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Multimodal therapeutic agents based on novel nanomaterials for multidrug resistance have attracted increasing attention in cancer therapy. In this study, we describe the construction of a programmed mesoporous silica-capped gold nanorod covered with nano-selenium overcoat (Se@Au@mSiO 2 ) nanoparticles as a multifunctional nanoplatform to incorporate materials with specific chemotherapeutic, chemoprevention, and photoablation/hyperthermia functions that collectively contribute to enhance anticancer efficacy in multidrug-resistant breast cancer. The triplecombination-based nanosized Se@Au@mSiO 2 /DOX effectively accumulates in the tumor and the release of the therapeutic cargo could be remotely manipulated by mild near-infrared (NIR) irradiation. Se@Au@mSiO 2 /DOX notably enhances the cell killing effect through induction of cell apoptosis. In addition, Se@Au@mSiO 2 /DOX inhibits tumor cell growth through cell cycle arrest and induction of apoptosis via suppression of the Src/FAK/AKT signaling pathways. Synergistic Se-photothermal-chemotherapy combination exhibits significant tumor growth suppression and delayed tumor progression in vivo. Immunohistochemistry analysis shows elevated numbers of caspase-3 and PARPimmunolabeled cells and decreased Ki-67 + and CD31 + cancer cells in the tumor mass. No noticeable signs of organ damage or toxicity are observed after treatment with Se@Au@mSiO 2 /DOX (NIR+), which is further supported by hematology and biochemical analyses. Thus, Se@Au@mSiO 2 /DOX has potential for the clinical treatment of metastatic breast cancers with little or no adverse effects.

Taken together, the data indicate that L-APNs can be promising therapeutic vehicles for enhanced delivery of PTX to tumor sites.