Nature communicationsMay 29, 2026

Protein-designed lipid nanoparticles for mRNA delivery with low immune response

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 28, 2026

Abstract

Essence

A polypeptide-based lipid nanoparticle platform delivered mRNA effectively in mice while provoking less repeat-dose antibody reactivity than PEG-based formulations.

Evidence

This formulation and mouse immunization study identified poly(D,L-serine) lipid nanoparticle designs with high mRNA encapsulation and transfection efficiency, superior spike mRNA delivery versus the BNT162b2-like ALC-LNP comparator, robust cellular and humoral responses, minimal anti-pDLS IgM after repeated dosing, and frozen stability beyond 6 months.

Caveat

The evidence is preclinical platform work centered on mouse immune responses and delivery performance, not human safety or repeated-dose clinical efficacy.

Simplified

Lipid nanoparticles (LNPs) have shown great potential for mRNA delivery, with polyethylene glycol (PEG) lipids playing a critical role in modulating particle size, stability and biodistribution. However, most PEGylated LNPs induce anti-PEG antibodies, leading to hypersensitivity and diminished efficacy upon repeated administration. Here we report hydrophilic, nonionic and biodegradable poly(D, L-serine) (pDLS) lipids as PEG-lipid alternatives in LNP formulations. Through systematic structural screening, we identify optimal lipid architectures that yield colloidally stable pDLS-LNPs with high mRNA encapsulation and transfection efficiency. Compared to the clinically approved BNT162b2 formulation (ALC-LNP), pDLS-LNPs loaded with SARS-CoV-2 spike mRNA achieve superior mRNA delivery, and elicit robust cellular and humoral immune responses in mice, without inducing systemic toxicity. Notably, repeated dosing with pDLS-LNPs triggers minimal anti-pDLS IgM production, unlike PEG-based counterparts. Furthermore, pDLS-LNPs remain stable under frozen storage for over 6 months. These findings establish polypeptide-based pDLS-LNPs as promising, immunologically inert alternatives to PEGylated LNPs for safe and effective mRNA delivery.