ROS-scavenging and oxygen-generating MgMn-LDH integrated smart injectable hydrogel for microenvironment-reprogrammable spinal cord injury repair

Abstract

Spinal cord injury (SCI) induces the formation of a complex pathological microenvironment characterized by excessive reactive oxygen species (ROS) accumulation, persistent hypoxia and severe inflammatory responses, which severely impairs the processes of neural regeneration and functional recovery. To address these critical issues, we constructed a hydrogel system for the synergistic repair of SCI by integrating magnesium-manganese layered double hydroxides (MgMn-LDHs) into a ROS/pH-responsive GelMA-PBA/HA-DA hydrogel matrix. Harnessing the redox activity of Mn³⁺, MgMn-LDHs efficiently scavenge excess ROS and create a regenerative microenvironment favorable for neural repair. Meanwhile, Mg²⁺ promotes axonal elongation, myelination and the polarization of anti-inflammatory M2 macrophages by regulating key neural differentiation signaling pathways. The GelMA-PBA/HA-DA hydrogel, crosslinked via dynamic boronate ester bonds, enables the precise and controlled release of MgMn-LDHs in the acidic and highly oxidative pathological microenvironment post-SCI. In vitro experiments demonstrated that this hydrogel system could effectively support the proliferation and neurite outgrowth of PC12 cells under hypoxic and ROS-enriched conditions, inhibit the secretion of pro-inflammatory cytokines, and significantly promote vascular regeneration. In vivo studies in a mouse SCI model revealed that the hydrogel system markedly improved locomotor function, reduced the expression levels of inflammatory markers, ameliorated the inflammatory status of injured tissues, and effectively facilitated axonal regeneration and remyelination at the injury site. This MgMn-LDHs-loaded GelMA-PBA/HA-DA hydrogel system establishes a multifunctional and translatable therapeutic platform for SCI treatment, and also provides valuable insights for the research on therapeutic strategies against other neurodegenerative diseases.