenia) change safety landscape; coagulation and infection surveillance are critical. Carrier sourcing feasibility (autologous versus alternatives) Peripheral immune cells often accessible; local delivery can use tumor-infiltrating leukocytes (when present). AML patients frequently neutropenic or cytopenic; autologous neutrophil sourcing may be limited—alternatives (acellular membranes, ex-vivo differentiation, platelet surrogates) are more often required. Preclinical model implications Orthotopic solid-tumor models and genetically engineered mouse models capture stroma/ECM barriers but can misrepresent human stromal heterogeneity. PDX/orthotopic intrafemoral models and humanized marrow models better recapitulate AML niche but engraftment variability and immune differences limit generalizability. Primary clinical endpoints & monitoring Tumor shrinkage, progression-free survival, intratumoral biomarker changes; imaging/biopsy feasible. Peripheral blast count, marrow blast burden, marrow-specific biomarkers; safety monitoring must emphasize infection surveillance, coagulation panels, and niche-related toxicity.

Accumulating preclinical data identify cellular hitchhiking as a mechanistically grounded and promising approach for targeted therapy in hematologic malignancies. Still, success depends on matching the carrier strategy to the disease biology (disseminated vs. marrow-confined), engineering adhesives that release payloads only in the intended niche, and prioritizing safety assays that capture thrombosis and NETosis risk. Near-term translational milestones should include ex vivo human blood and marrow perfusion models, standardized activation and coagulation readouts, and small animal models that recapitulate marrow trafficking, before any first-in-human studies (see Table 3 ).

Table 3 Preclinical evidence: neutrophil/platelet hitchhiking studies relevant to bone marrow or hematologic disease Study Model (species/setting) Carrier type/approach Payload/strategy Main preclinical outcome Safety readouts / practical notes Refs. Luo et al., 2023 Mouse models (bone/marrow disease models) Neutrophil hitchhiking—ex vivo or in-situ adsorption/internalization of NPs on neutrophils Drug-loaded nanoparticles (chemotherapeutics / bone-active agents) Markedly increased drug accumulation in the bone marrow compared to free drug; improved control of bone/metastatic lesions, and therapeutic efficacy in relevant models. Notes translational limits: neutrophil lifespan, payload burden versus chemotaxis; recommends marrow PD readouts. [ 9 ] Gong & Mitchell, 2023 Commentary / conceptual + references to primary experiments Neutrophil-guided rerouting (overview of primary studies) Reviewed NP rerouting strategies (adsorption/membrane coatings) Synthesizes primary demonstrations that neutrophil hitchhiking reroutes NPs to marrow/inflamed sites and amplifies local delivery. Emphasizes design tradeoffs (activation, shear, timing) for translation. [ 29 ] Su et al., 2023 Tumour-bearing mice (inflammation-primed models) Neutrophil-mediated carriage (cells ingest nanocrystals or bind particles after local priming) Nanocrystal drugs delivered via photoinduced inflammation to recruit neutrophils. Enhanced local delivery and anticancer efficacy in inflamed lesions compared to free drug, demonstrating the feasibility of inflammation-primed in-situ hitchhiking. Shows importance of limiting inadvertent activation/NETosis; recommends NET and coagulation panels. [ 36 ] Liu H. et al., 2025 Multiple myeloma mouse models (bone marrow–targeting) In vivo neutrophil hitchhiking—systemically injected liposomes that bind/are taken up and travel via neutrophils c(RGDfk)-modified liposomes (targeted liposomal formulation) Demonstrated increased liposome accumulation in the bone marrow and improved anti-myeloma activity compared to controls. Highlights in vivo (endogenous) hitchhiking routes and the need for marrow PD; consider payload versus neutrophil function tradeoffs. [ 118 ] Wang S. et al., 2020 & Han H. et al., 2022 Various murine tumour models Platelet-membrane-coated nanoparticles / platelet-derived EVs Drugs/prodrugs / membrane-coated NPs Platelet-membrane coating improved circulation time, immune evasion, and lesion targeting (enhanced local uptake and therapeutic index in tumour models). Platelet platforms risk pro-coagulant effects; therefore, we recommend using platelet activation/aggregation assays and thrombosis screens in preclinical studies. [ 32 , 35 ]

