Senomorphic Small Extracellular Vesicles Delivered by a Tissue‐Adhesive α‐Lipoic‐Acid Hydrogel Enable Immuno‐Rejuvenation for Bone‐Tendon Interface Regeneration

ABSTRACT 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.