pH-Responsive EGCG-Metal self-assembly as the carrier for rapid and prolonged insulin delivery

• A biocompatible glucose-responsive EGCG-metal self-assembly nanoparticle was prepared. • The nanoparticle enhanced the efficiency of the cascade reaction between GOX and CAT . • The nanoparticle showed glucose-responsive insulin release both in vitro and in vivo . • The nanoparticle can maintain normoglycemia > 24 h with negligible hypoglycemia. Glucose-responsive insulin delivery carriers based on glucose oxidase have been developed to mimic the function of native insulin. However, the remained challenges are to synthesize carriers with simple preparation processes, while achieving the expected rapid and prolonged insulin release. Here, a novel pH-sensitive metal-phenolic network (MPN) system based on the coordination chemistry of epigallocatechin gallate (EGCG) and ferric ions was developed using a one-step blend self-assembly method, and the results demonstrated its potential application for encapsulating enzymes (GOx and CAT) and insulin (MPN@GCI) to achieve glucose-responsive insulin delivery intelligently. The prepared MPN@GCI showed high protein loading efficiency and stability, preserved the structure and biological activity of the encapsulated protein, while also enhanced the efficiency of the cascade reaction between GOX and CAT . Both in vitro and in vivo analysis elucidated that MPN@GCI showed superior glucose-responsive insulin release properties. Specifically, a single subcutaneous injection of MPN@GCI in STZ-induced type I diabetic mice showed a rapid and effective response to glucose challenges, and leading to an optimal blood glucose level (＜200 mg/dL) for more than 24 h. Furthermore, the MPN@GCI possessed good biocompatibility with undetected cytotoxicity and systemic biotoxicity. Overall, the nanoparticle formulation based on EGCG and ferric ions in current study could provide an excellent biosafe, effective and multifunctional approach for the development of glucose-responsive insulin delivery system.