Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates

Abstract

Significance The safe, selective, and efficient delivery of siRNA is a key challenge to the broad application of siRNA therapeutics in humans. Motivated by the structure of lipoproteins, we developed lipopeptide nanomaterials for siRNA delivery. In vivo in mice, siRNA–lipopeptide particles provide the most potent delivery to hepatocytes (ED 50 ∼ 0.002 mg/kg for FVII silencing), with the highest selectivity of delivery to hepatocytes over nontarget cell types (orders of magnitude), yet reported. These materials also show efficacy in nonhuman primates.

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

“…A number of effective in vivo siRNA carriers for hepatic gene knockdown in healthy rodents and nonhuman primates have been reported with a main focus on delivery potency (3,4,6,8,43). Existing carriers are certainly outstanding for manipulating in vivo targets but may not be able to satisfy the low toxicity requirement in late-stage cancerous livers.…”

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…A class of lipopolymeric nanoparticles (LPNPs) has been formulated to maximize systemic delivery to vasculature-rich organs for antitumor RNAi therapies, and the combination of ionizable, low-molecular-weight lipopolymers custom synthesized to optimize cell entry facilitates tumor cell targeting when delivered directly (14)(15)(16)(17)(18)(19)(20)(21)(22). The polymers were synthesized by Significance Glioblastoma is a deadly brain tumor with no cure.…”

Editor’s choice: recent research highlights from the International Journal of Nanomedicine

“…12 Although emerging genome-analysis methods are now sufficiently powerful, fast, and reliable that they are underpinning efforts to elucidate the molecular mechanics of human cancers, that could prove to be helpful for target validation and molecular therapeutic interventions, unfortunately, our basic approach to treat cancer has remained essentially unchanged over decades and the medicines used have clear limitations. 13,14 Nevertheless, in the quest for better drug delivery, nanomedicine represents a new "powerful platform", which holds a great promise and is increasingly gaining momentum, 15 to deliver multiple drugs 16 at a time, which is profoundly an "advancing approach" to treat cancer patients.…”