Dual-network hyaluronic acid hydrogel incorporating FGF21 and layered black phosphorus nanosheets for anti-ferroptosis therapy in spinal cord injury

Ferroptosis-induced oxidative stress triggers mitochondrial damage in spinal cord injury (SCI), impairing residual neuronal function and driving microglial M1 polarization. Regulating neuronal mitochondrial function is an urgent problem in the field of tissue engineering. To address this, an injectable dual-network hyaluronic acid/black phosphorus (BP)/ fibroblast growth factor 21 (FGF21) composite hydrogel (ADBF) is explored, and the successful application of this functional hydrogel in SCI repair is demonstrated. The two-dimensional BP matrix enables high-efficiency loading of macromolecular drugs such as FGF21. Sustained FGF21 release from ADBF reduces neuronal oxidative stress and mitigates neurodegeneration. Subsequent exposure of BP nanosheet surfaces enhances cation adsorption (e.g., iron ions), thereby inhibiting ferroptosis. In a mouse model of SCI, behavioral, electrophysiology and immunohistochemistry investigations suggested that the composite ADBF hydrogels can effectively promote functional repair by enhancing remyelination, accelerating axonal regeneration, inhibiting neurons ferroptosis and regulating immune microenvironment of nerve regeneration. Mechanistically, ADBF attenuates ferroptosis by restoring mitochondrial function via the AMPK/AKT signaling axis, consequently promoting microglial M2 polarization. This strategy of integrating BP/FGF21 nanosheets into an injectable conductive hydrogel provides new insight into designing advanced anti-ferroptosis therapy biomaterials for SCI repair.