Translational considerations and challenges

Safety issues: thrombosis, immune activation, off-target effects

Translating platelet- and neutrophil-hitchhiking from experimental models to clinical application necessitates a comprehensive understanding of the intrinsic and context-dependent risks associated with leveraging endogenous cellular carriers. Foremost among these is thrombosis, a risk amplified in AML patients, who frequently exhibit baseline hypercoagulability, endothelial perturbation, and dysregulated platelet activation [ 163 , 164 ]. Platelets, when repurposed as therapeutic shuttles, retain their inherent procoagulant potential; even subtle modulation of their activation state—whether through ex vivo manipulation, cargo loading, or exposure to the circulation—can precipitate microvascular obstruction or disseminated thrombosis. This risk is compounded when platelet carriers interact with leukemic blasts or inflamed endothelium, creating microenvironments conducive to unwanted coagulation cascades. Similarly, neutrophils carry the latent capacity to trigger NETosis, which, while potentially beneficial for localized payload delivery, may inadvertently amplify thromboinflammatory events and vascular occlusion if uncontrolled [ 165 ].

Immune activation represents a second, equally nuanced concern. While engineered engagement of immune effector cells can potentiate anti-leukemic responses, inappropriate or systemic activation may provoke cytokine release syndromes, nonspecific cytotoxicity, or depletion of normal hematopoietic compartments. The same chemokine gradients, adhesion receptors, and inflammatory cues that guide carrier homing can inadvertently trigger off-target immune responses, particularly in patients with pre-existing inflammation or immunosuppression. The dualistic nature of platelets and neutrophils—as both therapeutic vectors and active mediators of vascular and immune homeostasis—creates a narrow therapeutic window in which precise control over cell activation is critical.

Off-target effects extend beyond immune and coagulation risks. Engineered carriers may adhere to healthy endothelium, accumulate in non-target organs, or release payloads prematurely due to shear forces, enzymatic cleavage, or intracellular degradation. Such misdelivery not only reduces therapeutic efficacy but also risks collateral tissue injury, systemic toxicity, and activation of compensatory inflammatory pathways. The heterogeneity of carrier populations—variability in platelet activation states, neutrophil age, and receptor expression—further complicates predictability and reproducibility.

Collectively, these safety challenges demand a rigorous, multi-layered preclinical evaluation framework. Effective translation requires integration of thrombosis models, in vitro and in vivo immune profiling, biodistribution and pharmacokinetic studies, and ex vivo human blood perfusion systems. Quantitative biomarkers—such as platelet activation indices, NET formation, cytokine panels, and coagulation assays—must be employed to define safe and efficacious dosing parameters. Furthermore, these studies should account for patient-specific variables, including baseline coagulopathy, inflammatory status, and marrow reserve, to establish individualized risk thresholds. Only through such systematic, mechanistic, and patient-informed approaches can platelet- and neutrophil-based hitchhiking platforms advance safely from the laboratory to first-in-human trials.

Biomaterial and chemical strategies for controlled cell engagement

Emerging biomaterial and chemical engineering strategies are central to reconciling the dual imperatives of efficacy and safety in platelet- and neutrophil-hitchhiking systems. By precisely modulating the interface between therapeutic cargo and cellular carriers, these approaches allow spatiotemporal control over engagement, activation, and payload release. One key paradigm is conditional engagement, wherein nanoparticles or drug conjugates are functionalized with ligands that respond selectively to disease-specific microenvironmental cues. For example, sensors for acidic pH, elevated ROS, or proteolytic activity can trigger receptor binding or drug release exclusively within leukemic marrow niches or inflamed tissues, minimizing off-target interactions in healthy vasculature [ 10 , 166 ].

Dynamic linkers—shear-responsive or enzyme-cleavable—offer a complementary layer of regulation, enabling mechanical or biochemical cues to control both cellular attachment and therapeutic release [ 167 ]. Under physiological shear conditions in circulation, such linkers prevent premature detachment, whereas local enzymatic activity within AML niches or inflammatory microenvironments triggers precise payload delivery. This strategy effectively converts endogenous blood flow and microenvironmental signals into programmable release triggers, integrating physiology directly into carrier design.

Chemical modifications further augment specificity and stability. PEGylation or zwitterionic coatings shield particles from opsonization and rapid clearance, prolonging circulation time and enhancing carrier availability [ 168 ]. Aptamer- or antibody-based recognition elements can selectively engage platelet or neutrophil subsets—such as senescent neutrophils with high CXCR4 expression or activated platelets expressing P-selectin—further restricting off-target activity and maximizing therapeutic index [ 169 , 170 ]. The careful selection of ligand density, multivalency, and spatial orientation on nanoparticle surfaces enables fine-tuning of adhesion strength, balancing carrier retention with timely release of the payload.

