Mn-based redox homeostasis disruptor for photothermal-enhanced chemodynamic synergistic therapy

Breaking the redox homeostasis of tumor microenvironment (TME) and reshaping it sustainably remain major challenges in chemodynamic therapy (CDT) of tumors. The low concentration of H₂O₂ and metal ions (Fe²⁺, Mn²⁺, Co²⁺, Cu⁺), insufficient tumor acidity, and overexpressed glutathione (GSH) in the tumor region severely limit the CDT effect. Herein, a Mn-doped mesoporous polydopamine nanoparticle modified with glucose oxidase (GOx) and hyaluronic acid (HA) (Mn-PDA-GOx@HA, MDGH) was constructed. Under near-infrared (NIR) light irradiation, the excellent photothermal conversion efficiency (55.2%) of MDGH was utilized to induce a rapid increase in temperature of the tumor site, resulting in the highly efficiency Mn²⁺-mediated Fenton-like reaction and the generation of reactive oxygen species (ROS). Besides, the overexpressed GSH could be consumed by high-valence Mn ions, enhancing the damage of ROS to tumor cells, and ultimately achieving superior anti-tumor PTT-CDT effects (95.95% tumor inhibition rate). The MDGH exhibited superior ¹H T₁-weighted magnetic resonance imaging (MRI) enhancement with a longitudinal relaxivity (r₁) value of 7.01 mM^-1 s^-1 at 9.4 T, which is 1.7 times that of the commercial Gd-DTPA. In vivo¹H T₁-weighted MRI results showed 43.8% enhancement of tumor signal intensity post i.v. injection of MDGH. This platform enhances the therapeutic efficacy of synergistic CDT-PTT by the release of Mn ions, self-supplying H₂O₂, and blocking nutrition supplies, providing a significant and promising strategy to develop more effective and practical treatment for tumors.