Photothermal nanozymes to self-augment combination cancer therapy by dual-glutathione depletion and hyperthermia/acidity-activated hydroxyl radical generation

Chemodynamic therapy (CDT) has emerged as a promising strategy for tumor treatment. Nevertheless, the low Fenton catalytic efficiency and the high concentration of glutathione (GSH) in cancer cells largely decline antitumor efficacy of CDT. To self-augment antitumor effect of the CDT by combining with photothermal therapy (PTT), the unique photothermal nanozymes that doubly depleted GSH, and generated massive hydroxyl radicals (center dot OH) in the hyperthermia/acidity-activated manner were developed. Through the coordination of Fe3+ ions with PEGylated chitosan (PEG-CS)-modified polydopamine (PDA) nanoparticles, the attained Fe3+@PEG-CS/PDA nanozymes showed outstanding colloidal stability, photothermal conversion efficiency and acidity-triggered Fe3+ release. By GSH-mediated valence states transition of Fe3+ ions and Michael reaction between GSH and quinone-rich PDA, the nanozymes sufficiently executed dual depletion of GSH with the elevated temperature. Under mimic tumor acidity and near-infrared (NIR) irradiation condition, the endocytosed nanozymes effectively converted intracellular H2O2 into toxic center dot OH upon amplified Fenton reaction, thereby potently killing 4T1 cancer cells and RAW 264.7 cells. Importantly, the nanozymes prominently suppressed 4T1 tumor growth in vivo and metastasis of cancer cells by CDT/PTT combination therapy without significant systemic toxicity. Our study provides novel visions in design of therapeutic nanozymes with great clinical translational prospect for tumor treatment.

Automated summary

Chemodynamic therapy (CDT) is a promising strategy for tumor treatment, but its efficacy is limited by low Fenton catalytic efficiency and high glutathione (GSH) concentration in cancer cells. To overcome these limitations, a novel photothermal nanozyme was developed to deplete GSH and generate hydroxyl radicals in an acidity-activated manner. The nanozyme showed excellent stability, photothermal conversion efficiency, and Fe3+ release. It effectively killed cancer cells in vitro and suppressed tumor growth in vivo without significant toxicity.