Ultrasound-Augmented Mitochondrial Calcium Ion Overload by Calcium Nanomodulator to Induce Immunogenic Cell Death

Immunogenic cell death (ICD), a manner of tumor cell death that can trigger antitumor immune responses, has received extensive attention as a potential synergistic modality for cancer immunotherapy. Although many calcium ion (Ca²⁺) nanomodulators have been developed for cancer therapy through mitochondrial Ca²⁺ overload, their ICD-inducing properties have not been explored. Herein, an acid-sensitive PEG-decorated calcium carbonate (CaCO₃) nanoparticle incorporating curcumin (CUR; a Ca²⁺ enhancer) (PEGCaCUR) was prepared using a simple one-pot strategy. PEGCaCUR served as not only a Ca²⁺ nanomodulator inducing efficient mitochondrial Ca²⁺ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of PEGCaCUR with ultrasound (US), PEGCaCUR+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca²⁺ overload, along with subsequent upregulation of reactive oxygen species levels. PEGCaCUR also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.