Poly(acrylamido) PEG-Alternative Lipids Rescue mRNA Efficacy during Repeated Dosing and Enhance Immune Cell Delivery

Following the successes of the messenger RNA (mRNA) lipid nanoparticle (LNP) vaccines against COVID-19, mRNA-LNPs are being explored for varied multidose applications including cancer immunotherapies and protein replacement therapies. LNPs rely on poly(ethylene glycol)-lipid (PEG-lipid) coatings for stability, but increasing anti-PEG antibody prevalence threatens repeat-dose efficacy and increases pseudoallergic risk, creating an urgent need for alternatives. Here, we introduce poly(acrylamido) lipids (PAM-lipids), a family of polymer lipids that effectively replace PEG-lipids in mRNA-LNP formulations. Systematic variation of monomer chemistry, molar mass, and end group reveals critical structure-activity relationships determining LNP size, polydispersity, and transfection efficiency. Varying PAM monomer chemistry allows minimization of antipolymer antibody cross-reactivity, with multiple PAM-lipids demonstrating no anti-PEG antibody binding. Several PAM-LNPs exhibit superior mRNA transfection efficacy to PEGylated clinical benchmarks in vitro and in vivo across multiple cell types, organs, routes of administration, and mRNA cargos. In particular, lead PAM-LNPs enhance mRNA delivery to dendritic cells (up to 120-fold in vitro and 3-fold in vivo) and macrophages (4-fold in vivo), with 2.5-fold superior lymph node expression, driven in part by increased cellular association and lymphoid targeting. Crucially, PAM-LNPs evade circulating anti-PEG antibodies to rescue lost mRNA efficacy after repeated dosing, resulting in 300% mRNA expression relative to that of PEG-LNPs. These findings demonstrate PAM-lipids as a chemically varied, immunologically compatible family of PEG alternatives for mRNA-LNP therapeutics.

Abstract from PubMed (PMID 42975285). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.