Biodegradable cascade nanocatalysts enable tumor-microenvironment remodeling for controllable CO release and targeted/synergistic cancer nanotherapy.

Gas therapy as an emerging therapeutic modality for cancer treatment is still facing critical challenges such as precise delivery and controllable release of therapeutic gas. Herein, we report a "tumor-microenvironment remodeling" strategy for in situ sustained release of CO gas and magnetic resonance imaging (MRI)-monitored targeted/synergistic cancer gas/starvation nanotherapy by engineering cascade biodegradable nanocatalyst. The nanocatalyst integrates the enzyme catalyst glucose oxidase (GOD) and H2O2-sensitive molecule manganese carbonyl (MnCO) entrapped biodegradable hollow mesoporous organosilica nanoparticles (HMONs). Especially, GOD is initially exploited as a gatekeeper, followed by surface engineering with arginine-glycine-aspartic acid (RGD) for specifically targeting αvβ3 integrin-overexpressed cancer cells. The GOD is dissociated under reduced pH to release the loaded MnCO, and sequentially produce gluconic acid and H2O2 to remodel the TME for facilitating the in situ generation of CO/Mn2+. As systematically demonstrated both at cellular level and in an animal tumor xenograft model, the engineered nanocatalyst achieves superior theranostics performance via combinatorial CO gas and starving-like nanotherapy. This work provides an effective strategy for augmenting CO-mediated antitumor efficacy by remodeling the tumor microenvironment.