Jzit Weii Chen, Fong Fong Liew, Hsiao Wei Tan, Ivy Chung
Nanomedicine has advanced drug delivery by addressing key challenges such as poor solubility, instability, and off-target effects. Yet, despite its promise, clinical translation remains limited, with few FDA-approved formulations and ongoing biocompatibility concerns. Extracellular vesicles (EVs), particularly those derived from mesenchymal stem cells, offer natural advantages as nanocarriers, including biocompatibility, immunomodulatory effects, and regenerative properties. However, their therapeutic application is constrained by low drug-loading capacity, rapid clearance, and batch-to-- batch variability. To overcome these limitations, biohybrid vesicles-fusions of natural EVs and synthetic liposomes-have emerged as an innovative platform. These hybrids combine the biological targeting and immune-evasive features of EVs with the scalability, structural stability, and tunable drug-release capabilities of liposomes. Advanced fabrication methods, including freeze-thaw cycling, co-extrusion, and pH-mediated fusion, enhance biohybrid vesicle integrity and production. Surface modifications such as PEGylation and ligand attachment further improve biodistribution and cell-specific uptake. This review focuses on extracellular vesicles (EVs), liposomes, and biohybrid vesicles, examining their cellular interactions, design strategies, and therapeutic potential. It also explores the biological pathways involved in tissue repair and regeneration, while addressing key translational challenges such as standardisation and large-scale manufacturing. By leveraging the complementary advantages of natural and synthetic systems, biohybrid EVs represent a promising next-generation platform for precision nanomedicine. The review summarises current progress and proposes a roadmap for advancing these technologies toward clinical application, with a specific focus on wound management.