Improving Nanomaterial Delivery into Mammalian Cells with Peptide Tools in the Bystander Manner

Abstract

Liposomes are commonly used as a drug delivery vehicle, but their therapeutic efficacy can be improved by increasing their cell entry efficiency. Conjugation with cell-penetrating peptides (CPPs) and other ligands has been a popular approach, but it requires chemical modifications that are not ideal for clinical use. Our previous study demonstrated that the transportan (TP) peptide could increase the cellular uptake of co-administered metallic nanoparticles without covalent conjugation, a process known as bystander uptake. We extended this work to liposomes and found that co-administration with TP improved the internalization of liposomes into various cell lines, primary cells, ex vivo tumor slices, and in vivo tumor tissues. Interestingly, this effect was not observed with cationic CPPs, which were previously known to induce bystander uptake. The TP-assisted bystander uptake of liposomes was found to be receptor-dependent and sensitive to macropinocytosis pathway inhibitors, indicating a potential cell entry mechanism. We also tested TP deletion analogs, which showed similar or even higher efficiency than TP, and had the potential to improve in vitro transfection efficiency. Our study presents a simple strategy for TP co-administration to increase liposome cell entry and could provide new avenues for TP peptide application in nanotherapeutics.