Reshaping psoriasis topical therapy: Continuous hydrogenation orchestrates 'redox-metabolic homeostasis' for efficient remission and relapse intervention.

Abstract

Psoriasis represents a globally prevalent and chronic dermatological disorder, characterized by persistent hyperkeratosis, self-sustaining inflammatory cycles, and frequent relapse, posing substantial challenges for conventional therapies of compromised efficacy and biosafety. Here, we introduce a transformative strategy of hydrogen-mediated topical psoriasis therapy based on the construction of an in-situ formed, microbubble hydrogel that facilitates significant H₂ generation and subsequently prolonged delivery. By fabricating and incorporating MgH₂ nanoparticles into an amphiphilic, thermosensitive hydrogel via self-assembly in saline, the hydrogen evolution reaction, generated microbubble morphology and storage can be well controlled, reaching optimized H₂ release profile at saturated concentration (∼0.8 mM) over days. We demonstrate marked alleviation of psoriasis-like pathologies with this local hydrogen treatment <i>in vitro</i> and <i>in vivo</i>, revealing superior efficacy compared to both Imiquimod-induced mice model and clinical Calcipotriol drug. Mechanistically, we disclose continuous hydrogenation directly suppresses psoriatic keratinocyte hyperproliferation via anti-Warburg effect and energy metabolic reprogramming through the PKM2-mediated pathway, and meanwhile coordinating redox homeostasis restoration which further disrupts the inflammation-immune feedback loop. We also identify the potency of this H₂-regulated energy metabolism strategy in preventing psoriasis recurrence. Collectively, this work delivers a proof-of-concept of hydrogen-mediated psoriasis energy therapy (HPET) with translatable promise for potentiating long-term management.