Preclinical efficacy and safety of plant-derived extracellular vesicles for diabetic wound healing: A systematic review and meta-analysis

Plant-derived extracellular vesicles (PDEVs) have emerged as a promising cell-free therapeutic paradigm in regenerative medicine, particularly for managing the impaired healing associated with diabetic foot ulcers. Grounded in the need for evidence-based clinical translation, this study employed a systematic review and meta-analysis to evaluate the preclinical efficacy and safety of PDEVs in diabetic wound models. A comprehensive search across PubMed, Web of Science, and Embase through May 10, 2026, identified 20 eligible studies, which were rigorously assessed using the SYRCLE risk-of-bias tool and CAMARADES checklist. Random-effects meta-analyses were performed for wound healing rate, angiogenesis, and collagen deposition. Quantitative synthesis demonstrated that PDEVs significantly improved wound healing rate across early (SMD = 2.45, 95% CI: 1.63–3.27, p < 0.00001), mid (SMD = 1.75, 95% CI: 1.15–2.36, p < 0.00001), and late stages (SMD = 1.54, 95% CI: 0.14–2.94, p = 0.03), while markedly enhancing angiogenesis (SMD = 2.13, 95% CI: 1.35–2.91, p < 0.00001) and collagen deposition (SMD = 2.49, 95% CI: 1.83–3.15, p < 0.00001). Qualitative evidence further suggested that PDEVs improve the diabetic wound microenvironment by modulating macrophage polarization, attenuating excessive inflammation, restoring endothelial function, promoting re-epithelialization, and facilitating extracellular matrix remodeling. Sensitivity analyses generally supported the robustness of the main findings, although late-stage wound healing and several subgroup results were influenced by individual studies. No serious adverse events were reported in the subset of studies that assessed them; however, safety evaluations were incomplete across included studies and largely limited to short-term observation. Overall, PDEVs show promising preclinical potential for diabetic wound repair, but current evidence remains preliminary due to constrained sample sizes, suboptimal reporting of randomization, and unstandardized quality control. Future studies should adopt rigorous experimental designs, standardized source documentation, scalable manufacturing, potency assays, and systematic toxicological evaluation to support clinical translation.