Glucose oxidase and L-arginine functionalized black phosphorus nanosheets for multimodal targeted therapy of glioblastoma

Glioblastoma (GBM) is the most common type of primary malignant brain tumor with few innovative therapies. Developing an efficient and "green" synergistic anticancer strategy for GBM treatment remains a pressing need. Herein, a novel strategy that combines photothermal therapy (PTT), tumor starvation and nitric oxide (NO) therapy based on functionalized black phosphorus nanosheets (BP) is developed. NO-functionalized BP (BPA) is prepared by esterification reaction between the carboxyl group of L-arginine (Arg) and the hydroxyl group (P OH) formed from the preliminary oxidation on the surface of BP. Then glucose oxidase (GOx) is further introduced to Arg by amidation to form a multimodal nanodrug (BPAG). The mild chemical modification empowers BP with superior stability under physiological condition and induce release of H2O2 and NO by the cascaded oxidation of glucose and Arg. This process can be significantly accelerated by PTT. To facilitate BPAG with tumor-targeting ability, the macrophage membrane is used to coat the nanoparticles under ultrasonic condition. The membrane-coated BPAG (M@BPAG) improves penetration through blood-brain barrier for GBM targeting. Taken together, M@BPAG combines GBM targeting, H2O2-NO release, and PTT effect, leading to reprogramming the tumor immune microenvironment and a significant synergistic antitumor performance without systemic toxicity.