Transcutaneous Immunotherapy for RNAi: A Cascade-Responsive Decomposable Nanocomplex Based on Polyphenol-Mediated...

Area of Science:

• Biotechnology
• Dermatology
• Nanomedicine

Background:

• Skin immune dysfunction underlies various diseases, including psoriasis, affecting over 125 million globally.
• RNA interference (RNAi) therapy shows promise but faces challenges in siRNA degradation and cell penetration.
• Transdermal delivery and controllable nanodrug systems are crucial for maximizing RNAi therapeutic efficacy.

Purpose of the Study:

• To develop a novel transdermal RNAi drug delivery system for enhanced treatment of skin immune diseases.
• To overcome the limitations of traditional RNAi therapies, such as rapid degradation and poor cellular uptake.
• To utilize tetrahedral framework nucleic acid (tFNA) for efficient and noninvasive transdermal gene transport.

Main Methods:

• Engineered a novel transdermal RNAi drug (STT) by integrating tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA.
• Designed STT for acid-responsive, controllable assembly and disassembly for targeted drug release.
• Evaluated STT's stability against enzymatic, serum, and lysosomal degradation and its transdermal transport capabilities.

Main Results:

• STT demonstrated enhanced resistance to degradation and efficient transdermal transport due to its tFNA carrier size.
• Transdermal administration of STT successfully silenced nuclear factor kappa-B (NF-κB) p65 in the skin.
• The treatment stabilized the skin's microenvironment and restored normal immune defense mechanisms.

Conclusions:

• STT represents a significant advancement in transdermal RNAi therapy for skin diseases.
• The controllable assembly/disassembly and enhanced stability of STT improve therapeutic outcomes.
• This novel nanodrug delivery system holds potential for future treatments of various skin-related immune disorders.