Lipid Nanoparticle-mediated Delivery of Small Interfering RNA for Cancer Therapy

Abstract

RNA interference (RNAi) effectors such as small interfering RNA (siRNA) and microRNA (miRNA) are promising drug candidates because of their selectivity, potency, and versatility. For the development of RNAi therapeutics, a practical delivery system is required to deliver siRNA to target cells because RNA is easily degraded by RNases and hardly internalized into the cells. Development of the delivery system is the most urgent and crucial thing for clinical use of RNAi effectors. In this review, we first discuss our current understanding of the challenges for the development of RNAi therapeutics and then focus on our recent progress in engineering lipid nanoparticles (LNP) loaded with siRNA. In our recent studies, we synthesized various types of polycationic lipid derivatives, used them to prepare LNP, and demonstrated their high potential for siRNA delivery. Peptide-modified LNP carrying cholesterol-grafted siRNA were designed for systemic targeted delivery and examined their biodistribution and therapeutic efficacy in tumor-bearing mice. Our results showed that peptide-modified LNP loaded with siRNA targeting mammalian target of rapamycin (mTOR) were selectively delivered to the tumor and significantly suppressed tumor growth. The present findings suggest that our LNP is useful for systemic targeted delivery of siRNA.