Hollow MnO₂ Nanozyme with NO Prodrug to Boost Synergistic CDT/PDT/Gas Therapy via Oxidative Stress Cascade

Photodynamic therapy (PDT) utilizes photosensitizers to generate reactive oxygen species (ROS) to kill tumors. However, the tumor's hypoxia and the limitations of a single ROS mechanism severely restrict its efficacy. This study aims to develop a synergistic nano-catalytic system (HMO) based on hollow manganese dioxide (HMnO₂) loaded with a novel nitric oxide (NO) donor (Methylene Blue - NO, MB-NO), which overcomes these obstacles through multiple synergistic effects.

Preliminary experiments confirmed the synthesis of HMO. Systematic studies were conducted on the chemodynamic therapy (CDT)/PDT/NO properties of HMO as well as its anti-tumor activity in vivo and in vitro. Finally, the in vivo safety of HMO was evaluated.

Preparation by the HMO is 189 nm nano particle size, Zeta potential for -37 ± 1.4 mV, exhibit excellent stability. In vitro experiments showed that the cellular uptake of HMO was time-dependent. In terms of cytotoxicity, the cell survival rate of the HMO group was 65.9%, significantly lower than that of the free HMnO₂ (89.1%) and MB-NO (85.1%); after 5 min of 660 nm laser irradiation, the cell survival rate of the HMO group further dropped to 48.5%. In the animal experiments of tumor xenograft models, the tumor inhibition rate of the HMO combined with 660 nm laser irradiation for 5 min group was as high as 81.3%, and it did not cause acute inflammation in the main organs, demonstrating good biological safety. In summary, the HMO nanoparticles exhibit excellent anti-tumor effects.

This strategy combines CDT/PDT/gas therapy, enabling the synergistic cascade of NO/ROS/reactive nitrogen oxide species (RNOS) to promote tumor cell apoptosis and inhibit tumor growth, thereby achieving a cascading amplification of therapeutic effects and providing a treatment solution to overcome the inherent limitations of traditional photodynamic therapy.