Transcutaneous Immunotherapy for RNAi: A Cascade‐Responsive Decomposable Nanocomplex Based on Polyphenol‐Mediated Framework Nucleic Acid in Psoriasis

Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.