Turmeric-derived extracellular vesicles loaded microneedle system attenuates rotator cuff degeneration by orchestrating energetic metabolism

Poor healing outcomes following rotator cuff injury are linked to insufficient endogenous repair capacity within tendon tissue. And the ATP deficiency caused by energy metabolic imbalance in tendon stem/progenitor cells (TSPCs) is a key pathological feature. Here, we identified energy metabolic changes under the oxidative stress microenvironment of rotator cuff injury, characterized by downregulated oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle in mitochondria, coupled with enhanced glycolysis. Our data showed that Turmeric-derived Extracellular Vesicles (Tur-EVs) rescued this energy crisis, as manifested by the restoration of mitochondrial function and enhanced energy supply, while preserving the proliferation and differentiation capacities of TSPCs. Furthermore, our study revealed that Tur-EVs enhanced mitophagy and endogenous antioxidant capacity through the AMPK-FOXO3 pathway, as a potentially functional mechanism. In rat and rabbit rotator cuff injury models, Tur-EVs-loaded microneedle significantly improved rotator cuff healing quality in terms of locomotor gait, biomechanics, and histopathological outcomes. In summary, our findings demonstrate the potential of plant-derived extracellular vesicles in regulating energy metabolism, and suggest the dysregulated energy metabolism as a crucial therapeutic target in tendon repair.