Tumor microenvironment-responsive cell-penetrating peptides: Design principle and precision delivery

Cell-penetrating peptides (CPPs) are promising vehicles for intracellular delivery of different cargoes. Although various CPPs are designed for targeted delivery of nanomedicines and anticancer drugs, their clinical approval is hampered by a lack of selectivity. In recent years, new approaches have been explored to address this drawback, and distinct strategies for tumor microenvironment (TME)-responsive activation have been developed. In this review, we first introduce the cellular uptake mechanisms of CPPs. We next extensively discuss the design principles and precision delivery of TME-responsive CPPs. Nine kinds of single stimulus-responsive CPPs, five kinds of multiple stimuli-responsive CPPs, three kinds of TME-responsive targeting CPPs, and two kinds of reversibly activatable CPPs (RACPPs) are systemically summarized. Then, TME-responsive CPPs for nanomedical applications are further discussed. Finally, we describe the translational applications of TME-responsive CPPs for anticancer drug delivery. These commentaries provide an insight into the design of next-generation activatable CPPs (ACPPs) for selective delivery of nanomedicines and anticancer drugs.