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

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 (Ca²⁺ ) nanomodulator (CaNM_CUR+CDDP ), i.e., a cisplatin (CDDP) and curcumin (CUR) co-incorporating calcium carbonate (CaCO₃ ) nanoparticle, is prepared by a facile one-pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca²⁺ -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 Ca²⁺ release, Ca²⁺ 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 Ca²⁺ nanomodulator will contribute to the development of multimodal bioimaging-guided organelle-targeted cancer therapy in the future.