Advanced healthcare materialsOct 25, 2025

Improving mRNA Treatments: pHLIP Helps Deliver Genes More Effectively Inside Cells Using Lipid Nanoparticles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Adding pHLIP to lipid nanoparticles improved mRNA release and expression in cells and mice, suggesting a route to stronger mRNA vaccines.

Evidence

This preclinical formulation experiment tested pHLIP-incorporated LNPs in multiple cell lines, mice, and a monkeypox A35R/M1R vaccine model, showing three- to fivefold higher in vitro expression and stronger in vivo protein or immune responses.

Caveat

The abstract reports cell and mouse results only, with no human efficacy or safety outcomes.

Simplified

Messenger RNA (mRNA) has emerged as a transformative technology for combating viral pandemics and malignancies, with lipid nanoparticle (LNP)-based mRNA vaccines playing a pivotal role in the COVID-19 pandemic. However, current LNP face challenges such as low endosomal escape efficiency (<5%), leading to cargo waste and increased costs. To address this, pHLIP-incorporated LNP (mRNA@LNP-pHLIP), leveraging the pH-dependent membrane-insertion properties of pHLIP is developed to enhance endosomal escape. pHLIP undergoes a conformational change in acidic environments, enabling it to insert into endosomal membranes and promote the release of mRNA into the cytosol. In vitro studies demonstrate a three to fivefold increase in mRNA expression across multiple cell lines, while in vivo experiments show sustained and higher protein expression in mice. Applied to a monkeypox vaccine encoding A35R and M1R antigens, mRNA@LNP-pHLIP elicited stronger immune responses, highlighting its potential for next-generation mRNA therapeutics and vaccines.