Mitochondrial Sulfenated-Protein-Targeted\nCovalent\nImmobilization Boosting Efficient Copper(II) Depletion for Enhanced\nCancer Treatment

Copper plays a vital role in cellular metabolism and\noxidative\nstress regulation. Visualizing and controlling the copper level in\nmitochondrion have been proven to be promising and efficient strategies\nfor the diagnosis and treatment of triple-negative breast cancer (TNBC).\nHowever, developing an advanced probe for simultaneous visualization\nand depletion of mitochondrial copper remains a huge challenge. Herein,\nwe for the first time report a mitochondria-anchorable, copper-responsive,\nand depleting probe d-IR-DPA and evaluate its potential for quantitative\nvisualization of intratumoral copper(II) and anti-TNBC <i>in\nvivo</i>. Taking advantage of the mitochondrion-targeting and\nsulfenated-protein-mediated covalent immobilization characteristics,\nthis probe not only enables the quantitative detection of Cu<sup>2+</sup> levels in various types of tumors through ratiometric photoacoustic\n(PA<sub>680 nm</sub>/PA<sub>800 nm</sub>) imaging but also\nscavenges the mitochondrial Cu<sup>2+</sup>, simultaneously igniting\nincreased oxidative stress and mitochondrial membrane damage and eventually\nleading to severe TNBC cell apoptosis. More notably, the depletion\nof Cu<sup>2+</sup> by d-IR-DPA can alter the cellular metabolic pathway\nfrom oxidative phosphorylation to glycolysis, inducing energy deprivation\nand significant suppression of TNBC tumor in living mice. Our probe\nmay provide a valuable and powerful means for the effective treatment\nof TNBC as well as other copper-associated diseases.