Engineered Nestin ⁺ TSPC‐Derived Exosomes Promote Tendon Repair Via Metabolic Reprogramming

Tendon repair remains a substantial clinical problem with limited treatment options. While Nestin + tendon stem/progenitor cells (TSPCs) are known to regulate tendon healing, their clinical translation faces challenges. Here, we show that exosomes derived from engineered Nestin‐overexpressing TSPCs (Nes‐EVs) significantly ameliorate tendinopathy in multiple mouse models. We isolated Nes‐EVs following lentiviral Nestin overexpression and demonstrated their capacity to reduce cellular senescence and promote tenogenic differentiation in vitro. In collagenase‐induced (WT and Nes‐Cre ERT2 ;iDTR ) and naturally aged murine tendinopathy models, Nes‐EVs robustly restored motor function, improved tissue architecture, reduced senescence markers and restored collagen homeostasis. Integrated transcriptomic and metabolomic profiling revealed a hallmark enrichment of the pantothenate and CoA biosynthesis pathway in both Nestin + TSPCs and their exosomes. Mechanistically, Nes‐EVs enhanced mitochondrial function in tenocytes, increasing ATP production and diminishing oxidative stress thereby revitalizing cellular metabolism in damaged tendons. Our findings unveil a fundamental mechanism where Nes‐EVs coordinate tendon metabolism and homeostasis, offering a promising acellular therapeutic strategy for tendinopathy.