Mitochondrial Sulfenated-Protein-Targeted Covalent Immobilization Boosting Efficient Copper(II) Depletion for Enhanced Cancer Treatment

Copper plays a vital role in cellular metabolism and oxidative stress regulation. Visualizing and controlling the copper level in mitochondrion have been proven to be promising and efficient strategies for the diagnosis and treatment of triple-negative breast cancer (TNBC). However, developing an advanced probe for simultaneous visualization and depletion of mitochondrial copper remains a huge challenge. Herein, we for the first time report a mitochondria-anchorable, copper-responsive, and depleting probe d-IR-DPA and evaluate its potential for quantitative visualization of intratumoral copper(II) and anti-TNBC in vivo. Taking advantage of the mitochondrion-targeting and sulfenated-protein-mediated covalent immobilization characteristics, this probe not only enables the quantitative detection of Cu²⁺ levels in various types of tumors through ratiometric photoacoustic (PA_680 nm/PA_800 nm) imaging but also scavenges the mitochondrial Cu²⁺, simultaneously igniting increased oxidative stress and mitochondrial membrane damage and eventually leading to severe TNBC cell apoptosis. More notably, the depletion of Cu²⁺ by d-IR-DPA can alter the cellular metabolic pathway from oxidative phosphorylation to glycolysis, inducing energy deprivation and significant suppression of TNBC tumor in living mice. Our probe may provide a valuable and powerful means for the effective treatment of TNBC as well as other copper-associated diseases.