期刊
TRAFFIC
卷 19, 期 6, 页码 421-435出版社
WILEY
DOI: 10.1111/tra.12566
关键词
bis(monoacylglycero)phosphate; cell-penetrating peptides; cellular delivery; endosomal escape; membrane leakage; supercharged molecules
类别
资金
- National Institute of General Medical Sciences [R01GM110137]
- Welch Foundation [A-1863]
- U.S. National Institutes of Health [R01GM11405]
Various densely charged polycationic species, whether of biological or synthetic origin, can penetrate human cells, albeit with variable efficiencies. The molecular underpinnings involved in such transport remain unclear. Herein, we assemble 1, 2 or 3 copies of the HIV peptide TAT on a synthetic scaffold to generate branched cell-permeable prototypes with increasing charge density. We establish that increasing TAT copies dramatically increases the cell penetration efficiency of the peptides while simultaneously enabling the efficient cytosolic delivery of macromolecular cargos. Cellular entry involves the leaky fusion of late endosomal membranes enriched with the anionic lipid BMP. Derivatives with multiple TAT branches induce the leakage of BMP-containing lipid bilayers, liposomal flocculation, fusion and an increase in lamellarity. In contrast, while the monomeric counterpart 1TAT binds to the same extent and causes liposomal flocculation, 1TAT does not cause leakage, induce fusion or a significant increase in lamellarity. Overall, these results indicate that an increase in charge density of these branched structures leads to the emergence of lipid specific membrane-disrupting and cell-penetrating activities.
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