Bidirectional Interactions Between Nanomaterials and Extracellular Vesicles: Molecular Insights and Translational Implications

Extracellular vesicles (EVs) are nanoscale carriers mediating intercellular communication via proteins, nucleic acids, and lipids. Concurrently, diverse nanomaterials (NMs) with tunable properties have emerged. Bidirectional interactions between NMs and EVs impact disease pathogenesis, diagnostics, and therapeutics. With translational relevance, NMs' physicochemical features (size, charge, coatings) modulate EV release, cargo enrichment (proteins, miRNAs, lipids), and downstream processes including immune regulation, angiogenesis, and tumor microenvironment remodeling. Conversely, EVs internalize NMs, inducing oxidative stress, inflammation, or apoptosis. However, while NMs' regulatory effects on EVs is well-characterized, the mechanisms of EVs-mediated NMs internalization, processing, and redistribution remain poorly understood-an asymmetry defining research priorities. Unresolved controversies persist-microenvironment-dependent immune effects, inconsistent cargo alterations, and the impact of EVs heterogeneity. This review synthesizes current knowledge on mutual NMs-EVs influences, emphasizing NMs-regulated EVs biogenesis/cargo/function and EVs uptake/response to NMs. We introduce the "NMs-EVs regulatory axis"-a bidirectional, dynamic network where NMs and EVs mutually shape function across molecular, cellular, and tissue levels, moving beyond linear carrier views. These interactions enable hybrid platforms for drug delivery, imaging, and diagnostics, positioning the NMs-EVs axis as a frontier in nanomedicine for precision therapeutics.