Microfracture is widely used for cartilage repair, but it often yields limited clinical benefit because it predominantly induces fibrocartilage formation. However, the mechanisms underlying this fibrocartilaginous repair remain insufficiently defined. This study reveals for the first time that ferroptosis acts as a critical "switch" regulating the differentiation trajectory of BMSCs, and demonstrates that curcuma-derived extracellular vesicles (CDEVs) can effectively intervene to promote high-quality hyaline cartilage regeneration.

Single‑cell RNA sequencing further delineated a bifurcating differentiation trajectory of bone marrow mesenchymal stem cells (BMSCs) toward either hyaline-like chondrocytes or fibrocartilaginous chondrocytes, with ferroptosis acting as a critical regulator at the branch point. Given the antioxidant and ferroptosis‑modulating activity of curcumin‑derived components, we hypothesized that curcuma‑derived extracellular vesicles (CDEVs) could suppress ferroptosis and bias the differentiation of BMSCs toward hyaline cartilage.To enhance its translational potential, we developed an injectable reactive oxygen species (ROS)-responsive hydrogel enabling sustained CDEVs delivery, which effectively reduced ferroptosis and promoted cartilage regeneration in vivo. 

We choose CDEVs as the inhibition of ferroptosis redirects the differentiation trajectory of BMSCs from a fibrocartilaginous toward a hyaline‑like chondrocytic fate. Our findings reveal Pvu‑miR‑159 delivered by CDEVs targets PTPN12, restoring downstream ERK1/2 phosphorylation and activating the ATF4 pathway, which upregulates GPX4 expression and enhances the capacity to scavenge lipid peroxides, thereby conferring ferroptosis resistance to BMSCs.

Together our findings uncover a ferroptosis‑driven mechanism contributing to suboptimal microfracture repair and support a plant‑vesicle‑based, ROS-responsive delivery strategy to reprogram BMSCs toward improved regenerative outcomes.