Direct Cytosolic Protein Delivery via Near-Infrared-Driven Membrane-Intercalating Conjugated Oligoelectrolytes

Abstract The intracellular delivery of functional proteins remains a major challenge due to the impermeability of the plasma membrane and inefficient endosomal escape. Here, we report a membrane-intercalating conjugated oligoelectrolyte (MI-COE, BBTN) that enables near-infrared (NIR)-triggered direct cytosolic protein delivery through molecular photoporation. Distinct from conventional carriers that require complex formulations and rely on endocytic uptake, BBTN spontaneously inserts into the lipid bilayer, enabling localized NIR-responsive membrane modulation. Upon mild NIR irradiation, BBTN induces transient and reversible membrane permeabilization, facilitating the direct transport of proteins into the cytosol while maintaining high cell viability. This loading-free platform exhibits broad compatibility with diverse proteins, including fluorescent proteins (GFP and R-PE), enzymes (β-galactosidase and horseradish peroxidase), and therapeutic proteins (caspase 3 and RNase A), while preserving their biological functions after delivery. Furthermore, BBTN enables NIR-II fluorescence imaging-guided protein delivery in vivo and enhances the therapeutic efficacy of RNase A against solid tumors. These results establish membrane-intercalating conjugated oligoelectrolytes as a versatile materials platform for intracellular macromolecular delivery and biomedical applications.