Mitochondrial targeting cyclometalated iridium scaffold antitumor drugs

Abstract

Cancer remains a persistent global challenge, with conventional metallodrugs like cisplatin facing limitations due to acquired resistance and side effects. Cyclometalated iridium(III) complexes have emerged as promising anticancer candidates, distinguished by their unique chemical properties, outstanding photophysical tunability, and precise biological targetability. Meanwhile, mitochondria, as the cellular energy factories, play a vital role in tumor cell survival. Based on these factors, this frontier article systematically compiles recent research advances on mitochondrial-targeted antitumor cyclometalated iridium scaffolds, comprehensively highlighting molecular design strategies and their implementations. Their tunable ligand affinity, negligible dark toxicity and stimulus-responsive therapeutic profiles endow them with significant potential for more effective treatments. Specifically, this frontier article details their exploitation in chemotherapy, immunotherapy, and photodynamic therapy, and outlines activatable metalloprodrug mechanisms. Regarding future directions, we discuss outlooks for current challenges, including drug delivery, performance optimization, clinical translation and scalable synthesis, aiming to inspire next-generation anticancer agent innovation.