Exosome camouflaged coordination-assembled Iridium(III) photosensitizers for apoptosis-autophagy-ferroptosis induced combination therapy against melanoma

Melanoma represents the most fatal form of skin cancer due to its resistance mechanisms and high capacity for the development of metastases. Among other medicinal techniques, photodynamic therapy is receiving increasing attention. Despite promising results, the application of photodynamic therapy is inherently limited due to interference from melanin, poor tissue penetration of photosensitizers, low loading into drug delivery systems, and a lack of tumor selectivity. To overcome these limitations, herein, the coordination-driven assembly of Ir(III) complex photosensitizers with Fe(III) ions into nanopolymers for combined photodynamic therapy and chemodynamic therapy is reported. While remaining stable under physiological conditions, the nanopolymers dissociated in the tumor microenvironment. Upon exposure to light, the Ir(III) complexes produced singlet oxygen and superoxide anion radicals, inducing cell death by apoptosis and autophagy. The Fe(III) ions were reduced to Fe(II) upon depletion of glutathione and reduction of the GPX4 levels, triggering cell death by ferroptosis. To provide tumor selectivity, the nanopolymers were further camouflaged with exosomes. The generated nanoparticles were found to eradicate a melanoma tumor as well as inhibit the formation of metastases inside a mouse model.