Modulation of hypoxia and redox in the solid tumor microenvironment with a catalytic nanoplatform to enhance combinational chemodynamic/sonodynamic therapy

The efficacy of reactive oxygen species-mediated therapy is generally limited by hypoxia and overexpressed glutathione (GSH) in the tumor microenvironment (TME). To address these issues, herein, a smart Mn₃O₄/OCN-PpIX@BSA nanoplatform is rationally developed to enhance the combinational therapeutic efficacy of chemodynamic therapy (CDT) and sonodynamic therapy (SDT) through TME modulation. For constructing the catalytic nanoplatform (Mn₃O₄/OCN-PpIX@BSA), Mn₃O₄ nanoparticles were grown in situ on oxidized g-C₃N₄ (OCN) nanosheets, and the as-prepared Mn₃O₄/OCN nano-hybrids were then successively loaded with protoporphyrin (PpIX) and coated with bovine serum albumin (BSA). The catalase-like Mn₃O₄ nanoparticles are able to effectively catalyze the overexpressed endogenous H₂O₂ to produce O₂, which could relieve hypoxia and improve the therapeutic effect of combinational CDT/SDT. The decomposition of Mn₃O₄ by GSH enables the release of Mn²⁺ ions, which not only facilitates good T₁/T₂ dual-modal magnetic resonance imaging for tumor localization but also results in the depletion of GSH and the Mn²⁺-driven Fenton-like reaction, thus further amplifying the oxidative stress and achieving improved therapeutic efficacy. It is worth noting that the Mn₃O₄/OCN-PpIX@BSA nanocomposites exhibit minimal toxicity to normal tissues at therapeutic doses. These positive findings provide a new strategy for the convenient construction of TME-regulating smart theranostic nanoagents to improve the therapeutic outcomes towards malignant tumors effectively.