Integrated O2 and H2 Gas Therapy via Microneedle-Assisted Photocatalytic Water Splitting for Accelerating Diabetic Full-Thickness Skin Wound Healing.

Impaired wound healing in diabetes is closely associated with cellular ferroptosis. Microneedle-assisted gas therapy exerts molecular regulation of ferroptosis, representing a promising approach for accelerating diabetic wound healing. To date, O2 and H2 gas therapies have consistently been conducted independently and have never been integrated into a single system. Whether and how their synergy might be realized remains a defining challenge. Herein, we propose a concept of integrated O2 and H2 gas therapy, demonstrated by fabricating a gas-producing microneedle material. Platinum@MIL-101(Fe)-NH2@phosphotungstic acid (PMP) nanoparticles are synthesized as a visible light-driven photocatalyst for H2 and O2 co-evolution. The rational design of a spatially separated structure boosts their photocatalytic efficiency under physiological conditions. PMP nanoparticles are further incorporated with bilayer gelatin methacryloyl (GelMA)/PMP composite microneedles (denoted as GPM microneedles). The obtained GPM microneedles enable transdermal delivery of PMP nanoparticles for integrated O2 and H2 gas therapy, and demonstrate desirable biocompatibility and pro-regenerative effects. The mechanism of integrated O2 and H2 gas therapy has been identified as a TNFAIP3/hnRNPA1 ubiquitination/ferroptosis signaling axis, establishing for the first time a direct link to ferroptosis. In conclusion, this study yields a transformative concept and a ferroptosis-targeting microneedle material with well-defined molecular mechanism for diabetic wound management.