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.