Curvature-Sensing Peptide Functions as a <i>Membrane Interfactant</i> That Glues Small Extracellular Vesicles to Cell Membranes and Enhances Vesicle Cellular Uptake

Small extracellular vesicles (sEVs) are lipid nanoparticles secreted from mammalian cells that are involved in the transfer of information or therapeutically effective substances between cells. Although the scope of research on sEVs as biocompatible carriers for drug delivery to diseased tissues and cells is expanding, there is still room for improvement in the efficiency of drug loading on and in sEVs and their subsequent uptake into cells. It is desirable to alleviate the energy barriers associated with the cellular uptake of sEVs and minimize the perturbation of sEVs when loading drugs onto them. In this study, we developed a simple drug-loading system for sEVs using a dimeric curvature-sensing peptide, which enhances sEV accumulation on the cell surface by acting as an adhesive, subsequently inducing endocytic uptake of sEVs through a clathrin-mediated pathway. The dimeric curvature-sensing peptide selectively binds to the sEV surface within 10 min, even in the presence of serum proteins, and functions as a <i>membrane interfactant</i> to reduce the energy barriers for the cellular uptake of sEVs. The cellular uptake of sEVs and the dimeric curvature-sensing peptide under coexisting conditions increased to over 5-fold and 20-fold, respectively, compared with those administered alone. Furthermore, the dimeric curvature-sensing peptide can efficiently load anticancer drugs onto the surface of sEVs, and the system effectively induces apoptosis in two types of cancer cells. Dimeric curvature-sensing peptide is a technique with potential applications in drug delivery.