Bioactive siRNA‐Based Liposomes Promoted Tendon‐Bone Healing in Osteoporotic Mice by Recovering the Stemness of CD248 ⁺ TSPCs

Abstract Osteoporosis significantly impairs tendon‐bone healing, increasing the risk of rotator cuff tears and postoperative retearing. Tendon stem/progenitor cells (TSPCs) are vital for tendon repair, with their stemness crucial to healing outcomes. This study investigated the role of CD248 in regulating TSPC stemness and assessed the therapeutic potential of si‐CD248‐loaded liposomes in promoting tendon‐bone healing under osteoporotic conditions. Single‐cell RNA sequencing (scRNA‐seq) identified increased TSPC populations, particularly a unique subcluster, TSPC‐0, with elevated CD248 expression in osteoporotic tendon samples. CD248 ⁺ TSPCs displayed reduced proliferation, increased apoptosis, and impaired migration, driven by altered FAK‐JAK‐STAT1 signaling. si‐CD248‐loaded liposomes were formulated and characterized, demonstrating efficacy in inhibiting CD248 expression, restoring TSPC stemness, and promoting tendon‐bone healing. In osteoporotic mice, liposome treatment significantly enhanced tissue regeneration, improving histological scores, collagen organization, and biomechanical properties. This study reveals that elevated CD248 expression negatively impacts TSPC stemness and impairs healing under osteoporotic conditions. Targeting CD248 using si‐CD248‐loaded liposomes effectively restores TSPC regenerative potential, representing a promising therapeutic strategy to enhance tendon‐bone healing in osteoporotic patients.