Stapling of short cell-penetrating peptides for enhanced tumor cell-and-tissue dual-penetration

Effective delivery of therapeutics to tumors is generally hampered by the limited penetration of biological barriers imposed by the tumor microenvironment. Despite the broad applications of cell-penetrating peptides (CPPs) for intracellular delivery of therapeutics across membrane bilayers, the discovery of novel CPPs with enhanced tumor tissue permeability remains largely unexplored. Herein, we identified two short stapled CPPs with aromatic cross-links that confer superior dual-penetration in tumor cells and tissues over their linear counterparts. This work may benefit the future applications of constrained CPPs as powerful molecular transporters to access deeper tumor tissues.