Using siRNA-Based Anti-Inflammatory Lipid Nanoparticles for Gene Regulation in Psoriasis.

Background: Psoriasis is a chronic inflammatory autoimmune disease, yet it affects hundreds of millions of people. Long-term effective intervention of the disease by targeting the causative genes via RNAi (RNA interference) has become a reality. However, its further application is hindered by inflammatory side effects caused by delivery systems such as LNP (lipid nanoparticles). Purpose: This study aimed to develop a novel anti-inflammatory LNP rationally tailored for topical application in psoriasis and to validate its potential to deliver Stat3 (signal transducer and activator of transcription 3) siRNA for the treatment of psoriasis. Methods: To assess the transfection efficiency, anti-inflammatory capacity of LNPs. The therapeutic effect of modified anti-inflammatory LNP delivery of Stat3 siRNA on psoriasis was evaluated both in vitro and in an imiquimod-induced mice. Results: LNPs exhibit both superior transfection efficiency and significant anti-inflammatory effects. In vitro functional studies showed that in an inflammatory DC model, anti-inflammatory LNP (C8B2) inhibited inflammatory mediators much better than classical LNPs by delivering Stat3 siRNA; in pathological HaCat cells, Stat3 siRNA reduced cell proliferation and promoted apoptosis. In the imiquimod-induced mouse model, the C8B2-si-Stat3 group demonstrated a clear reduction in psoriasis progression, whereas the C8B2 carrier group also exhibited a notable decrease in inflammation. Conclusion: In this study, we successfully developed a novel anti-inflammatory LNP, which demonstrated notable advantages in delivery capacity, anti-inflammatory effect, and targeting therapy against STAT3, providing new ideas and strategies for nucleic acid therapy of psoriasis. This LNP platform could be broadly applicable to various inflammatory conditions, offering a versatile tool for targeted gene modulation and inflammation control.