Conjugation of a Cyclometalated Ir(III) Complex to Human Serum Albumin for Oncosis-Mediated Photodynamic Therapy

Anticancer agents often rely on apoptosis, limiting their effectiveness and leading to drug resistance. To address these issues, alternative cell death mechanisms have gained attention. To date, only very few metal complexes that trigger oncosis have been reported. Herein, the conjugation of a cyclometalated Ir(III) complex to human serum albumin for oncosis mediated photodynamic therapy is reported. While being non-toxic in the dark, the conjugate showed strong therapeutic effects upon irradiation in cancer cells and tumor spheroids. Biological mechanistic analyses revealed that the conjugate preferentially accumulated in mitochondria, induced NADH oxidation, caused oxidative damage to the cell membrane, depleted ATP, and triggered Ca²⁺ influx, inducing cellular swelling and vacuolization of the cytoplasm as well as the formation of organelle-free blisters, ultimately leading to cell death by oncosis. This work presents the first example of a photo-responsive metal complex human serum albumin conjugate that induces oncosis.