Breaking the Chains of Therapeutic Blockade: Pyroptosis-Induced Photothermal-Chemotherapy with Targeted Nanoprobes in Triple-Negative Breast Cancer

There is an important clinical need and social significance, especially for young patients, to explore a new breast-conserving strategy that is not dependent on biomarkers for anti-triple-negative breast cancer. Disulfiram, historically employed for the treatment of chronic alcoholism, has recently emerged as a promising antitumor agent in combination with Cu²⁺. However, reported disulfiram-Cu²⁺ codelivery regimens often suffer from instability as well as inadequate drug metabolism, which is detrimental to the production and action of the antitumor active ingredient copper(II) bis(diethyldithiocarbamate). To address this obstacle, this study tested nanosystems ICG-CuET@PLGA-CS-HA (IC@PCH) nanoparticles (NPs) carrying the chemotherapeutic agent copper(II) bis(diethyldithiocarbamate) and photosensitizer indocyanine green for the efficient delivery of antitumor drugs. Benefiting from the involvement of hyaluronic acid, the prepared IC@PCH NPs not only targeted CD44 on the surface of tumor cells but also showed a longer in vivo circulation time. The in vitro and in vivo results demonstrated that IC@PCH NP-mediated photothermal-chemotherapy treatment led to pyroptosis via the NLRP3/caspase-1 classical pathway, which had a significant therapeutic effect on triple-negative breast cancer. In addition, targeting IC@PCH NPs allows photoacoustic-magnetic resonance-fluorescence trimodal imaging, which is capable of detecting more insidious cancer foci and opens up new avenues for precise cancer diagnosis and treatment.