Ca²⁺ overload has attracted an increasing attention due to its benefit of precise cancer therapy, but its efficacy is limited by the strong Ca²⁺ excretion of cancer cells. Moreover, monotherapy of Ca²⁺ overload usually fails to treat tumors satisfactorily. Herein, we develop a multifunctional nanosystem that could induce Ca²⁺ overload by multipathway and simultaneously produce chemotherapy for synergistic tumor therapy. The nanosystem (CaMSN@CUR) is prepared by synthesizing a Ca-doped mesoporous silica nanoparticle (CaMSN) followed by loading the anticancer drug curcumin (CUR). CaMSN serves as the basis Ca²⁺ generator to induce Ca²⁺ overload directly in the intracellular environment by acid-triggered Ca²⁺ release, while CUR could not only exhibit chemotherapy but also facilitate Ca²⁺ release from the endoplasmic reticulum to the cytoplasm and inhibit Ca²⁺ efflux out of cells to further enhance Ca²⁺ overload. The in vitro and in vivo results show that CaMSN@CUR could exhibit a remarkable cytotoxicity against 4T1 cells and significantly inhibit tumor growth in 4T1 tumor-bearing mice via the synergy of Ca²⁺ overload and CUR-mediated chemotherapy. It is expected that the designed CaMSN@CUR has a great potential for effective tumor therapy.

中文翻译：

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多通道 Ca2+ 发生器通过细胞内 Ca2+ 过载和化疗协同治疗肿瘤

Ca ²⁺超载因其有利于精准癌症治疗而引起了越来越多的关注，但其疗效受到癌细胞强Ca ²⁺排泄的限制。此外，Ca ²⁺过载的单一疗法通常不能令人满意地治疗肿瘤。在此，我们开发了一种多功能纳米系统，该系统可以通过多途径诱导 Ca ²⁺超载，同时产生用于协同肿瘤治疗的化学疗法。纳米系统 (CaMSN@CUR) 是通过合成 Ca 掺杂的介孔二氧化硅纳米颗粒 (CaMSN) 并负载抗癌药物姜黄素 (CUR) 制备的。CaMSN作为基础Ca ²⁺发生器诱导Ca ^{2+通过酸触发的 Ca 2+}释放直接在细胞内环境中超载，而 CUR 不仅可以表现出化学疗法，还可以促进 Ca ²⁺从内质网释放到细胞质并抑制 Ca ²⁺流出细胞以进一步增强 Ca ^{2 +}过载。^{体外和体内结果表明，CaMSN@CUR 对 4T1 细胞具有显着的细胞毒性，并通过 Ca 2+}超载和 CUR 介导的化疗的协同作用显着抑制 4T1 荷瘤小鼠的肿瘤生长。预计设计的 CaMSN@CUR 对有效的肿瘤治疗具有巨大的潜力。