Molecular engineering on Primary–Auxiliary Ligand Co-regulation

Two-photon photodynamic therapy (TP-PDT) is a clinically valuable cancer treatment modality owing to its deep tissue penetration, high spatial selectivity, and minimal damage to normal tissues. Here, Ir(III) complex photosensitizers for PDT were designed and investigated through cooperative C^N/N^N dual-ligand modification of [Ir(ppy)2(osip)] (PF6) (Ir-1). The origin of the performance loss arising from combining two individually optimized ligands was elucidated using DFT/TD-DFT calculations. The N^N ligand provides the charge-transfer framework governing triplet energy and the dominant two-photon absorption (TPA) channel, while C^N substituents fine-tune electron–hole separation, rigidity, and excited-state relaxation within this framework. When combined with an electron-withdrawing N^N ligand, electron-donating substitution on the C^N ligand red-shifts the TPA maximum of Ir-a3 to 668.4 nm, within the biological window, and extends its triplet lifetime to 2995.06 μs. In contrast, strong electron-withdrawing substituents on the C^N ligand deactivate intersystem crossing and consequently suppress PDT activity. All T1-accessible complexes also meet the thermodynamic requirements for Type I and Type II photosensitization, with LogP values of 1.59–2.51. Owing to its longest triplet lifetime, TPA maximum within the biological window and balanced solubility (ΔGsolv = -47.93 kcal/mol) and lipophilicity (LogP = 2.12), Ir-a3 is expected to be a promising PDT candidate. The cooperative, rather than simply additive, nature of the dual-ligand effect is explicitly demonstrated for the first time. These findings establish a strategy for the cooperative modification of primary and auxiliary ligands in Ir(III) complex photosensitizers.