Neuropilin-1 and heparan sulfate proteoglycans cooperate in cellular uptake of nanoparticles functionalized by cationic cell-penetrating peptides

摘要: Cell-penetrating peptides (CPPs) have been widely used to deliver nanomaterials and other types of macromolecules into mammalian cells for therapeutic diagnostic use. Cationic CPPs that bind heparan sulfate (HS) proteoglycans on the cell surface induce potent endocytosis; however, role receptors in this process is unclear. We describe convergence an HS-dependent pathway with C-end rule (CendR) mechanism enables peptide ligation neuropilin-1 (NRP1), a receptor known be involved angiogenesis vascular permeability. NRP1 binds carrying positive residue at carboxyl terminus, feature compatible cationic CPPs, either intact or after proteolytic processing. CPP CendR peptides, as well HS- NRP1-binding motifs from semaphorins, explore commonalities differences HS pathways. show CendR-NRP1 interaction determines ability also ultrastructural level, using novel entry synchronization method, both pathways can initiate macropinocytosis-like visualize these CPP-cargo complexes going through various endosomal compartments. Our results provide new insights how exploit multiple intracellular delivery.