Together, these strategies represent a synergistic convergence of hematology, nanomedicine, and materials science, transforming cellular hitchhiking into a highly programmable platform. By embedding environmental sensing, mechanical responsiveness, and molecular specificity into the carrier design, engineered platelets and neutrophils can traverse the complex circulatory and marrow landscapes of AML while minimizing thrombosis, immune activation, and off-target toxicity. Such precision engineering lays the foundation for translationally viable, safe, and highly effective cell-mediated drug delivery systems.

Potential integration with existing AML therapies and immunotherapy

The translational potential of platelet- and neutrophil-hitchhiking systems is amplified when considered as precision augmenters rather than standalone interventions within current AML treatment paradigms. By leveraging the innate homing capabilities and circulatory persistence of these cellular carriers, chemotherapeutic payloads can be concentrated directly within leukemic niches, reducing collateral toxicity to healthy marrow progenitors and mitigating systemic side effects that often limit dose intensity. Neutrophil-mediated delivery, in particular, enables targeted modulation of specialized microenvironments that sustain leukemic stem and progenitor cells—compartments that are notoriously resistant to conventional chemotherapy and represent key drivers of relapse.

Beyond cytotoxic therapy, hitchhiking platforms offer synergistic opportunities with immunotherapy. Platelet- or neutrophil-bound carriers can modulate the immune microenvironment by delivering immune-stimulatory agents, checkpoint inhibitors, or cytokines directly to sites enriched in leukemic blasts [ 151 , 171 ]. Such localized modulation has the potential to reverse T cell exhaustion, enhance effector cell infiltration, and overcome the immunosuppressive cues that often protect AML cells from immune-mediated clearance. Moreover, co-administration with bispecific T cell engagers or CAR-T cells could exploit the carriers’ trafficking patterns to improve engagement with target leukemic cells, increasing both efficacy and spatial precision.

Strategic integration requires a rigorous, multidimensional approach: dosing regimens must be synchronized with conventional chemotherapy cycles to avoid antagonistic interactions; pharmacokinetic and pharmacodynamic profiles of both cargo and carrier must be mapped to marrow residency and circulation kinetics; and safety endpoints—thrombosis, off-target immune activation, and NET formation—must be evaluated alongside anti-leukemic efficacy. By thoughtfully combining cellular hitchhiking platforms with established and emerging therapies, it becomes possible to maximize therapeutic indices, reduce redundant toxicity, and transform AML treatment from broad cytotoxicity to highly targeted, microenvironment-aware interventions. Table 4 compares platelet versus neutrophil hitchhiking strategies in patients with AML.

Table 4 Comparison of Platelet- versus Neutrophil-based hitchhiking platforms for AML Feature / Criterion Platelet-based platforms Neutrophil-based platforms Comment Biology / natural tropism Adhere to activated endothelium, bind exposed matrix; form platelet–blast aggregates. Home to inflamed tissues and bone marrow (senescent neutrophils via CXCR4). Determines where and when the carrier will deposit the cargo. Typical loading methods Surface adsorption or membrane-coated nanoparticles; platelet-derived EV loading. Internalization (incubation with NPs), membrane coating, or EVs. Affects payload protection, release timing, and carrier function. Circulation half-life (typical) Longer (days for platelets)—more persistent circulation. Short (hours to ~ 1–2 days); aged subsets re-enter marrow. Influences dosing schedule and timing versus chemotherapy windows. Payload types best suited Small molecules, prodrugs, immunomodulators, membrane-coated NPs. Nanocrystals, encapsulated chemotherapeutics, gene vectors, EV payloads. Match chemistry to the carrier to preserve function and release. Key engineering levers Membrane coating, stealth coatings, shear-sensitive linkers. Control of load burden, CXCR4/CXCR2 priming, and L-selectin modulation. Optimize homing versus safety (avoid activation). Major advantages Immune camouflage, long circulation, and strong adhesion at vascular injury. Natural marrow trafficking, active migration across sinusoids, and high uptake capacity. Choose based on desired niche and payload kinetics. Principal safety concerns Thrombosis, platelet activation, pro-coagulant effects, and potential platelet-mediated blast shielding. NETosis, degranulation, and impaired host defense (increased infection risk) occur when neutrophils are altered. Must be monitored and mitigated in preclinical assays. Quality control assays (suggested) Platelet activation index, P-selectin expression, aggregation under shear, sterility, EV profiling. Viability/chemotaxis, CXCR4/CXCR2 expression, NETosis assays, payload retention, sterility. QC ensures safety and functional delivery. Translational maturity/evidence Multiple proof-of-concept preclinical studies and platelet-membrane NP reports; GMP scale-up still a bottleneck. Strong preclinical marrow-targeting data (neutrophil hitchhiking studies), but lifespan/loading tradeoffs remain. Use this column to justify the next experimental steps and clinical translation plan. Recommended immediate experiments Ex vivo human blood shear assays; thrombosis panels; platelet-blast interaction functional tests. Dose–response of loading versus chemotaxis; infection challenge models; marrow biodistribution kinetics. Directly addresses the practical translational gaps you discuss.

