<p>A multifunctional liposomal hydrogel nanoplatform (CMH@lip@Res-TCeO₂) was developed for the targeted treatment of psoriasis-like skin inflammation through combined antioxidant and anti-inflammatory mechanisms. The system integrates resveratrol (Res) and mitochondria-targeted cerium oxide nanozymes (TPP-CeO₂) within a thermo-responsive hydrogel matrix, enabling sustained transdermal delivery and enhanced local drug retention. Network pharmacology and transcriptomic analyses identified 36 key targets and highlighted the ROS/mTOR/HIF-1α axis as a critical pathway in neutrophil regulation. Single-cell RNA sequencing revealed fibroblasts, keratinocytes, and neutrophils as key cellular contributors to psoriasis pathogenesis. CMH@lip@Res-TCeO₂ effectively suppressed mitochondrial reactive oxygen species (ROS) accumulation, inhibited mTOR/HIF-1α activation, reduced neutrophil extracellular trap (NET) formation, and alleviated keratinocyte dysfunction. In IMQ-induced psoriasis-like mice, the treatment significantly decreased inflammatory cytokine expression and improved histopathological features. These findings demonstrate that CMH@lip@Res-TCeO₂ exerts multi-level regulation of oxidative stress, metabolism, and inflammation, offering a promising nanotherapeutic strategy for psoriasis and other chronic inflammatory skin disorders.</p> Graphical Abstract <p></p>