Supramolecularly engineered bacteria mediated calcium overload and immunotherapy of tumors

Intracellular Ca²⁺ 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 Ca²⁺ overload and immunotherapy of tumors. Methods: A supramolecular conjugate of engineered living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) with CaCO₃ nanoparticles was developed for targeted delivery of curcumin-loaded CaCO₃ into tumors. Results: Both CaCO₃ nanoparticles and the loaded Ca²⁺ efflux inhibiting agent, curcumin (CUR), demonstrated significant enhancement of intracellular Ca²⁺ 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. Conclusion: The conjugate of VNP and CaCO₃ not only enhances the efficiency of common cancer treatments but also synergizes Ca²⁺ overload with cancer immunotherapy, thereby offering a promising approach for improving therapeutic outcomes in cancer treatment.