Future directions and innovation

Personalized, patient-derived platelet/neutrophil platforms

The next frontier in cellular hitchhiking for AML lies in the development of personalized, patient-derived carriers. Utilizing autologous platelets and neutrophils as drug delivery vehicles offers intrinsic biocompatibility, minimizing immunogenicity and reducing the risk of clearance or adverse immune reactions. By harnessing each patient’s own hematologic profile, these platforms enable the precise tuning of drug payloads, release kinetics, and circulation dynamics, ensuring that therapeutic interventions are tailored to the unique characteristics of individual disease phenotypes. A salient, patient-level constraint for autologous neutrophil-based delivery that requires explicit consideration is the frequent presence of neutropenia and neutrophil maturation defects in AML. Disease- and treatment-related suppression of granulopoiesis commonly produces low circulating neutrophil counts and expanded immature/low-density granulocyte populations with demonstrable functional impairment (reduced chemotaxis, altered degranulation and defective NET formation), which in turn increase susceptibility to infection and limit the availability of competent autologous carrier cells [ 172 , 173 ]. Consequently, translational pathways should not assume readily available autologous neutrophils in all patients; instead, preclinical and early-phase clinical study designs must prospectively incorporate explicit patient-selection criteria (for example, minimum absolute neutrophil count thresholds and validated maturation/function panels), contingency strategies for alternative carrier sources (allogeneic cells, membrane/EV-based acellular platforms), and integrated infection-safety monitoring and stopping rules [ 174 ].

Beyond mere autologous sourcing, ex vivo priming or genetic modulation of platelets and neutrophils presents opportunities to enhance their natural homing, trafficking, and immune-interactive capacities. For instance, selective upregulation of CXCR4 or modulation of surface adhesion molecules could bias carrier cells toward leukemic niches, while controlling activation thresholds could minimize inadvertent thrombosis or systemic inflammation. Such strategies could also address the heterogeneity of AML subtypes, tailoring both the cellular vehicle and its cargo to the specific microenvironmental and molecular context of a patient’s disease.

To strengthen the patient-centred translational pathway, we emphasize three practical considerations. First, the choice of technology should prioritize minimal ex-vivo handling and rapid turnaround: neutrophils have limited ex-vivo lifespan and are difficult to cryopreserve, so strategies that require fresh isolation and immediate use (or short closed-system processing) are most feasible [ 175 ]. Second, realistic timeframes must be acknowledged—leukapheresis/collection and bedside processing commonly require on the order of tens of minutes to a few hours, whereas engineered cell products such as CAR-T cells require weeks of manufacturing; this contrast favors point-of-care or automated rapid workflows for neutrophil/platelet hitchhiking rather than long centralized manufacturing [ 176 ]. Third, preserving functionality is a major barrier: platelets are prone to a storage lesion and have a limited shelf-life under current standards, and granulocyte/neutrophil preparations retain functional capacity only for hours unless special methods are used—thus quality control must include short-interval functional assays (e.g. phagocytosis/oxidative burst, adhesion, and ex-vivo T-cell suppression where relevant) and rapid release criteria [ 177 – 180 ].

In sum, patient-derived cellular platforms represent a paradigm shift from conventional, “one-size-fits-all” nanomedicine to truly individualized therapeutics, where the circulatory system itself becomes a programmable, precision delivery network capable of responding dynamically to the biology of both the host and the malignancy.

