Solamargin-functionalized gold nanoparticles codelivering photothermal-immunotherapy for triple-negative breast cancer

The high rates of metastasis and recurrence in triple-negative breast cancer (TNBC) underscore the limitations of current therapies. Solamargin (SM), a bioactive glycoside, possesses potential antitumor activity, but its efficacy is limited by low potency and off-target effects. We engineered Au@PEG-SM, a nanoconjugate designed for targeted delivery. Beyond traditional direct killing, we employed vascular endothelial cell models, STING-specific inhibitors (H-151), and cytokine neutralization assays to rigorously validate the molecular mechanism. Systemic immune profiling, including the analysis of lymph node dendritic cells, and bilateral tumor models were used to assess antitumor efficacy. Au@PEG-SM synergizes with photothermal therapy (PTT) to achieve a potent 1 plus 1 greater than 2 therapeutic effect. Mechanistically, low-dose SM sensitizes the cGAS-STING pathway in vascular endothelial cells; upon synergistic activation by PTT-released DNA, this triggers a massive secretion of IFN-β and TNF-α, leading to indirect tumor cell apoptosis. This process, combined with robust immunogenic cell death (ICD) and promoted dendritic cell maturation in lymph nodes, triggers a systemic antitumor response. Comprehensive immune profiling revealed that this combination therapy significantly increases the infiltration of NK cells and CD8 + T cells while markedly reducing immunosuppressive MDSCs and regulatory T cells (Tregs) in both primary and distant tumors. When combined with anti-PD-L1 blockade, the therapy eradicated primary tumors and established durable immune memory. This study establishes Au@PEG-SM as a powerful platform that achieves systemic immune activation via a sensitized STING-secretome-DC cascade. By providing rigorously validated mechanistic insights and a holistic immune landscape, our work offers a promising multimodal paradigm for overcoming TNBC.