Poly(acrylamido) PEG-Alternative Lipids Rescue mRNA Efficacy during Repeated Dosing and Enhance Immune Cell Delivery
5 affiliations
- 1UCL School of Pharmacy, University College London, London WC1N 1AX, U.K.
- 2UCL Cancer Institute, Department of Haematology, University College London, London WC1E 6DD, U.K.
- 3UCL Centre for Advanced Biomedical Imaging, University College London, London WC1E 6DD, U.K.
- 4School of Pharmacy, University of Nottingham to Division of Molecular Therapeutics and Formulation, Boots Science Building, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
- 5ISIS Neutron and Muon Source, Rutherford Appleton Laboratory, Didcot OX11 0DE, U.K.
Abstract
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.
Related
- Novel modifications of small extracellular vesicles to enhance cardiac-specific delivery of siPKA RNA and edaravone against ischemia-reperfusion cardiac injury
- Vitamin K3 (Menadione) Targets TBK1 to Enhance the Efficacy of Pirfenidone in a Mouse Model of Bleomycin-Induced Pulmonary Fibrosis
- Alternative splicing of a species- and skeletal muscle-specific microexon diversifies the menu of clathrin heavy chains in mice and rats
- Structural basis of phospholipid sensing nuclear receptor LRH-1 recognition by carboxylic acid bioisosteres reveals an alternative ligand interaction site
- Lactate promotes mitochondrial biogenesis and fusion via GPR81 to enhance synaptic plasticity-related protein expression in hippocampal cells
BibTeX
@article{fiedler2026polyacrylamido,
title = {{Poly(acrylamido) PEG-Alternative Lipids Rescue mRNA Efficacy during Repeated Dosing and Enhance Immune Cell Delivery}},
author = {Benjamin M. Fiedler and Charlotte Galley and Margarita Strimaite and Nga Man Cheng and Najet Mahmoudi and Zhiping Feng and Tammy L. Kalber and Maria-Jose Martinez-Bravo and Christopher J. Morris and Jenny K. W. Lam and Daniel J. Stuckey and Gareth R. Williams and Clare L. Bennett and Pratik Gurnani},
journal = {ACS Nano},
year = {2026},
month = oct,
doi = {10.1021/acsnano.6c11940},
url = {https://doi.org/10.1021/acsnano.6c11940},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Poly(acrylamido) PEG-Alternative Lipids Rescue mRNA Efficacy during Repeated Dosing and Enhance Immune Cell Delivery
AU - Benjamin M. Fiedler
AU - Charlotte Galley
AU - Margarita Strimaite
AU - Nga Man Cheng
AU - Najet Mahmoudi
AU - Zhiping Feng
AU - Tammy L. Kalber
AU - Maria-Jose Martinez-Bravo
AU - Christopher J. Morris
AU - Jenny K. W. Lam
AU - Daniel J. Stuckey
AU - Gareth R. Williams
AU - Clare L. Bennett
AU - Pratik Gurnani
PY - 2026
DA - 2026/10/22
JO - ACS Nano
DO - 10.1021/acsnano.6c11940
UR - https://doi.org/10.1021/acsnano.6c11940
AB - 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.
SN - 1936-0851
SN - 1936-086X
ER -