Endogenous copper manipulation based on multifunctional gold nanoparticles elicit precise and self-reinforcing photothermal-chemodynamic therapy for effective treatment of metastatic breast cancer

Synergistic photothermal therapy (PTT) and chemodynamic therapy (CDT) represent a promising strategy for the treatment of metastatic breast cancer. However, the specificity and therapeutic efficacy of current approaches remain insufficient for clinical translation. Herein, multifunctional gold nanoparticles (ABSF NPs) co-modified with benzoylthiourea (BTU), S-nitrosothiol (SNO), and folic acid (FA) were fabricated to enable precise and efficient primary tumor elimination together with metastasis suppression for improved breast cancer treatment via Cu²⁺-triggered PTT/CDT, copper-catalyzed nitric oxide (NO) production, NO-enhanced CDT, and metastasis inhibition driven by intratumoral copper deprivation. Specifically, the novelty of this study lies in fabricating an intelligent nanomaterial to respond to and manipulate abnormally elevated Cu²⁺ levels in tumor cells. This system not only uses intracellular Cu²⁺ as an endogenous stimulus to simultaneously trigger photothermal therapy and NO-enhanced chemodynamic therapy for highly precise and efficient synergistic tumor treatment, but also performs on-demand copper deprivation to significantly suppress copper-mediated tumor metastasis. After administration, ABSF NPs preferentially accumulated at the tumor site via the enhanced permeability and retention (EPR) effect and FA-mediated targeting, followed by efficient cellular internalization. They then chelated excess intracellular Cu²⁺ through the BTU moieties, leading to a 52% reduction in intracellular copper levels in tumor cells. This chelation not only induced nanoparticle aggregation to generate in situ photothermal agents capable of raising the tumor temperature to ~52 °C under irradiation, but also converted captured Cu²⁺ into Cu⁺, which served as a catalyst for reactive oxygen species (ROS) generation and NO release, thereby enabling tumor-specific PTT/CDT and NO-enhanced therapy. More importantly, compared with the PBS group, the ABSF+PTT treatment reduced the final average tumor volume and tumor weight by 67% and 78%, respectively, and decreased the number of lung metastatic nodules by 85%. In addition, while all mice in the PBS group died by day 28, the ABSF+PTT group maintained an 86% survival rate at day 35. Both in vitro and in vivo results demonstrated that ABSF NPs safely and effectively inhibited tumor growth and metastasis, providing a novel paradigm for the treatment of malignant tumors.