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) ((CaCUR)-Ca-PEG) was prepared using a simple one-pot strategy. (CaCUR)-Ca-PEG served as not only a Ca2+ nanomodulator inducing efficient mitochondrial Ca2+ overload but also an ICD inducer during improved synergistic cancer therapy. Combination of (CaCUR)-Ca-PEG with ultrasound (US), (CaCUR)-Ca-PEG+US, led to an enhanced ICD effect attributable to the enhanced mitochondrial Ca2+ overload, along with subsequent upregulation of reactive oxygen species levels. (CaCUR)-Ca-PEG also facilitates photoacoustic/fluorescence dual-mode imaging, as well as effectively suppressing tumor growth and metastasis, indicating promising theranostic properties.

Automated summary

This study developed an acid-sensitive nanoparticle ((CaCUR)-Ca-PEG) that induces mitochondrial Ca2+ overload and acts as an ICD inducer in improved cancer therapy. Combination with ultrasound (US) enhances the ICD effect, showing promising therapeutic and diagnostic properties.