Spatiotemporal Co‐Delivery of Hydrogen and Magnesium via Microneedle Patches for Neuroinflammation Modulation After Spinal Cord Injury: A Multi‐Modal In Vivo Study

Spinal cord injury (SCI) treatment is hindered by a "triple barrier:" the physical dura, a chemical storm of reactive oxygen species (ROS), and an immune barrier mediated by pro-inflammatory microglia. To address these, we developed a "Hydrogen/Magnesium dual-engine microneedle" (MN-Mg) system by embedding magnesium (Mg) microparticles within a methacrylated hyaluronic acid (HAMA) hydrogel matrix via micromolding. Possessing high mechanical strength, Mg-MNs penetrate the dura mater. Upon implantation, the system triggers a controllable magnesium-water reaction, initiating a spatiotemporally synergistic dual-engine therapeutic mode. The "hydrogen engine" rapidly releases high-concentration hydrogen gas (H₂) during the acute SCI phase. It efficiently scavenges ROS storm (reducing levels by 55%) by inhibiting the MAPK pathway and downregulating AP-1 transcription, creating an antioxidant window for neural repair. Subsequently, the "magnesium engine" provides sustained Mg² ⁺ release during the subacute phase, exerting a dual restorative effect: induces microglia polarization toward the pro-reparative M2 phenotype (4.8-fold increase) and promotes axonal regeneration (2.9-fold increase). This synergy leads to locomotor recovery in a rat SCI model, with scores improving from 5.5 ± 1.05 (Controls) to 14.8 ± 1.17 at 8 weeks. This "Penetration-Confinement-Dual-Engine Modulation" paradigm enables spatiotemporal synergistic H2/Mg therapy supported by an elucidated ROS-MAPK/AP-1 regulatory axis, advancing SCI treatment from symptomatic relief to targeted neural microenvironment reconstruction.