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

AbstractPyroptosis 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.