Self-assembled iridium(III) photosensitizers induce cuproptosis without copper supplementation for efficient anticancer therapy

Photodynamic therapy (PDT) is a promising treatment that uses reactive oxygen species (ROS) generated by light-irradiated photosensitizers (PSs) in the presence of molecular oxygen (O₂). However, its efficiency is heavily compromised in aqueous environments and living systems. Here, we report a series of self-assembled Ir(III) complex-based PSs based on a targetable diphenylalanine-derivative peptide assembly strategy. The complexes (1 − 3) form spherical nanoparticles (NPs), with complexes 2 and 3 exhibiting aggregation-induced emission (AIE) characteristics in water, and strong type I/II mixed PDT in aqueous solution. With the assistance of a tumor-targeting biotin fragment, these complexes could target TNBC cells with precise phototoxicity at a low dose (IC50 = 0.127 μM), low irradiation power (30 mW cm−2), and short exposure time (2 min). Moreover, complexes 1 and 2 can induce cuproptosis without copper ion loading, amplifying its anticancer activity. This is the first example of luminescent metal complexes that can trigger cuproptosis without copper supplementation. Photodynamic therapy (PDT) faces challenges in aqueous environments and living systems due to compromised efficiency. Here, the authors develop self-assembled Ir(III) complex-based photosensitizers that form nanoparticles with aggregation-induced emission, enabling precise phototoxicity against TNBC cells and inducing cuproptosis without copper loading.