| Summary: | Xiangyang Cheng,1,* Dejian Li,2,* Aiqi Lin,3 Jun Xu,1 Liang Wu,1 Huijie Gu,1 Zhongyue Huang,1 Jiangyi Liu,1 Yiming Zhang,1 Xiaofan Yin1 1Department of Orthopedics, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, China; 2Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201301, China; 3Department of Retired, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai 201199, China *These authors contributed equally to this work Introduction: For an ideal drug delivery system, the outstanding drug-loading capacity and specific control of the release of therapeutics at the desired lesions are crucial. In this work, we developed a triple-responsive nanoplatform based on copper sulfide (CuS)-capped yolk-shell-structured periodic mesoporous organosilica nanoparticles (YSPMOs) for synergetic chemo-photothermal therapy. Methods: Herein, the YSPMOs were employed as a drug carrier, which exhibited a high doxorubicin (DOX) loading capacity of 386 mg/g. In this controlled-release drug delivery system, CuS serves as a gatekeeper to modify YSPMOs with reduction-cleavable disulfide bond (YSPMOs@CuS). CuS could not only avoid premature leakage in the delivery process, but also endowed the excellent photothermal therapy (PTT) ability. Results: Upon entering into cancer cells, the CuS gatekeeper was opened with the breaking of disulfide bonds and the DOX release from YSPMOs(DOX)@CuS in response to the intracellular acidic environment and external laser irradiation. Such a precise control over drug release, combined with the photothermal effect of CuS nanoparticles, is possessed by synergistic chemo-photothermal therapy for cancer treatment. Both in vitro and in vivo experimental data indicated that the synergistic effect of YSPMOs(DOX)@CuS showed efficient antitumor effect. In addition, low systemic toxicity was observed in the pathologic examinations of liver, spleen, lungs, and kidneys. Conclusion: This versatile nanoplatform combination of PTT, chemotherapeutics, and gating components shows general potential for designing multifunctional drug delivery systems. Keywords: periodic mesoporous organosilica, CuS, triple-responsive release, chemo-photothermal therapy
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