Curcuma-derived nanovesicle-loaded ROS-responsive hydrogels reprogram iron metabolism to enhance cartilage regeneration after microfracture

Microfracture (MF) 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. In this study, temporal histopathological profiling and integrative bioinformatic analyses of post-microfracture specimens revealed that early extracellular iron accumulation was positively associated with ferroptosis severity. 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. Mechanistically, in vitro assays identified Pvu-miR-159 in CDEVs as a key functional cargo that attenuates ferroptosis via the PTPN12-ERK1/2-ATF4-GPX4 pathway. 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. Together, these 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.