Bioinspired cell-hitchhiking nanotherapeutics in acute myeloid leukemia: targeting the EV–platelet–NET axis and the leukemic bone marrow niche

Acute myeloid leukemia (AML) is increasingly understood as a microenvironment-influenced malignancy in which persistence and relapse are shaped by both leukemic-cell intrinsic programs and protective signals from the bone marrow niche. Among these signals, extracellular vesicles (EVs), platelet activation, and neutrophil extracellular trap (NET)-associated inflammation form a biologically relevant but unevenly validated network. AML-derived EVs provide the strongest disease-specific evidence. By transferring bioactive proteins, RNAs, lipids, and metabolic cargo, they can reprogram stromal, endothelial, immune, and hematopoietic cells, thereby supporting leukemic stem-cell survival, angiogenic and metabolic adaptation, and therapy resistance. Platelet-derived vesicles may add a thromboimmune and chemoresistance-associated layer through platelet–blast interactions and vesicular signaling. In contrast, NET-associated pathways may contribute to inflammatory, endothelial, coagulation, and immune remodeling. However, platelet-derived vesicle and NET mechanisms in AML remain less mature than the EV literature and are partly supported by associative, preclinical, or extrapolated evidence. This review presents the EV–platelet–NET axis as an emerging, evidence-calibrated framework linking marrow-niche remodeling, measurable residual disease (MRD), therapy resistance, and mechanism-guided nanotherapeutic design. Building on this biological framework, we critically examine AML-relevant nanoplatforms, including marrow-homing lipid nanoparticles, biomimetic membrane-coated carriers, stimulus-responsive systems, and platelet- or neutrophil-hitchhiking strategies. Particular emphasis is placed on carrier chemistry, physicochemical design, targeting selectivity, payload selection and release, biodistribution, and translational limitations. These bioinspired strategies remain investigational and require AML-specific validation of leukemia-versus-normal-hematopoiesis selectivity, thrombogenicity, carrier-cell function, safety, manufacturing reproducibility, and antileukemic efficacy. Integrating EV-, platelet-, NET-, metabolic-, and MRD-associated biomarkers may ultimately support mechanism-based patient selection, response monitoring, and precision marrow-directed therapy.