Senomorphic Small Extracellular Vesicles Delivered by a Tissue-Adhesive α-Lipoic-Acid Hydrogel Enable...

Chronic inflammation-driven bone loss in aging compromises bone regeneration and further impairs the bone-tendon interface (BTI). However, the cellular mechanisms by which inflammation exacerbates cellular senescence and consequently disrupts BTI healing remain unclear. Here, we identify M1 macrophage-mediated inflammation as a key driver of bone marrow-derived mesenchymal stem cells (BMSCs) senescence and bone microstructural deterioration. This senescence-associated decline in BMSCs ultimately compromises osteogenesis and delays BTI repair. To counteract these effects, we engineered a senomorphic and immunomodulatory platform by incorporating quercetin-primed senomorphic small extracellular vesicles (Sm-sEV) into a tissue-adhesive α-lipoic acid hydrogel (αLA-Gel) for sustained local delivery. The composite material modulates the inflammatory-senescent microenvironment by attenuating M1 macrophage-driven inflammation and enhancing BMSC resilience to inflammation-exacerbated senescence. Mechanistic analyses revealed that Sm-sEV/αLA-Gel suppresses cGAS-STING-NF-κB signaling, thereby reducing inflammation and improving BMSC resistance to senescence. In an osteoporotic rat rotator cuff repair model, Sm-sEV/αLA-Gel enhanced bone formation and fibrocartilage maturation, thereby promoting superior BTI integration and mechanical strength. Together, these findings identify inflammation-exacerbated BMSC senescence as a key pathological driver and demonstrate that dual regulation of inflammation and stem cell resilience enables robust regeneration of bone and the BTI under osteoporotic conditions.