Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200127, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China.
Theranostics. 2024 Oct 7;14(17):6560-6570. doi: 10.7150/thno.99931. eCollection 2024.
Intracellular Ca nanogenerators, such as calcium carbonate, calcium peroxide, and calcium phosphate nanoparticles, have shown promise in calcium overload-mediated tumor therapy. However, their effectiveness is often hampered by poor targeting, low accumulation, and limited penetration into tumor cells, leading to suboptimal therapeutic outcomes. This strategy aims to achieve synergistic Ca overload and immunotherapy of tumors. A supramolecular conjugate of engineered living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) with CaCO nanoparticles was developed for targeted delivery of curcumin-loaded CaCO into tumors. Both CaCO nanoparticles and the loaded Ca efflux inhibiting agent, curcumin (CUR), demonstrated significant enhancement of intracellular Ca overload, resulting in apoptosis of tumor cells via mitochondrial dysfunction. Moreover, VNP exhibited excellent tumor-targeting ability, colonization in tumor tissues, and anticancer activity with minimal side effects. The conjugate of VNP and CaCO not only enhances the efficiency of common cancer treatments but also synergizes Ca overload with cancer immunotherapy, thereby offering a promising approach for improving therapeutic outcomes in cancer treatment.
细胞内 Ca 纳米发电机，如碳酸钙、过氧化钙和磷酸钙纳米颗粒，已在钙过载介导的肿瘤治疗中显示出前景。然而，它们的有效性常常受到靶向性差、积累低和有限渗透进入肿瘤细胞的限制，导致治疗效果不理想。本策略旨在实现协同的 Ca 过载和肿瘤免疫治疗。 一种工程化活细菌（兼性厌氧鼠伤寒沙门氏菌 VNP20009、VNP）与 CaCO 纳米颗粒的超分子缀合物被开发用于靶向递送至肿瘤细胞内负载姜黄素的 CaCO。 CaCO 纳米颗粒和负载的 Ca 外排抑制剂姜黄素 (CUR) 均显著增强细胞内 Ca 过载，通过线粒体功能障碍导致肿瘤细胞凋亡。此外，VNP 表现出优异的肿瘤靶向能力、在肿瘤组织中的定植和抗癌活性，且副作用最小。 VNP 和 CaCO 的缀合物不仅提高了常见癌症治疗的效率，而且还协同 Ca 过载与癌症免疫治疗，从而为改善癌症治疗的治疗效果提供了一种有前途的方法。
