Apoptotic extracellular vesicles (ApoEVs) are important mediators of intercellular communication in a broad spectrum of physiological and pathological processes, playing a central role in immunomodulation and the maintenance of cellular homeostasis. However, the exact function and fundamental mechanisms underlying tendon stem/progenitor cell (TSPC)-derived apoEVs in tendinopathy remain elusive. Here, we demonstrated that TSPC-apoEVs enhance macrophage efferocytosis and promote anti-inflammatory M2 polarization by activating the PPAR-γ coactivator 1α-nuclear respiratory factor 1-mitochondrial transcription factor A signaling, thereby restoring mitochondrial homeostasis and suppressing oxidative stress under inflammatory conditions. To optimize local delivery, we engineered porous gelatin microspheres to load apoEVs (GM@ApoEVs), which combined the immunomodulatory effects of apoEVs with the sustained-release properties of microspheres. Notably, GM@ApoEVs also regulated the lineage differentiation of TSPCs, promoting tenogenic differentiation and suppressing aberrant osteochondral fates. In a rat model of Achilles tendinopathy established via collagenase induction, GM@ApoEVs injection markedly improved tendon regeneration, as evidenced by aligned collagen matrix, reduced inflammatory infiltration, and diminished heterotopic ossification. Our findings revealed that TSPC-apoEVs, especially delivered by gelatin microspheres, represent a promising bioactive strategy for immunomodulation and tendon repair in tendinopathy.
Shi et al. (Mon,) studied this question.