Integration with single-cell omics, AI, and precision oncology

The fusion of single-cell multi-omics and artificial intelligence (AI) represents a transformative avenue for optimizing cellular hitchhiking strategies in AML. Single-cell transcriptomic, proteomic, and epigenomic profiling now permits high-resolution mapping of the heterogeneous leukemic microenvironment, revealing how malignant blasts manipulate platelets, neutrophils, and other immune subsets to their advantage. These datasets provide not only static snapshots but also dynamic insights into cell-state transitions, activation signatures, and intercellular communication networks that are critical for effective carrier targeting.

Machine learning and predictive modeling can leverage these rich datasets to inform rational carrier design: selecting the most appropriate cell type, identifying optimal surface markers for selective engagement, and forecasting potential resistance or off-target interactions. AI-driven simulations may also optimize drug loading strategies, release kinetics, and trafficking dynamics under patient-specific circulatory and marrow conditions. By integrating these computational insights with real-time functional assays, cellular hitchhiking can evolve from a generalized delivery concept into a precision-guided, adaptive therapy platform.

Embedding these approaches within a precision oncology framework enables the personalization of treatments to individual immune landscapes, disease burden, and genetic subtype, transforming the delivery of cytotoxic, immunomodulatory, or gene-editing payloads into a data-driven, patient-specific intervention. In essence, the convergence of single-cell omics, AI, and cellular engineering establishes a closed-loop system in which biological insight, computational modeling, and therapeutic delivery inform and refine one another, accelerating discovery while enhancing translational fidelity and clinical impact.

Toward transformative AML therapies using cellular hitchhiking

The ultimate hypothesis underpinning hitchhiking is that combined precision delivery and immune modulation can improve niche-target engagement. This remains a testable hypothesis requiring standardized marrow PK/PD, head-to-head preclinical comparisons, and careful early-phase human studies. By leveraging the intrinsic homing and circulatory persistence of platelets and neutrophils, hitchhiking systems can concentrate therapeutics in leukemic niches, penetrate sanctuary sites such as bone marrow or splenic white pulp, and mitigate systemic exposure that traditionally drives toxicity.

Beyond targeted cytotoxicity, cellular hitchhiking holds the capacity to reshape the leukemic microenvironment, modulating stromal support, inflammatory cues, and immune suppression. By delivering immunomodulatory agents or RNA therapeutics in situ, these carriers may restore T cell function, counteract leukemic stem cell niches, and disrupt protective circuits exploited by malignant cells. Moreover, when integrated with emerging modalities—including checkpoint inhibitors, bispecific T cell engagers, CAR-T therapies, and targeted kinase inhibitors—hitchhiking platforms can act as synergistic amplifiers, bridging the gap between drug delivery and active disease modulation.

Notably, the versatility of these systems allows for dynamic adaptation to patient-specific disease biology. By adjusting carrier selection, payload composition, and release kinetics, clinicians can tailor therapy to the AML subtype, disease burden, and immune landscape, achieving a level of personalization previously unattainable in hematologic malignancies. If fully realized, this approach could transform AML outcomes, shifting the focus from temporary disease control toward durable remission, eradication of minimal residual disease, and ultimately, curative interventions. Cellular hitchhiking thus represents a convergence of biology, engineering, and precision medicine, poised to redefine both how and where AML therapeutics act.

Near-term goals to accelerate translation

To convert the conceptual opportunities described above into reproducible, de-risked clinical pathways, we have highlighted two immediate, operational goals for academic–industry translational teams:

Standardize and qualify a minimal , carrier-specific potency and functional assay panel that quantifies carrier identity/viability, targeted homing (chemotaxis or ligand-binding surrogates), safety-relevant activities (platelet activation indices, NETosis propensity, procoagulant activity), and product potency (drug release kinetics and functional payload bioactivity). These assays should be validated under process-relevant (GMP-compatible) conditions and used as lot-release/bridging endpoints in preclinical PK/PD work. This objective aligns with regulatory expectations for potency/CMC for cellular and gene therapy products [ 181 ]. Implement a staged , human-centric preclinical de-risking pipeline that couples (i) comprehensive in-vitro human assays (human stromal co-culture, whole-blood perfusion, coagulation/complement panels), (ii) orthogonal in-vivo testing in humanized/PDX or orthotopic models to evaluate biodistribution, marrow PK/PD and acute safety, and (iii) focused GLP/GLP-like safety pharmacology studies that measure translational biomarkers (coagulation parameters, cytokines, infection susceptibility). Data packages from this pipeline should be explicitly mapped to first-in-human safety monitoring and prespecified stopping rules to reduce translational risk [ 9 ].

