Photo‐induced proton release of spiropyran‐derived nanomaterials for mRNA delivery in hard‐to‐transfect cells

Abstract Messenger RNA (mRNA) therapy has been explored as a treatment for various genetic disorders. Significant progress has been made in developing mRNA delivery systems. However, efficient delivery of mRNA in hard‐to‐transfect cells remains a considerable challenge. Here, we constructed a series of spiropyran‐derived lipid‐like materials, named SPALs, to enhance mRNA delivery efficiency in cells that are difficult to transfect. In this design, we focused on strengthening the internal escape mechanism of mRNA nanoparticles via photo‐induced proton production by SPALs. Specifically, the spiropyran structure can undergo ring‐closing isomerization under light irradiation (460 nm) and produce a proton. The protons then mediate the protonation of tertiary amines in the lipid tail in situ, which subsequently disrupts the potential and size of nanoparticles and finally promotes their endosome escape. It ultimately enhances mRNA expression in live cells. SPALs are demonstrated to reduce the pH value up to 0.53 pH units after light irradiation in solution. They are also proven to decrease the pH value after light irradiation as observed through fluorescence ratio imaging in live cells. After screening the materials, we identified SPAL1 as a lead material for increasing the enhanced green fluorescent protein‐positive rate in Raw 264.7 cells by 22% after light irradiation, from 59% to 72%. This transfection efficiency is significantly higher than that of the lipo3000 in the same cell line. Consequently, we developed a new strategy to improve mRNA transfection efficiency, which merits further evaluation and development for mRNA‐based therapy.