Robust and smart polypeptide-based nanomedicines for targeted tumor therapy.

Nanomedicines based on synthetic polypeptides are among the most versatile and advanced platforms for tumor therapy. Notably, several polypeptide-based nanodrugs are currently under human clinical assessments. The previous (pre)clinical studies clearly show that dynamic stability (i.e. stable in circulation while destabilized in tumor) of nanomedicines plays a vital role in their anti-tumor performance. Various strategies have recently been developed to design dynamically stabilized polypeptide-based nanomedicines by e.g. crosslinking the nanovehicles with acid, reactive oxygen species (ROS), glutathione (GSH), or photo-sensitive linkers, inter-crosslinking between vehicles and drugs, introducing π-π stacking or lipid-lipid interactions in the nanovehicles, chemically conjugating drugs to vehicles, and forming unimolecular micelles. Interestingly, these robust and smart nanodrugs have demonstrated improved tumor targetability, anti-tumor efficacy, as well as safety profiles in different tumor models. In this review, representative strategies to robust and smart polypeptide-based nanomedicines for targeted treatment of varying malignancies are highlighted. The exciting development of dynamic nanomedicines will foresee further increasing clinical translation in the future.