Black Phosphorus Nanosheet-Promoted Prodrug Activation for Enhanced Cancer Therapy

Tumor hypoxia-activated prodrugs possess great potential for cancer therapy. However, their therapeutic effects are still limited by several factors, including suboptimal conversion to the active pharmaceutical ingredient in complex tumor environments. Here, we demonstrate a strategy using black phosphorus nanosheets (BPNSs) to boost the activation and therapeutic effects of a tumor hypoxia-activated prodrug, banoxantrone dihydrochloride (AQ4N). BPNSs can facilitate the activation of AQ4N to a toxic anticancer drug through their degradation, which consumes oxygen and acidifies the surrounding environment, and their selective interaction with AQ4N under slightly acidic conditions, which can activate AQ4N. Moreover, the combination of BPNSs and AQ4N can result in synergistic anticancer effects as an additional benefit. Using the features of BPNSs, an enhanced cancer therapy without obvious toxic side effects was achieved using AQ4N in a mouse model. • BPNSs promote AQ4N activation under acidic and hypoxic tumor conditions. • BPNS degradation consumes O 2 and acidifies tumors to boost prodrug efficacy. • BPNSs plus AQ4N suppress tumors in vivo with minimal systemic toxicity.