Injectable natural Tremella-derived hydrogel for reversing ferroptosis-mediated osteoporotic microenvironment imbalance and promoting osteoregeneration.

Osteoporotic bone defects constitute a global health predicament due to their restricted self-repairing capacity. Ferroptosis arising from iron overload represents a crucial pathological characteristic of osteoporosis, depleting osteoblasts and disturbing bone metabolism. Inspired by natural tremella polysaccharide (TP), we developed an injectable composite hydrogel (OGP@DTrep) capable of inhibiting cell ferroptosis via dual mechanisms. Following the incorporation of methacrylated TP, oxidized TP, thioketal (TK), and osteogenic growth peptide (OGP), OGP@DTrep exhibits a range of biological activities including intelligent reactive oxygen species (ROS) response and drug release, immunomodulation, promotion of angiogenesis, and inhibition of osteoclast activity. More importantly, since the carboxyl group in TP and the hydroxyl group of the sugar unit can form salt bridge interactions and hydrogen bond linkages with free iron ions, respectively, OGP@DTrep can efficiently chelate excessive iron ions in the microenvironment. Moreover, OGP@DTrep increases the intracellular antioxidant capacity, inhibits osteoblast ferroptosis, and enhances bone matrix secretion. In a rat model of osteoporotic bone defects, it reversed iron metabolism imbalance, restoring bone mass and microstructure. This study presents a naturally derived biomaterial with multiple activities, such as a ROS response and iron metabolism regulation, offering a new perspective for treating osteoporotic bone defects and other bone diseases.