A Substrate-Selective Enzyme-Catalysis Assembly Strategy for Oligopeptide Hydrogel-Assisted Combinatorial Protein Delivery

Oligopeptide hydrogels for localized protein delivery have considerable potential to reduce systemic side effects but maximize therapeutic efficacy. Although enzyme catalysis to induce formation of oligopeptide hydrogels has the merits of unique regio- and enantioselectivity and mild reaction conditions, it may cause the impairment of function and activity of the encapsulated proteins by proteolytic degradation during gelation. Here we report a novel enzyme-catalysis strategy for self-assembly of oligopeptide hydrogels using an engineered protease nanocapsule with tunable substrate selectivity. The protease-encapsulated nanocapsule shielded the degradation activity of protease on the laden proteins due to the steric hindrance by the polymeric shell weaved around the protease, whereas the small-molecular precursors were easier to penetrate across the polymeric network and access the catalytic pocket of the protease to convert to the gelators for self-assembling hydrogel. The resulting oligopeptide hydrogels supported a favorable loading capacity without inactivation of both an antiangiogenic protein, hirudin and an apoptosis-inducing cytokine, TRAIL as model proteins. The hirudin and TRAIL coloaded oligopeptide hydrogel for combination cancer treatment showed enhanced synergistic antitumor effects both in vitro and in vivo.