Poly(N-methyl-N-vinylacetamide): A Strong Alternative to Peg for Lipid-Based Nanocarriers Delivering Sirna.

Lipid-based nanocarriers such as liposomes or lipid nanoparticles (LNPs) have demonstrated high interest in delivering genetic material. This has been recently emphasized by the approval of Onpattro ® and COVID-19 vaccines. PEGylation is known to provide lipid-based nanocarriers with stealth properties, but it also leads to reduced cellular uptake and endosomal escape, and to the production of anti-PEG antibodies causing accelerated blood clearance (ABC) and hypersensitivity reactions (HSR). This work highlights the great potential of amphiphilic poly(N-methyl-N-vinylacetamide) (PNMVA) derivatives as alternatives to lipid-PEG for post-insertion into lipoplexes and pre-insertion into LNPs designed for siRNA delivery. PNMVA compounds with different degrees of polymerization and hydrophobic segments, such as octadecyl and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), were synthesized. Among them, DSPE-PNMVA efficiently integrated into lipoplex and LNP membranes and prevented protein corona formation around these lipid carriers, exhibiting stealth properties comparable to DSPE-PEG. However, unlike DSPE-PEG, DSPE-PNMVA 24 showed no adverse impact on lipoplexes cell uptake and endosomal escape. In in vivo study with mice, DSPE-PNMVA 24 lipoplexes demonstrated no liver accumulation, indicating good stealth properties, extended circulation time after a second dose, reduced immunological reaction, and no systemic pro-inflammatory response. Safety of DSPE-PNMVA 24 was confirmed at the cellular level and in animal models of zebrafish and mice. Overall, DSPE-PNMVA is an advantageous substitute to DSPE-PEG for siRNA delivery, offering comparable stealth and toxicity properties while improving efficacy of the lipid-based carriers by minimizing the dilemma effect and reducing immunological reactions, meaning no ABC or HSR effects. This article is protected by copyright. All rights reserved.