Low-intensity focused ultrasound-augmented Cascade chemodynamic therapy via boosting ROS generation

Fenton reaction-mediated chemodynamic therapy (CDT), which destroys tumor cells by converting H₂O₂ into cytotoxic hydroxyl radical (OH) and singlet oxygen (¹O₂) species, is a promising field. However, Fenton-based CDT is severely impaired by the inappropriate tumor environment associated with undesirable intratumoral acidity and insufficient H₂O₂ supply in tumor microenvironment (TME). Therefore, a strategy that can address these concerns is highly desired and beneficial for boosting such treatment. Herein, a magnetic nanoreactor system (denoted as poly (lactic-co-glycolic acid) (PLGA)-superparamagnetic iron oxide (SPIO)&vitamin C (Vc) was constructed with Vc in the core, SPIO on the shell, and PLGA as the building carrier. Upon low-intensity focused ultrasound irradiation, on-demand Vc release can locally decompose into H₂O₂, which can generate a favorable condition for facilitating SPIO-based Fenton-like reaction and result in continuous O₂ and OH/¹O₂ generation. The TME modulation-augmented CDT by this nanoreactor based on the reinforced Fenton reaction tremendously improved the antitumor outcomes, especially under increased accumulation contributed by magnetic targeting combined with enhanced permeability and retention effect. Moreover, the explosive production of oxygen can be monitored by real-time photoacoustic imaging, offering a noninvasive means to forecast the treatment efficacy. Therefore, this established microenvironment modulation strategy for augmenting Fenton reaction-based CDT paves a new avenue to realize highly efficient cancer theranostics.