Poly(N‐methyl‐N‐vinylacetamide): A Strong Alternative to PEG for Lipid‐Based Nanocarriers Delivering siRNA

Abstract Lipid‐based nanocarriers have demonstrated high interest in delivering genetic material, exemplified by the success of Onpattro and COVID‐19 vaccines. While PEGylation imparts stealth properties, it hampers cellular uptake and endosomal escape, and may trigger adverse reactions like 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 siRNA delivery. PNMVA compounds with different degrees of polymerization and hydrophobic segments, are synthesized. Among them, DSPE (1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine)‐PNMVA efficiently integrates into lipoplexes and LNP membranes and prevents protein corona formation around these lipid carriers, exhibiting stealth properties comparable to DSPE‐PEG. However, unlike DSPE‐PEG, DSPE‐PNMVA 24 shows no adverse impact on lipoplexes cell uptake and endosomal escape. In in vivo study with mice, DSPE‐PNMVA 24 lipoplexes demonstrate 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 is 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.