Platelet-rich plasma cues program M2 macrophage–derived exosome mimetics to regenerate the tendon–bone interface

Surgical repair of rotator cuff injuries is frequently complicated by high retear rates, driven by persistent inflammation and inadequate tissue regeneration. Exosomes derived from M2 macrophages represent a promising therapeutic avenue due to their innate immunomodulatory and regenerative properties. However, their clinical application is hindered by low yields and complex purification processes. In this study, we employed an extrusion technique to isolate exosome mimetics from platelet-rich plasma (PRP) pretreated M2 macrophages. These engineered vesicles, termed PRP-M2-EM, acquired additional bioactive factors from PRP, which significantly enhanced their pro-angiogenic and immunoregulatory functions compared to standard M2-EM. This biomimetic engineering strategy successfully transposes the therapeutic benefits of PRP into a stable, nanoscale delivery system, overcoming the limitations of PRP's short half-life and high production costs. Mechanistically, we identified the enrichment of miR-21a-5p within PRP-M2-EM as a primary driver of their superior efficacy. Further mechanistic investigation revealed that the high expression of miR-21a-5p in PRP-M2-EM targets and inhibits the tissue inhibitor of metalloproteinase 3 (TIMP3) gene, facilitating a regenerative environment. In conclusion, our study introduces engineered PRP-M2-EM as a potential therapeutic strategy. This approach promotes rotator cuff regeneration through enhanced angiogenesis and immunomodulation, with the miR-21a-5p/TIMP3 axis potentially contributing to these effects.