Transfersomes with core and surface‐loaded NF‐κB p65 siRNA for enhanced transdermal transfection and effective treatment of psoriasis

Abstract Psoriasis, an immune‐mediated skin disorder, affects over 125 million people worldwide. Its primary manifestations include abnormal keratinocyte proliferation, epidermal inflammatory cell infiltration, and excessive neovascularization, and no fundamental intervention is currently available. Although siRNA therapy based on the RNA interference mechanism has opened a new avenue for the definitive treatment of psoriasis, its clinical application is limited by rapid degradation and low transfection efficiency, compounded by the skin's dense structure that hinders noninvasive transdermal delivery. To address these issues, we developed a transdermal siRNA delivery system using polyethylenimine (PEI) and Tween 80‐modified transfersomes (TCPL) as carriers for NF‐κB p65 siRNA (TCPL@siNF‐κB). By embedding Tween 80 and PEI into the TCPL, the system achieves excellent proton buffering capacity, enabling multilayer encapsulation of siNF‐κB at both the core and surface levels, effectively preventing its degradation in serum and enzymatic environments. This strategy resolves the molecular weight‐dependent conflict between the transfection efficiency and toxicity of PEI, achieving a balanced performance. Moreover, TCPL exhibits ultradeformability, and this study demonstrates the advantages of Tween 80 in promoting transdermal gene transfection. TCPL@siNF‐κB demonstrated efficient lysosomal escape and intracellular delivery via clathrin‐mediated endocytosis and macropinocytosis, achieving high transfection efficiency. In vitro inflammatory models and a psoriasis‐like mouse model confirmed that TCPL@siNF‐κB enables efficient gene delivery through simple topical application, effectively silences NF‐κB signaling, modulates the immune microenvironment, inhibits aberrant angiogenesis, and significantly alleviates psoriatic symptoms, while exhibiting excellent biocompatibility. Therefore, this study offers a promising non‐invasive gene therapy strategy for psoriasis and other potential inflammatory skin disorders.