Rationally designed mitochondria-impairing small molecule-enabled chemo-phototherapy to potentiate apoptosis and autophagy in cancer cells.

Mitochondria, central regulators of cellular bioenergetics, biosynthesis, and stress signaling, represent an attractive yet challenging target for cancer therapy. Although phototherapy offers a non-invasive approach with high spatiotemporal control, the development of small-molecule systems capable of precise mitochondrial targeting for combined chemo and phototherapeutic modalities remains limited. Here, we report a rationally engineered small-molecule platform that integrates a cationic heptamethine cyanine scaffold with non-steroidal anti-inflammatory drugs (NSAIDs) to enable multifunctional chemo-phototherapy. The heptamethine cyanine unit acts as a mitochondrial targeting vector, intrinsic fluorescent reporter, and phototherapeutic module, while the NSAID component provides chemotherapeutic activity through inhibition of mitochondrial cyclooxygenase-2 (Cox-2). Biological evaluation identified the indomethacin-conjugated derivative 7a as a lead candidate that self-assembles into nanoscale structures and selectively accumulates in the mitochondria of HCT-116 colon cancer cells. Near-infrared light activation induces photothermal heating and reactive oxygen species generation (ROS), causing mitochondrial membrane depolarization, structural disruption, and oxidative stress. This mitochondrial damage triggers apoptosis via inhibition of Bcl-2, Cas-3/9, PARP and Cox-2, as well as upregulation of BAX, alongside inducible autophagy that can be pharmacologically regulated. This heptamethine cyanine-NSAID conjugate establishes a versatile mitochondria-targeted chemo-phototherapeutic system and advances light-activated organelle-directed chemical biology as a promising strategy for minimally invasive cancer therapy.