Strength in numbers: cell penetrating peptide clusters to build next-generation therapeutics

The delivery of large molecules across biological barriers and into intracellular environments is one of the grand challenges of biomedical research. The recent development of cell penetrating peptide (CPP) clusters to transport antibodies, proteins, enzymes, and peptides across biological barriers at therapeutically relevant concentrations, marks a fundamental shift in our understanding of CPP functionality, providing a blueprint for crafting potent intracellular therapies. This review introduces the CPP clustering paradigm, delineates CPP clustering strategies and their effectiveness, highlights seminal contributions to the field, addresses challenges for the future, and summarises the clinical trial status of CPP therapeutics. Finally, we provide design guidelines for developing the next generation of CPP clusters and intracellular therapeutics, with a focus on translation into clinical practice.