Glucose oxidase-driven self-accelerating drug release nanosystem based on metal-phenolic networks orchestrates tumor...

Nanocarriers responding to tumor microenvironment have been extensively exploited to improve the antitumor outcome of chemotherapeutic drugs. However, selectively and completely releasing drugs within the tumor remains a challenge, thereby limiting the therapeutic effect of drug delivery nanosystem. To tackle this challenge, a metal-phenolic networks (MPNs)-based nanosystem (F-MGD) showing the capability of self-accelerating drug release was originally fabricated in this study. Glucose oxidase (GOx) encapsulated in F-MGD could conduct the glucose transformation in tumor to cause the oxygen consumption and the production of gluconic acid and H₂O₂. Therefore, F-MGD with acid and hypoxia sensitivities thoroughly disintegrated under the aggravated acidity and hypoxia to achieve a more complete drug release. Besides, the product of H₂O₂ was readily decomposed into hydroxyl radicals via the iron ion-mediated Fenton reaction, which markedly augmented the oxidative stress in tumor cells and promoted ferroptosis. The results of both in vitro and in vivo assays demonstrated the significant antitumor efficacy of F-MGD. Collectively, this study proposes a strategy to expedite drug release in tumor and improve the tumor treatment effect by combining ferroptosis-based therapy and chemotherapy.