Trace PEG-lipid engineering unlocks superior mRNA delivery via albumin-mediated liver targeting and enhanced endosomal escape.

Lipid nanoparticles (LNPs) represent a leading non-viral platform for mRNA delivery, yet achieving efficient tissue-specific targeting and cytosolic release remains challenging. This study addresses this issue by engineering the structure of trace PEG-lipids-a minor but critical component of LNPs. A library of 45 novel PEG-lipids was constructed, and Pr-181-277-featuring an asymmetric linker-was identified as a potent enhancer of hepatic mRNA delivery. Replacing the conventional PEG-lipid in standard LNPs with Pr-181-277 led to a 4.5-fold increase in luciferase mRNA expression and a 5.3-fold improvement in Cre-mediated gene editing efficiency in the liver. Mechanistic studies reveal a synergistic two-step mechanism: 1) In vivo, Pr-181-277 drives the formation of a protein corona enriched with albumin, which could explain the observed liver accumulation. 2) Its structure concurrently enhances membrane instability, which facilitates rapid endosomal escape and cargo release. Our work demonstrates that minimal, rational redesign of the PEG-lipid structure can coordinately overcome both extracellular and intracellular barriers, providing a powerful and simple strategy to advance LNP-based therapeutics.