Protein Modifications for Cellular Protein Delivery

Intracellular delivery of functional proteins is emerging as a powerful strategy to interrogate and control cellular pathways with high spatial and temporal precision. Recent advances in chemical biology now enable the design of cell-permeable proteins through precise chemical and biochemical modification, bringing the field closer to achieving intracellularly targeted biologics as a "new class of drugs". By overcoming the limitations of genetic manipulation, researchers create solutions for basic research and medicine. In this review, we outline the key motivations that drive intracellular protein delivery. We highlight central mechanistic paradigms for protein entry, important parameters influencing protein delivery, and summarize analytical tools to assess successful delivery. We outline different chemical and biochemical conceptional approaches that resulted in breakthrough studies to achieve functional protein transport. Finally, we discuss ongoing efforts, highlighting the challenges for future research on protein delivery.