Copper-based theranostic nanocatalysts for synergetic photothermal-chemodynamic therapy

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site Cu^II can be reduced to Cu^I by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H⁺ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more Cu^II and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying Cu^I and H⁺ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. STATEMENT OF SIGNIFICANCE: The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the Cu^II can be reduced to Cu^I by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H⁺ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more Cu^II and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying Cu^I and H⁺ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT.