MetallopeptiGELs: Injectable Short-Peptide Supramolecular Hydrogels Self-Assembled by Pd Nanosheets for Bioorthogonal Therapy

Abstract Controlling the delivery of chemotherapy to the tumor site is a long-standing goal of the medical field, as it could not only enhance the anticancer activity of the treatment but also reduce damage to the rest of the body. The emergence of bioorthogonal catalysis as a strategy capable of mediating continuous drug production in a nonenzymatic fashion has created the opportunity to develop so-called “bioorthogonal therapies,” which aim to generate the anticancer agents inside the tumors. Herein, we describe a novel class of supramolecular materials comprising ultrathin palladium nanosheets and fluorenylmethoxycarbonyl-diphenylalanine that self-assemble in water to form injectable, self-healing, biocompatible catalytic gels that convert inactive prodyes and prodrugs into active small molecules. The relatively weak physicochemical cross-links generated by the hybrid metal-peptide fibers facilitate the flow of the gel under mild shear stress (shear-thinning), thereby enabling precise intratumoral injections in vivo and localized prodrug activation. The strategy was validated in an aggressive pancreatic cancer xenograft model in mice, setting out a new direction for the field of bioorthogonal therapies.