Injectable Chitosan Hydrogels Doped with 2D Peptide Nanosheet‐Drug Conjugates for Glutathione‐Responsive Sustained Drug Delivery

Abstract The development of novel and effective drug delivery systems aimed at enhancing therapeutic profile and efficacy of therapeutic agents is a critical challenge in modern medicine. This study presents an intelligent drug delivery system based on self‐assembled two‐dimensional peptide nanosheets (2D PNSs). Leveraging the tunable properties of amino acid structures and sequences, we design a peptide with the sequence of Fmoc‐FKKGSHC, which self‐assembles into 2D PNSs with uniform structure, high biocompatibility, and excellent degradability. Covalent attachment of thiol‐modified doxorubicin (DOX) drugs to 2D PNSs via disulfide bond results in the peptide‐drug conjugates (PDCs), which is denoted as PNS‐SS‐DOX. Subsequently, the PDCs are encapsulated within the injectable, thermosensitive chitosan (CS) hydrogels for drug delivery. The designed drug delivery system demonstrates outstanding pH‐responsiveness and sustained drug release capabilities, which are facilitated by the characteristics of the CS hydrogels. Meanwhile, the covalently linked disulfide bond within the PNS‐SS‐DOX is responsive to intracellular glutathione (GSH) within tumor cells, enabling controlled drug release and significantly inhibiting the cancer cell growth. This responsive peptide‐drug conjugate based on a 2D peptide nanoplatform paves the way for the development of smart drug delivery systems and has bright prospects in the future biomedicine field.