ROS-responsive bilayer microneedles loaded with methotrexate and cerium oxide nanoparticles for synergistic treatment of psoriasis.

Psoriasis, a chronic inflammatory skin disease, is characterized by excessive keratinocyte proliferation, dysregulated inflammation, and reactive oxygen species (ROS) accumulation, forming a refractory "ROS-inflammation-proliferation" cycle. Methotrexate (MTX) has poor skin bioavailability due to the stratum corneum, while cerium oxide (CeO2) nanoparticles suffer from short local retention, limiting their efficacy. Here, we developed a ROS-responsive bilayer microneedle (MN) system: the lower polyvinyl alcohol-TSPBA (PVA-TSPBA, ROS-labile) tip loads MTX, and the upper photocrosslinkable methacrylamide gelatin (GelMA) backing encapsulates CeO2, fabricated via two-step mold-casting. The optimal formulation (10% PVA-3% TSPBA tip, 10% GelMA backing) yielded MNs with intact sharp tips, sufficient mechanical strength, and a clear bilayer structure. In vitro, PVA-TSPBA showed ROS-dependent MTX release, GelMA enabled sustained CeO2 release, and HaCaT cell experiments confirmed good biocompatibility. In psoriasis mice, MTX/CeO2-loaded MNs alleviated lesions, normalized epidermal thickness, and downregulated Ki67 and pro-inflammatory cytokines (TNF-α, IL-17A, IL-6, IL-23) versus drug-free MNs. This system achieves spatiotemporal synergy to disrupt psoriasis' pathological cycle, providing a novel local treatment strategy.