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Despite the long list of therapeutic proteins available for treating various human diseases, the vast majority of commercial protein-based drugs, such as cytokines, hormones, and monoclonal antibodies, have been limited to extracellular mechanisms of action. Many intracellular proteins with great potential as biopharmaceutical drugs have been identified; however, many of the challenges associated with intracellular protein delivery have yet to be solved. Although protein transduction and lipid nanoparticle-mediated protein delivery methods have been proposed for direct protein delivery into target cells and tissues, many obstacles remain before these methods can be successfully employed in vivo, including low purification efficiency, failure to separate from nanoparticles in recipient cells, and induction of immune responses against host immune cells. To address these limitations, we developed an opto-genetically …