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Abstract: Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria‐targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH‐BBR), as a new mitochondria‐targeting probe capable of self‐assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X‐ray crystallography revealed that the self‐assembly process was attributed to a synergy of different molecular interactions, including π–π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH‐BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH‐BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self‐assembly and tune antitumor activity of mitochondria‐targeting probes, which can facilitate to improve cancer treatment in vivo. [ABSTRACT FROM AUTHOR]

Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells. [ABSTRACT FROM AUTHOR]