A spatiotemporally controlled MNE@PDA-Diz/GP hydrogel system: enhancing spinal cord injury repair via ROS scavenging, calcium influx inhibition, and macrophage polarization.

Spinal cord injury (SCI) is a severe type of central nervous system trauma. It not only causes the loss of sensory and motor function but also triggers a series of secondary injuries, especially oxidative stress and inflammation. Current therapeutic methods fail to effectively address the multi-pathological cascade reactions, highlighting an urgent need for integrated treatment strategies that can simultaneously repair the damaged microenvironment and promote neural regeneration. In this study, a multifunctional thermosensitive MNE@PDA-Diz/GP hydrogel was designed. We incorporated a core-shell structured manganese nanozyme@polydopamine (MNE@PDA), modified with dizocilpine, into gelatin methacryloyl and a poly(N-isopropylacrylamide) hydrogel (GP hydrogel), featuring a thermosensitive polymer. The MNE@PDA-Diz/GP hydrogel, which was crosslinked under UV-vis light, provides a biocompatible three-dimensional scaffold that mimics the natural mechanical properties of the spinal cord, thereby supporting cell adhesion and proliferation. Meanwhile, the photothermal properties of polydopamine and the thermosensitivity of poly(N-isopropylacrylamide) enable spatiotemporally controlled release of dizocilpine. These three components work in synergy: the manganese nanozyme scavenges reactive oxygen species to exert anti-oxidative effects, polydopamine modulates macrophage polarization to alleviate inflammation, and dizocilpine inhibits calcium influx to provide neuroprotection. This work presents a novel and versatile platform for multi-targeted SCI therapy and promotes the development of regenerative strategies.