Mitochondria‐Targeted Cancer Therapy Using an Endogenous Stimuli‐Responsive Prodrug With Aggregation‐Induced‐Emission Features

ABSTRACT

Theranostic agents derived from aggregation‐induced emission luminogens (AIEgens) offer significant potential, yet platforms that provide controlled drug release, organelle‐specific action, and self‐reporting capability are highly desired. Herein, we report a mitochondria‐targeted prodrug system that integrates an AIE fluorophore with excited‐state intramolecular proton transfer (ESIPT) characteristics, covalently linked to the anticancer drug dasatinib. The amphiphilic prodrug self‐assembled into nanoparticles of around 210 nm with a spherical morphology. The probe is initially non‐fluorescent due to ESIPT inhibition. Following cellular internalization, intracellular esterases cleave the carbonate linker, initiating two simultaneous processes: (1) the cytosolic release of dasatinib to inhibit proliferation‐associated tyrosine kinases, and (2) the restoration of ESIPT and subsequent aggregation of the fluorophore, yielding a ratiometric fluorescence turn‐on signal for real‐time monitoring. The liberated probe, appended with a triphenylphosphine moiety, then selectively targets mitochondria, where it generates reactive oxygen species (ROS), inducing mitochondrial damage and promoting apoptosis. This combination of cytosolic kinase inhibition and mitochondria‐targeted ROS production creates a powerful synergistic anticancer effect, demonstrating significantly enhanced efficacy over dasatinib alone. This multifunctional design pioneers a theranostic approach that merges precise drug activation, dynamic imaging, and organelle‐specific therapy.