Biomaterials advancesOct 13, 2026

pH-sensitive polymer that changes from water-attracting to water-repelling to help cells take in mRNA using light

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 14, 2026

Abstract

The polymer conjugate achieved more than 80-fold photoenhancement for cell-specific delivery of mRNA in cultured cells.

A polymer containing phenylboronic acid moieties can act as a delivery system for photosensitizers in targeted therapies.
At extracellular pH, the phenylboronic acid groups form boronate esters with L-DOPA, leading to selective uptake by cancer cells.
The acidic environment in endo-/lysosomes breaks these boronate esters, which releases L-DOPA and alters the polymer's properties.
This alteration enhances the polymer's ability to interact with endo-/lysosomal membranes, improving photochemical internalization.
Light-selective mRNA expression was demonstrated in tumor tissue within a murine model using this delivery system.

Simplified

Cell-specific intracellular delivery of messenger RNA (mRNA) remains a challenge in the development of RNA therapeutics. Photochemical internalization (PCI) is a useful technology for the spatially controllable cytosolic delivery of such molecules in a light-selective manner, but cellular-level precision has yet to be realized due to the intrinsic amphiphilicity of conventional photosensitizers (PSs). Here, we report that a polymer conjugate bearing phenylboronic acid (PBA) moieties in the side chain can be utilized as a PS delivery system for cell-specific PCI. At extracellular pH, the PBA moieties can form boronate esters with l-3, 4-dihydroxyphenylalanine (L-DOPA), and this PS-polymer with L-DOPA shows hydrophilicity and achieves selective internalization into cancer cells through amino acid transporter-mediated endocytosis. The acidic pH of endo-/lysosomes then cleaves the boronate esters, liberating L-DOPA and inducing a hydrophilic-to-hydrophobic conversion of the polymer. This conversion facilitates the interaction of the polymer with the endo-/lysosomal membrane, which is preferable for PCI. Indeed, the polymer accomplished cell-specific PCI of co-administered mRNA polyplexes with more than 80-fold photoenhancement in cultured cells and achieved light-selective mRNA expression in the tumor tissue of a murine model. The concept of our polymer based on boronic acid chemistry may offer a unique approach to develop mRNA therapeutics.

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pH-sensitive polymer that changes from water-attracting to water-repelling to help cells take in mRNA using light

Abstract

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