Small (Weinheim an der Bergstrasse, Germany)Jul 23, 2026

Changing the Fat and Connector Parts of PEG-Lipids Helps mRNA Nanoparticles Target Muscle Cells More Precisely

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 24, 2026

Abstract

P1B LNPs achieve highly efficient and selective mRNA delivery to skeletal muscle with drastically minimized hepatic off-targeting.

P1B LNPs were derived from a 45-member PEG-lipid library and showed improved muscle cell uptake.
The unique branched, asymmetric tail of P1B LNPs enhances interactions with muscle cell membranes.
In Ai9 reporter mice, P1B LNPs enabled effective muscle-specific gene editing while reducing off-target effects.
As an RSV mRNA vaccine, P1B LNPs produced strong antigen-specific IgG responses and increased polyfunctional CD8+ T cells.
Re-engineering the trace PEG-lipid may address targeting limitations present in classical lipid nanoparticles.

Simplified

Intramuscular mRNA lipid nanoparticles (LNPs) often exhibit undesirable liver accumulation, compromising safety and efficacy. While optimization efforts focus on ionizable and helper lipids, the role of trace PEG-lipids remains underexplored. To address this, we constructed a 45-member PEG-lipid library via Ugi/Passerini reactions, keeping the PEG chain constant at 2 kDa while systematically diversifying the hydrophobic tail and linker structures. High-throughput screening identified Pr-182-BNT (P1B LNP) as a lead candidate. P1B LNPs enable highly efficient and selective mRNA delivery to skeletal muscle while drastically minimizing hepatic off-targeting. This precise tropism originates from enhanced muscle cell uptake and optimized membrane interactions, driven by the lipid's unique branched, asymmetric tail. In Ai9 reporter mice, P1B LNPs drive potent muscle-specific gene editing and reduce off-target recombination. As an RSV mRNA vaccine, they elicit robust antigen-specific IgG titers and expands polyfunctional CD8⁺IFN-γ⁺ T cells, indicating a Th1-skewed response. By re-engineering only the trace PEG-lipid, this work overcomes a key targeting limitation of classical LNPs and establishes a translatable platform for safer, more effective mRNA vaccines and therapeutics.