Copper-coordinated engineered nanoreactors with self-amplifying O2 and cascade chem-drug synthesis for enhanced sonodynamic-mediated oncotherapy

Efficient synthesis of chemotherapeutic drugs within the tumor microenvironment (TME) holds great potential for enhancing sonodynamic-mediated synergistic oncotherapy. Herein, an engineered nanoreactor composed of Cu²⁺, indocyanine green (ICG), and 1,5-dihydroxynaphthalene (DHN) (termed DCI) with self-amplifying reactive oxygen species (ROS) and cascade chemo-drug synthesis in tumor cells was constructed by coordination-driven co-assembly of sonosensitizer ICG, transition metal copper (Cu²⁺), and nontoxic DHN. Upon intravenous administration, DCI selectively accumulated in tumor tissues and performed excellent photoacoustic (PA) and near-infrared fluorescence (NIRF) imaging capabilities compared to free ICG. Once DCI was internalized into tumor cells, it rapidly disassembled and generated a chemo-drug under the stimuli of acidic lysosome and sonodynamic radiation. The released Cu²⁺ efficiently decomposed endogenous hydrogen peroxide (H₂O₂) into hydroxyl radical (·OH) and O₂ and glutathione (GSH). The generated O₂ efficiency alleviated tumor hypoxia and enhanced sonodynamic therapy (SDT) efficiency. Notably, a large amount of the singlet oxygen (¹O₂) generated by SDT could efficiently oxidize the released nontoxic DHN into hydroxynaphthoquinone (HPN) with higher toxicity. Overall, this work provides a simple, flexible, and effective strategy for oncotherapy.