Suppression of Hepatic Inflammation via Systemic siRNA Delivery by Membrane-Disruptive and Endosomolytic Helical Polypeptide Hybrid Nanoparticles

Treatment of inflammatory diseases represents one of the biggest clinical challenges. RNA interference (RNAi) against TNF-alpha provides a promising modality toward anti-inflammation therapy, but its therapeutic potential is greatly hampered by the by the lack of efficient siRNA delivery vehicles in vivo. Herein, we report a hybrid nanoparticulate (HNP) system based on a cationic helical polypeptide PPABLG for the efficient delivery of TNF-alpha siRNA. The helical structure of PPABLG features pore formation on cellular and endosomal membranes to facilitate the direct translocation as well as endosomal escape of TNF-alpha siRNA in macrophages, representing a unique superiority to a majority of the existing polycation-based gene vectors that experience severe endosomal entrapment and lysosomal degradation. As such, HNPs containing TNF-alpha siRNA afforded effective systemic TNF-alpha knockdown following systemic administration at a low dose of 50 mu g of siRNA/kg and thus demonstrated a potent anti-inflammatory effect to rescue animals from LPS/D-GalN-induced hepatic sepsis. This study therefore verifies that the bioactive secondary structure of polypeptides significantly dominates the in vivo siRNA delivery efficiency, and the unique properties of PPABLG HNPs render remarkable potentials for anti-inflammation therapies.