Programmable “triple attack” cancer therapy through in situ activation of disulfiram toxification combined with phototherapeutics

Abstract

Effectively and completely eliminating residual tumor cells is the key to reducing the risk of tumor metastasis and recurrence. Designing an “ideal” nanoplatform for programmable cancer therapy has great prospects for completely eliminating residual tumor cells. Herein, an intelligent nanoplatform of disulfiram (DSF)-loaded CuS-tannic acid nanohexahedrons (denoted as “DSF-CuS@TA”) with thermal- and pH-sensitive degradation, as well as near-infrared (NIR-II) phototherapeutics properties, was constructed. And then, it was employed for in situ DSF toxification activation programmable “triple attack” cancer therapy. After accumulating in the tumor, DSF-CuS@TA first releases the loaded Cu(DTC)₂, and simultaneously degrades and releases Cu²⁺ and DSF under mildly acidic stimulation to trigger instant intratumoral Cu(DTC)₂ chelation, thereby achieving the “first strike.” Next, under irradiation by a NIR-II laser, light energy is converted into heat to generate NIR-II photothermal therapy, thereby achieving the second strike. Subsequently, under thermal stimulation, DSF-CuS@TA degrades further, triggering the chelation of Cu(DTC)₂ for a second time to reach the third strike. As expected, in vitro and in vivo studies showed that the synergistic integration of DSF-based programmed chemotherapy and NIR-II phototherapeutics could achieve effective tumor removal. Therefore, we propose a novel type of programmed therapy against cancer by designing a nanoplatform via “nontoxicity-to-toxicity” chemical chelation transformation.