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

ABSTRACT 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 (H ₂ ) 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 Mg ^{2 +} 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.