Shedding light on photo-redox catalysis of a NIR iridium( <scp>iii</scp> ) complex for high photocytotoxicity against cisplatin resistant ovarian cancer in 3D tumor spheroids

The clinical translation of photodynamic therapy (PDT) is often hindered by the lack of photosensitizers (PSs) that achieve potent cytotoxicity at clinically relevant concentrations. This limitation stems from an incomplete understanding of photochemical mechanisms underlying PDT efficacy. Here, we report RM2, a near-infrared Ir(III)-based PS with a high molar absorption coefficient (17 700 M^-1 cm^-1 at the excitation wavelength), a key feature for attaining low IC₅₀ values. Upon irradiation, RM2 undergoes two distinct single-electron transfer (SET) pathways: catalytic oxidation of NADH with a turnover frequency (TOF) of 690 h^-1, and Type-I ROS generation (O₂˙^- and H₂O₂), confirmed by EPR spectroscopy and H₂O₂ detection assays. In addition, RM2 displays a triplet state energy of 37.68 kcal mol^-1 (1.63 eV, 762 nm) with a 5 µs lifetime, enabling efficient energy transfer to ³O₂ and a singlet oxygen quantum yield (<i>φ</i>_Δ) of 0.75 in cell-free media. Encapsulation of RM2 in DSPE-mPEG₂₀₀₀ nanoparticles further amplified its activity, enhancing photocytotoxicity by 8.3-fold and achieving an IC₅₀ of 60 nM against ovarian cancer cells. Remarkably, RM2-NPs retained this potency in cisplatin-resistant ID8 cells (IC₅₀ = 60 nM), whereas cisplatin itself showed drastically reduced efficacy (IC₅₀ = 10.46 µM in wild-type and 30.41 µM in resistant cells). Additionally, RM2-NPs exhibited pronounced efficacy against 3D ovarian tumor spheroid models, underscoring their translational potential. These results establish RM2 as a multifunctional photosensitizer, in which the synergy of long-lived triplet energy and favorable redox potentials enables diverse photochemical mechanisms, encompassing NADH oxidation and both Type-I and Type-II ROS generation. This multifaceted mechanism of action offers a powerful strategy to overcome hypoxia and drug resistance, significantly advancing the potential of PDT for effective cancer therapy.