Polymer-photosensitizer conjugate exerting pH-responsive hydrophilic-to-hydrophobic conversion for cell-specific photochemical internalization of mRNA.

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.