Tumor Microenvironment-Activated Nanocomposite for Self-Amplifying Chemodynamic/Starvation Therapy Enhanced...

Disrupting intracellular redox homeostasis combined with immune checkpoint blockade therapy is considered as an effective way to accelerate tumor cell death. However, suppressed tumor immune microenvironment and lower cargo delivery restrict the efficiency of tumor therapy. In this study, a multifunctional tumor microenvironment (TME)-responsive nanocomposite is constructed using manganese tetroxide (Mn₃ O₄ )-decorated disulfide-bond-incorporated dendritic mesoporous organosilica nanoparticles (DMONs) to co-deliver indoleamine 2,3-dioxygenase (IDO) inhibitor Epacadostat (IDOi) and glucose oxidase (GOx) following modification with polyethylene glycol. Owing to the responsiveness of Mn₃ O₄ -decorated DMONs to the mildly acidic and glutathione (GSH) overexpressed TME, the nanocomposite can rapidly decompose and release inner contents, thus substantially improving the cargo release ability. Mn₃ O₄ can effectively catalyze hydrogen peroxide (H₂ O₂ ) decomposition to generate oxygen, enhance the ability of GOx to consume glucose to produce H₂ O₂ , and further promote the generation of hydroxyl radicals (•OH) by Mn²⁺ . Furthermore, Mn²⁺ -mediated GSH depletion and the production of •OH can disrupt intracellular redox homeostasis, contributing to immunogenic cell death. Simultaneously, IDOi can inhibit IDO to reverse inhibited immune response. The results show that self-amplifying chemodynamic/starvation therapy combined IDO-blockade immunotherapy synergistically inhibits tumor growth and metastasis in vivo.