Biodegradable Ca²⁺ Nanomodulators Activate Pyroptosis through Mitochondrial Ca²⁺ Overload for Cancer Immunotherapy

Pyroptosis provides a new direction and broad prospects for cancer immunotherapy. However, the development of a nanoplatform as a pyroptosis inducer is limited, and the discovery of a new type of nano-pyroptosis inducer for cancer immunotherapy is still imminent. Herein, biodegradable Ca²⁺ nanomodulators (CaNMs) are prepared as pyroptosis inducers for cancer immunotherapy via mitochondrial Ca²⁺ overload. The obtained CaNMs can decompose under low pH to release Ca²⁺ and curcumin, leading to a sudden surge in mitochondrial Ca²⁺ ions, eventually resulting in pyroptosis. We not only confirm the occurrence of mitochondrial Ca²⁺ overload-triggered pyroptosis for the first time but also reveal the robust immune responses via CaNMs, along with remarkably suppressing tumor proliferation and lung metastasis. This work will provide new strategies and inspiration for pyroptosis-mediated cancer treatments, greatly contributing to the further development of Ca²⁺ nanomodulators.