The reliance of many anticancer agents on apoptosis often limits their therapeutic efficacy and contributes to the development of drug resistance. To overcome these challenges, alternative mechanisms of cell death such as oncosis have garnered increasing attention. However, few metal complexes capable of inducing oncosis have been reported to date. In this study, we describe the polymeric encapsulation of a cyclometalated iridium(III) complex within Pluronic F-127 to form nanosized micelles for oncosis-inducing photodynamic therapy. Upon light activation, these nanoparticles exhibited photocatalytic production of singlet oxygen and oxidation of NADH. The nanoparticles demonstrated potent therapeutic effects in cancer cells and tumor spheroids at low nanomolar concentrations under irradiation. Mechanistic investigations revealed that the therapeutic action was mediated by reactive oxygen species (ROS)-induced disruption of the cell membrane, mitochondrial dysfunction, ATP depletion, and morphological changes characteristic of oncotic cell death.
Linero-Artiaga et al. (Wed,) studied this question.