Photo-uncaging of a ferrocene-bridged dinuclear iridium(iii) complex for three-photon photoimmunotherapy against hypoxic melanoma

Abstract

The complexity of solid tumors in terms of light scattering, oxygen insufficiency, and redox imbalance complicates the strategic design of photoactivated therapy. In this work, an unprecedented photoactivated homolysis process of ferrocene is driven by the photochemistry of a conjugated cyclometalated iridium(III) complex upon 970 nm three-photon excitation, exhibiting photo-uncaging, biocatalysis, and an ROS storm all in one moiety. Trapping assays, ultrafast spectroscopy, and DFT calculations reveal the release of Fe²⁺ ions, the location of carbon-centered radicals, and the essential single electron transfer (SET) process for their generation. Such a photo-uncaging pattern harnesses peripheral substrates (O₂, H₂O_2, and H₂O) for ROS generation. It continuously degrades the biomolecule homeostasis (GSH and NADH), inducing high immunogenic ferroptosis and necroptosis in hypoxic melanoma models for long-term photoimmunotherapy. The uncaging of the photostable ferrocene by transition metal photochemistry develops an elegant paradigm for multi-functional molecular photoactivated therapy.