Antioxidant MnO2 nanozymes-encapsulated hydrogel synergistically regulate the spinal ROS microenvironment and promote spinal cord repair

Traumatic spinal cord injury (SCI) usually leads to neuronal death and axon destruction, resulting in long-term dysfunction, permanent functional impairment, significant caregiving demands, and substantial financial burden. Therefore, a crucial aspect of SCI recovery lies in understanding how to inhibit neural stem cell (NSC) death, regulate the spinal microenvironment and promote the regeneration of neurons and axons. Herein, we designed dopamine (DA)-modified hyaluronic acid (HA) with the bridging of CeCl3 molecules, termed the CHD hydrogel. To confer regenerative properties to the hydrogel, we incorporated metformin (Met) and manganese dioxide (MnO2) to form the MnO2/Met@CHD hydrogel. The MnO2/Met@CHD hydrogel could promote the NSC adhesive growth and nerve tissue bridging, and improve neuronal differentiation and neurite outgrowth in a pathological ROS microenvironment, suggesting its excellent effect against oxidative stress. Furthermore, the MnO2/Met@CHD hydrogel can facilitate the migration and accumulation of nestin+ NSCs and inhibit GFAP+ astrocytic scar formation, thereby providing optimized microenvironments for axonal regeneration. Collectively, the MnO2/Met@CHD hydrogel system shows great promise as a novel approach for the treatment of SCI.