Conclusion

Acute myeloid leukemia (AML) epitomizes the formidable challenge of treating a highly disseminated, dynamic malignancy in which conventional therapies frequently fall short—both in efficacy and tolerability. Despite gradual progress through targeted agents and supportive care, many patients still experience refractory disease, early relapse, and significant treatment-related toxicity. The bone marrow microenvironment functions as both a protective niche and an active mediator of resistance, shielding leukemic cells from chemotherapeutic pressure while amplifying systemic vulnerability. These persistent clinical gaps—limited therapeutic selectivity, marrow sanctuary effects, and infection-prone cytopenias—underscore an urgent need for delivery systems that can engage diseased compartments with precision while sparing normal hematopoiesis.

In this context, cellular hitchhiking, which harnesses the intrinsic trafficking, adhesion, and immune-modulatory capacities of platelets and neutrophils, offers a paradigm-shifting framework for systemic precision therapy. Unlike synthetic carriers, these endogenous cells exhibit “contextual intelligence,” naturally navigating the circulatory and marrow microenvironments, homing to inflamed or leukemic niches, and dynamically interfacing with immune pathways. Through rational bioengineering, these properties can be redirected for selective payload delivery, enabling controlled targeting, reduced off-target toxicity, and potentially even microenvironmental reprogramming. This approach transforms the circulatory network from a barrier into a vehicle for precision medicine.

Translating this promise into clinical reality demands meticulous attention to safety, standardization, and scalability. Future priorities should include harmonized potency and safety assays, human-centric preclinical models aligned with clinical endpoints, and adaptive sourcing strategies for cytopenic patients. Advances in biomaterials, gene editing, membrane engineering, and AI-driven design now make it feasible to reprogram these cells into programmable, patient-specific vectors. This review aggregates preclinical and translational work that explores hematogenous cell-based delivery strategies. Limitations include the predominance of small-animal models with variable experimental designs, frequent absence of standardized quantitative PK reporting (e.g., marrow AUC), and the current lack of clinical trial data. Additionally, the safety profile of cell-based delivery in immunocompromised or thrombocytopenic AML patients is incompletely characterized. Consequently, many assertions about potential clinical benefit should be regarded as hypothesis-generating and contingent on rigorous preclinical de-risking and early-phase clinical evaluation.

Ultimately, cellular hitchhiking constitutes a promising, hypothesis-driven convergence of hematology, immunology, and bioengineering. Its ability to meaningfully improve clinical endpoints (e.g., durable remission, MRD eradication, overall survival) is not yet proven and should be framed as an objective for rigorous preclinical de-risking and staged clinical evaluation.

Abbreviations

Antibody–drug conjugate

Acute myeloid leukemia

Area under the concentration–time curve

Bone marrow

B-cell lymphoma 2

Cell-adhesion-mediated drug resistance

Chimeric antigen receptor T cell

Citrullinated histone H3

Extracellular vesicle

Fatty-acid oxidation

FMS-like tyrosine kinase 3

Good Manufacturing Practice

Hypomethylating agent

Hematopoietic stem cell

Isocitrate dehydrogenase 1/2

Liquid chromatography–tandem mass spectrometry

Low-density granulocyte

Leukemic stem cell

Myeloid-derived suppressor cell

Myeloperoxidase

Measurable residual disease

Neutrophil extracellular trap

Next-generation sequencing

Nanoparticle/nanoparticles

Oxidative phosphorylation

Pharmacodynamic

Programmed cell death protein 1

Patient-derived xenograft

Platelet-derived extracellular vesicle

Platelet factor 4

Pharmacokinetic

Platelet-membrane-coated nanoparticles

P-selectin glycoprotein ligand-1

Reactive oxygen species

Signal regulatory protein alpha

T-cell immunoglobulin and mucin-domain containing-3

Total-body irradiation

Tyrosine kinase inhibitor

Vascular cell adhesion molecule-1

Very late antigen-4 (integrin α4β1)

Publisher’s Note

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

Acknowledgements

None.

Author contributions

**Farshad Heydari** served as first author, leading literature review, figure design, conceptual synthesis, and drafting of the manuscript. **Jalal Naghinezhad** , as corresponding author, provided overall supervision, critical intellectual guidance, and manuscript revision. **Michael R. Hamblin** , as co-corresponding author, contributed to the conceptual framework, figure conceptualization, and critical review of the manuscript. All authors discussed the content, approved the final version, and take responsibility for the integrity of the work.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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