Advances in peptide-drug conjugate-based supramolecular hydrogel systems for local drug delivery

•Through spontaneous or stimuli-instructed assembly processes, the PDC system is capable of creating supramolecular hydrogel.•The PDC based hydrogel is capable of concentrating the drug in the target sites and deploys as a local reservoir for extended release of therapeutic agents, effectively mitigating toxic side effects and improving treatment outcomes.•This self-supporting hydrogel contains only prodrug, thereby avoiding any toxicities from additional carrier, possessing great potential in clinical trials and future translation. Peptide-drug conjugate (PDC) systems consisting of peptide, linker and drug, have attracted extensive attention in drug delivery applications. With the assistance of peptides, the PDC systems have competitive advantages over other drug delivery vehicles, with excellent biocompatibility, easy accessibility, biodegradability, and multifunctionality. Through self-assembly or stimuli-instructed assembly processes, the PDC system is capable of creating supramolecular hydrogel scaffolds with discrete filamentous nanostructures that undergo subsequent elongation and supramolecular network entanglements to form a macroscopic hydrogel. Notably, the hydrogel can serve as a prospective localized delivery platform for concentrating the drug in the target site, thus improving the drug bioactivity and attenuating the off-target toxicity. Additionally, the incorporation of peptide-containing targeting or bioactive elements can enhance the hydrogel’s multifunctionality, facilitating drug penetration in the deep disease tissue or exerting therapeutic effect. In this review, we will summarize recent research on PDC-based supramolecular hydrogels for localized drug delivery, as well as briefly discuss the challenges and prospects for clinical applications.