Fusogenic Lipid-layered RNA Nano-assemblies for Enhanced siRNA Delivery
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RNA nanotechnology has made significant progress in biomedical applications by harnessing various RNA functions. This technology develops RNA nanoparticles that encapsulate and protect siRNA molecules, ensuring sustained therapeutic effects. However, endosomal escape efficiency, low siRNA packaging efficiency, short half-life inside the cytosol remain major challenges. To overcome these issues, we developed fusogenic lipid-layered RNA nano-assemblies for delivering highly packaged siRNA therapeutics via a membrane-fusion-mediated pathway. Fusogenic lipid layers facilitate nanoparticle fusion with cellular membranes, enabling direct cytoplasmic delivery of siRNA and bypassing endosomal entrapment. Our fusogenic lipid-layered RNA nano-assemblies demonstrate high packaging of siRNA, highly efficient intracellular delivery, and sustained siRNA release, resulting in RNAi effects of above 50% up to 7 days. The novel delivery system enhances the potential of siRNA therapeutics for more effective gene silencing therapies.