Abstract
Although disruptions in metal ion homeostasis leading to severe cellular damage and regulated cell death are a promising strategy for cancer immunotherapy, challenges in overloading these ions to tumor cells without premature release have limited their therapeutic applications. In this study, we develop binary mineral nanoparticles incorporating both Ca2+ and Na+ ions to enhance the cytotoxic effects of ion interference in cancer immunotherapy. Engineered using a microfluidic system for uniform size distribution and scalability, these nanoparticles exhibit pH-sensitive ion release. Systemically administered, they preferentially accumulate in tumors, elevating intracellular Ca2+ and Na+ levels and inducing immunogenic cell death without calcium channel activators or other small-molecule inducers. Our binary mineral nanoparticles significantly enhance antitumor immunity, especially when combined with an immune checkpoint inhibitor, leading to long-term immunity and inhibition of metastasis. This nanotechnology-enabled synergistic delivery of Ca²⁺ and Na⁺ ions represents a promising adjunct to existing metalloimmunotherapy strategies for cancer eradication.
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Acknowledgements
This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (Grant No. RS-2022-NR070844 to J.K. and J.O.K., RS-2024-00343765 to J.K., RS-2025-02303064 and RS-2025-14292970 to J.O.K.). The authors thank the Core Research Support Center for Natural Products and Medical Materials (CRCNM, Yeungnam University) for technical support.
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J.K. and J.O.K. conceived the idea. B.L.N., J.K. and J.O.K. designed the experiments. B.L.N., N.D.L., T.O.O.N., D.A., B.R.P., B.K., J.M.L., and S.K.K. performed the experiments and analyzed the data. C.D.P., D-V.P., J.H., and J-H.C. helped the data interpretation. J.H., J-H.C., and S.K.K. provided constructive advice for data analysis and manuscript writing. B.L.N., J.K., and J.O.K. wrote the manuscript with feedback from all authors.
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Nguyen, B.L., Le, N.D., Nguyen, T.O.O. et al. Binary mineral nanoparticles enable intravascular delivery of metal ions to tumors for metalloimmunotherapy. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68279-y
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DOI: https://doi.org/10.1038/s41467-025-68279-y
