Hydrogel-extracellular vesicle engineering delivery system: a promising therapeutic strategy for wound healing

Chronic refractory wounds, such as diabetic foot ulcers, present significant clinical challenges due to a dysregulated healing microenvironment. Extracellular vesicles (EVs) have emerged as promising therapeutic agents owing to their pro-angiogenic, anti-inflammatory, and regenerative properties. However, their clinical translation is hampered by rapid clearance and instability at the wound site. Hydrogel-based delivery systems offer an effective strategy to overcome these limitations by providing a protective and tunable platform for sustained EVs release. This review systematically synthesizes contemporary advances in EVs hydrogel (EVH) systems for chronic wound therapy. We critically evaluate design strategies encompassing various hydrogel matrices (natural, synthetic, and smart responsive), engineering approaches for EVs modification, and controlled-release mechanisms that collectively enhance therapeutic efficacy. By integrating findings from preclinical studies across diverse wound models, we highlight the synergistic roles of EVH systems in promoting angiogenesis, modulating immune responses, and accelerating tissue regeneration. Furthermore, this review addresses key translational challenges, including scalable EVs production, standardization, biosafety, and regulatory pathways. Finally, we provide forward-looking perspectives on the clinical translation of next-generation, intelligent EVH systems, aiming to bridge the gap between innovative design and practical therapeutic application.