One-pot synthesis of a self-reinforcing cascade bioreactor for combined photodynamic/chemodynamic/starvation therapy.

The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) have attracted a great deal of interest, but tumor hypoxia and glutathione (GSH) overproduction still limit their further applications. Herein, an intelligent reactive oxygen species (ROS) nanogenerator Ce6/GOx@ZIF-8/PDA@MnO (denoted as CGZPM; Ce6, GOx, ZIF-8, PDA, MnO are chlorin e6, glucose oxidase, zeolitic imidazolate framework-8, polydopamine and manganese dioxide respectively) with O-generating and GSH-/glucose-depleting abilities was constructed by a facile and green one-pot method. After intake by tumor cells, the outer MnO was rapidly degraded by the acidic pH, and the overexpression of hydrogen peroxide (HO) and GSH with abundant Mn and O produced would eventually achieve multifunctionality. The Mn acted as an ideal Fenton-like agent and magnetic resonance (MR) imaging contrast agent, while the O promoted the PDT via hypoxia relief and facilitated the intratumoral glucose oxidation by GOx for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, sufficient HO was generated to improve the CDT efficacy through Mn-mediated Fenton-like reaction. Notably, MnO and PDA could decrease the tumor antioxidant activity by consuming GSH, resulting in remarkably enhanced PDT/CDT. Such a novel cascade bioreactor with tumor microenvironment (TME)-modulating capability opens new opportunities for ROS-based and combinational treatment paradigms.