Unlocking a Novel [2+1+1+1+1] Coordination Framework through One-Pot Synthesis of an AIE-Active Iridium(III) Photoredox Catalyst for Enhanced Photocytotoxicity via Apoptosis, Ferroptosis, and Oncotic-like Cell Death

Abstract

Photodynamic therapy (PDT) has emerged as a powerful platform for cancer treatment. However, the clinical translation of PDT is hindered by several limitations, including the synthetic complexity of metal-based photosensitizers (PSs), aggregation-caused quenching-mediated reduction in PDT efficacy, and the inherent dependence on 3O2, restricting activity in hypoxic solid-tumor microenvironments. Elevated intracellular antioxidant levels, particularly glutathione (GSH), further attenuate ROS-mediated cytotoxicity in tumors. To address these limitations, we report a facile-to-synthesize Ir(III) [2+1+1+1+1] framework (AM1), prepared within 8 h, that exhibits pronounced aggregation-induced emission (AIE) driven by two triphenylphosphine (PPh3) rotor units. AM1 displays a long-lived excited state (τ ≈ 18.2 µs, 2 eV) and a 51-fold emission enhancement under oxygen-depleted conditions, leading to a high singlet-oxygen (1O2) quantum yield (ΦΔ ≈ 0.88). Beyond conventional PSs, AM1 also functions as a photoredox catalyst, enabling NADH/NADPH oxidation (TOF ≈ 290 h–1) and cytochrome c reduction, thereby sustaining activity under both hypoxic and normoxic conditions. Concurrent depletion of intracellular GSH and cysteine further amplifies oxidative stress. A nanoparticle formulation of AM1 (AM1@NP, size ∼92 nm) enhances AIE effect and cellular uptake; consequently, AM1@NP exhibits potent light-triggered cytotoxicity (IC50 ≈ 83 nM) and induces multimodal cell death via apoptosis, ferroptosis, and oncotic-like cell death, and retains high efficacy in 3D tumor spheroids. Overall, this work establishes an effective and scalable iridium platform that integrates AIE, photoredox catalysis, and oxygen-independent activity to address the key limitations of PDT.