An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation‐Mediated Combination Tumor Therapy

Abstract Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP‐1 peptide is reported. The resulting generation 5 (G5) dendrimer‐based nanodevice, known as G5‐PEG‐LyP‐1‐CuS‐DMXAA NPs (GLCD NPs), possess good colloidal stability, pH‐sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP‐1‐targeted killing effect on breast tumors by combining CuS‐mediated photothermal therapy (PTT) and DMXAA‐induced vascular disruption, while also triggering antitumor immune responses through PTT‐induced immunogenic cell death and DMXAA‐mediated immune regulation via M1 polarization of tumor‐associated macrophages and dendritic cell maturation. In addition, with the LyP‐1‐mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two‐pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation‐mediated combination tumor therapy with potential for clinical translations.