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 B3Cl 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.