Organosilica-Based Hollow Mesoporous Bilirubin Nanoparticles for Antioxidation-Activated Self-Protection and Tumor-Specific Deoxygenation-Driven Synergistic Therapy.

A major concern about glucose oxidase (GOx)-mediated cancer starvation therapy is its ability to induce serious oxidative damage to normal tissues through the massive production of HO byproducts in the oxygen-involved glucose decomposition reaction, which may be addressed by using a HO scavenger, known as an antioxidation agent. Surprisingly, HO removal accelerates the aerobic glycometabolism of tumors by activating the HO-dependent "redox signaling" pathway of cancer cells. Simultaneous oxygen depletion further aggravates tumor hypoxia to increase the toxicity of a bioreductive prodrug, such as tirapazamine (TPZ), thereby improving the effectiveness of cancer starvation therapy and bioreductive chemotherapy. Herein, a "nitrogen-protected silica template" method is proposed to design a nanoantioxidant called an organosilica-based hollow mesoporous bilirubin nanoparticle (HMBRN), which can act as an excellent nanocarrier to codeliver GOx and TPZ. In addition to efficient removal of HO for self-protection of normal tissues antioxidation, GOx/TPZ-coloaded HMBRN can also rapidly deplete intratumoral glucose/oxygen to promote a synergistic starvation-enhanced bioreductive chemotherapeutic effect for the substantial suppression of solid tumor growth. Distinct from the simple combination of two treatments, this study introduces antioxidation-activated self-protection nanotechnology for the significant improvement of tumor-specific deoxygenation-driven synergistic treatment efficacy without additional external energy input, thus realizing the renaissance of precise endogenous cancer therapy with negligible side effects.