Boosting mRNA Therapeutics: pHLIP Enhances Endosomal Escape and Gene Expression in Lipid Nanoparticle

Oct 25, 2025Advanced healthcare materials

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

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Current lipid nanoparticle (LNP) systems have less than 5% efficiency in endosomal escape.

Low endosomal escape efficiency in existing LNP systems results in significant cargo waste.
The development of pHLIP-incorporated LNP (mRNA@LNP-pHLIP) aims to improve this efficiency.
pHLIP undergoes a change in acidic environments, facilitating the release of mRNA into the cytosol.
In vitro studies indicate a three to fivefold increase in mRNA expression across various cell lines.
In vivo experiments in mice show sustained and higher protein expression compared to traditional methods.
Application of mRNA@LNP-pHLIP to a monkeypox vaccine resulted in stronger immune responses.

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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.