Harnessing Plant-derived Extracellular Vesicles in Advanced Biomaterials: From Structural Scaffolds to Responsive Systems for Next-Generation Wound Therapeutics

Abstract Chronic non-healing wounds, particularly diabetic foot ulcers, persist as a significant clinical challenge due to the limited availability of therapeutic options and the complexity of their pathological microenvironments. Plant-derived extracellular vesicles (PDEVs), which are nanoscale lipid carriers rich in bioactive molecules, have emerged as a promising therapeutic approach due to their low immunogenicity, antioxidant and anti-inflammatory properties, and their ability to promote angiogenesis. Structurally, the biomaterial protects the integrity of PDEVs and extends their residency through modulated release. Biologically, PDEVs enhance the regenerative potential of the material by profoundly reprogramming the local cellular and immune microenvironments. However, their clinical application is severely impeded by their inherent instability in the dynamic wound microenvironment, which includes susceptibility to enzymatic degradation, disruption due to pH fluctuations, and rapid clearance by wound exudate. These factors collectively lead to premature cargo loss and reduced therapeutic efficacy. This review synthesizes how engineered biomaterials, serving as tailored structural platforms for controlled delivery, can overcome these stability challenges specific to PDEVs. By examining loading strategies and design principles, we demonstrate how composite systems surpass single-component therapies in diabetic wound models. Lastly, we address translational challenges and propose a development framework that integrates AI-driven design with mechanism-guided material optimization. This work lays the groundwork for the rational development of next-generation vesicle-enabled wound therapeutics.