Mitochondria‐Damaging Self‐Reporting Probe for Cancer Therapy

ABSTRACT Mitochondrial damage induced by chemotherapeutic agents through disruption of the mitochondrial membrane potential (Δ Ψ m ) remains a central challenge in drug development and evaluation. However, the assessment of Δ Ψ m ‐targeting drugs using commercially available fluorescent probes is often unreliable, as these dyes can interfere with, mask, or artificially amplify drug‐induced mitochondrial dysfunction, frequently resulting in misleading conclusions and translational failure. Herein, we report a class of cationic chemotherapeutic small molecules ( DPPs ) possessing intrinsic fluorescence migration‐based self‐reporting capability, which enables direct and non‐invasive monitoring of drug action without the need for external probes. Among them, DPP‐1 and DPP‐2 disrupt mitochondrial function, trigger excessive reactive oxygen species generation, and induce highly selective apoptosis. Remarkably, both compounds exhibit concentration‐dependent mitochondrial‐to‐nuclear translocation, enabling the real‐time visualization of therapeutic progression at the subcellular level. In vivo studies further confirm their potent tumor growth inhibition and negligible systemic toxicity effects. This self‐reporting mitochondria‐targeted chemotherapeutic platform provides a highly promising strategy for integrated cancer diagnosis and precision therapy.