Oxygen Nanobubbles Enhance ICG/Fe(III)-Mediated Dual-Modal Therapy To Induce Ferroptosis in Tumor Treatment

Noninvasive therapies such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), which rely on reactive oxygen species (ROS), are gaining attention for their low toxicity. However, single-modal treatments have individual limitations that restrict the therapeutic efficacy. Fe(III) can coordinate with the hydrophilic regions of indocyanine green (ICG) molecules to form the ICG/Fe(III) complex, making it a promising dual-modal agent for combined PDT and CDT. However, coordination with Fe(III) leads to the aggregation quenching of ICG, hindering its application in dual-modal therapy. We innovatively utilize oxygen nanobubbles, prepared solely from water and oxygen, to significantly reverse the aggregation-induced quenching of the ICG/Fe(III) complex, thereby enhancing its stability in aqueous environments. In this system, Fe(III) assembles at the nanobubble interface, coordinating with ICG's hydrophilic regions to form the ICG/Fe(III)-NBs. The oxygen nanobubbles boost PDT efficiency by improving the ICG/Fe(III) complex stability and oxygen content, while Fe(III) achieves CDT by generating hydroxyl radicals (^•OH) through the Fenton reaction. This dual-modality treatment significantly disrupts the tumor's redox balance, induces ferroptosis, and demonstrates strong antitumor efficacy, reducing tumor volume to 34% of its initial size in mice. The strategy offers a promising and clinically viable approach to cancer treatment.