Calcium-Overloaded Multifunctional Nanoparticles for Synergistically Enhanced Photothermal and Chemotherapy and Immune Activation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly invasive subtype characterized by high recurrence rates and the absence of specific therapeutic targets, resulting in limited treatment efficacy and immune insensitivity. Nanoparticle-based photothermal therapy holds promise due to its selective tumor heating and minimal invasiveness; however, its effectiveness is constrained by limited biocompatibility and localized heat transfer. To address these challenges, a multifunctional therapy utilizing CaO@C@PTX@TG nanoparticles was developed for TNBC treatment. This platform combines multiple mechanisms, with the CaO@C core enabling photothermal and chemothermal conversion while simultaneously releasing calcium ions. In parallel, paclitaxel (PTX) enhances chemotherapy synergy. The TG modification improves nanoparticle biocompatibility and supports efficient drug release within target cells. Under light activation, the platform induces calcium-overload, generating synergistic effects with photothermal therapy, promoting apoptosis and enhancing the antitumor immune response through immunogenic cell death (ICD). In vivo and in vitro experiments demonstrated that the CaO@C@PTX@TG system effectively inhibited tumor growth and metastasis. This approach integrates thermotherapy, photothermal therapy, chemotherapy, calcium-overload and immune activation, presenting an effective treatment strategy for TNBC.