The evolution of extracellular vesicles: From passive transporters to active architects of microenvironmental homeostasis

Abstract

Once dismissed as mere cellular waste, extracellular vesicles (EVs) have undergone a conceptual redefinition, emerging as programmable therapeutic scaffolds with broad biomedical applications. Modern EVs design has progressed past the conventional framework of localized cargo delivery to isolated recipient cells; instead, the focus has shifted toward systemic, multi-cellular niche remodeling aimed at restoring tissue-level homeostasis. This review provides a comprehensive analysis of the engineering strategies to overcome the biological bottlenecks of naive EVs, specifically rapid systemic clearance and inefficient cytosolic delivery. We detail current strategies for active loading and for bypassing endolysosomal entrapment to facilitate in-situ translation of therapeutic mRNA. Furthermore, we discuss how the synergy between engineered EVs and responsive biomaterial scaffolds provides the spatiotemporal control necessary for localized reprogramming of diseased microenvironments. Finally, by examining application paradigms across oncology, regenerative medicine, and neurodegeneration alongside existing regulatory classification frameworks, this review provides a roadmap for transitioning intelligent vesicle platforms from benchtop discovery to clinical-grade compliance.