A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction‐Mediated Cancer Therapy

Abstract Subcellular organelle‐targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off‐target side effects. Herein, a multichannel calcium ion (Ca 2+ ) nanomodulator (CaNM CUR+CDDP ), i.e., a cisplatin (CDDP) and curcumin (CUR) co‐incorporating calcium carbonate (CaCO 3 ) nanoparticle, is prepared by a facile one‐pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca 2+ ‐overload‐induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNM CUR+CDDP ( PEG CaNM CUR+CDDP ) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca 2+ release, Ca 2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria‐targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca 2+ nanomodulator will contribute to the development of multimodal bioimaging‐guided organelle‐targeted cancer therapy in the future.