Breaking the Psoriatic Inflammation–Proliferation Loop Through a Dual‐Engineered High‐Entropy Alloy Featuring Predictable Multi‐Enzyme Activity and STAT3‐Sponge Function

ABSTRACT Psoriasis is sustained by a self‐amplifying loop in which reactive oxygen species (ROS) drive proinflammatory cytokine release, while activated JAK–STAT3 signaling reciprocally elevates keratinocyte ROS production. Current nanozyme strategies mainly target the ROS arm, leaving the upstream STAT3 signaling insufficiently addressed. In this study, a dual‐engineering paradigm combining atomic composition design and surface charge engineering was established on PtPdCuFe high‐entropy alloy nanoparticles (HEA NPs) to disrupt both arms. All‐atom simulations revealed that local atomic neighborhoods governed their surface electronic structures and enzyme‐like activities. In imiquimod (IMQ)‐induced psoriatic mice, these compositions attenuated epidermal hyperplasia through the restoration of suppressor of cytokine signaling 1 (SOCS1), which bridged ROS rebalancing to JAK–STAT suppression; meanwhile, residual STAT3 activation remains unresolved. Surface charge engineering across five chemistries yielded a therapeutic hierarchy (negative > neutral ≈ positive > zwitterionic > polyvinylpyrrolidone). Proteomics, isothermal titration calorimetry, and proximity ligation assays demonstrated that anionic surfaces electrostatically sequester STAT3. Prior treatment also attenuated, without abolishing, recurrence upon IMQ rechallenge, and subcutaneous delivery was well‐tolerated for over 28 days. The dual mechanism coupled an inside‐out pathway (SOD‐catalyzed SOCS1 restoration) with an outside‐in pathway (electrostatic STAT3 capture), establishing catalytic–electrostatic dual‐loop disruption as a paradigm for anti‐inflammatory therapy.