Tumor-targeting multi-shelled hollow nanospheres as drug loading platforms for imaging-guided combinational cancer therapy

In this work, we developed multi-shelled hollow nanospheres [RGD@a_m-ZnO@CuO@Au@DOX HNSs] as multifunctional therapeutic agents to achieve effective and targeted Zn²⁺/Cu²⁺ therapy, induced drug delivery under low pH/red-light conditions, and enhanced phototherapy under single red-light. The photothermal and photodynamic performance of a_m-ZnO@CuO@Au HNSs was enhanced relative to that of am-ZnO nanoparticles (NPs) or a_m-ZnO@CuO HNSs by utilizing the resonance energy transfer process and broad red-light absorption. The pH-sensitive am-ZnO@CuO@Au HNSs were dissolved to Zn²⁺/Cu²⁺ in the acidic endosomes/lysosomes of cancer cells, resulting in a cancer cell killing effect. The release performance of doxorubicin (DOX) from RGD@a_m-ZnO@CuO@Au@DOX HNSs was evaluated under low pH and red-light-irradiated conditions, and targeting of HNSs was confirmed by dual-modal imaging (magnetic resonance/fluorescence) of the tumor area. Moreover, in vivo synergistic therapy using RGD@a_m-ZnO@CuO@Au@DOX HNSs was further evaluated in mice bearing human pulmonary adenocarcinoma (A549) cells, achieving a remarkable synergistic antitumor effect superior to that obtained by monotherapy. This study validated that RGD@a_m-ZnO@CuO@Au@DOX HNSs can be a promising candidate for efficient postoperative cancer therapy.