Discovery of actinators, actin-derived bioactive peptides that modulate cytoskeleton and actin-related cellular activities

The cortical actin cytoskeleton serves as a structural support and force-generating machinery in cells, but the actin meshwork can also act as a barrier, hindering the delivery of extracellular substances. To address the issue of the cortical actin barrier, we engineered synthetic libraries of human β-actin-derived peptides to promote actin dynamics. Here, we report the discovery of six major peptides, collectively termed actinators, that are biologically active in selective modulation of actin-related cellular activities. Using retro- and lentiviral vector transduction of CAR T cells as a model, we demonstrate that an actinator markedly enhances viral vector transduction 20- to 30-fold. An individual actinator can also selectively modulate cellular functions such as regulating surface receptors, enhancing T cell adhesion, and promoting the cellular uptake of exosomes. Molecular docking and protein phosphorylation studies confirmed that actinators can modulate actin-binding proteins like cofilin. Actinators represent a class of actin-derived bioactive peptides with diverse applications in gene and immune therapies, drug delivery, and disease treatment.