Dehydroberberine Analogue Nanoassemblies for Inducing and Self-Reporting Mitochondrial Dysfunction in Tumor Cells.

Mitochondria-targeting probes that allow us to induce and report mitochondrial dysfunction have become promising theranostic agents for cancer; however, the lack of selectivity toward tumor cells over normal tissue cells has impeded the treatment outcome. Herein, we develop 10 fluorescent dehydroberberine derivatives ( B1-B10 ) capable of lighting up mitochondria and exerting moderate cytotoxicity against tumor cells. To enable the selectivity toward tumor cells over normal tissue cells, we introduced a lipophilic anion tetraphenylborate (TPB - ) into the most potent compound B3 + Cl - to drive molecular self-assembly into monodisperse organic nanoassemblies ( B3NPs ) in aqueous solution, which efficiently enhance the delivery of B3 + into HeLa cells assisted by an electrostatic interaction-driven anion-exchange process. Fluorescence imaging reveals that B3 + can initially accumulate in the mitochondria after entering HeLa cells, followed by inducing mitochondrial dysfunction and then migrating into the nucleus. Strong B3 + fluorescence translocating from mitochondria to nucleus can be monitored in real-time, allowing for self-reporting of mitochondrial dysfunction in HeLa cells. Moreover, we demonstrate that B3NPs exert significantly higher cytotoxicity against seven different tumor cells (e.g., U87MG, HeLa, MDA-MB-468, MDA-MB-435, MDA-MB-231, MCF-7, and HCT116 cells) compared to human normal tissue cells (e.g., HUVEC, HEK293). This work highlights the utility of the self-assembly approach to improve the cytotoxicity and selectivity of mitochondria-targeting agents against tumor cells.