Photodynamic therapy (PDT) is a promising cancer treatment modality that leverages photoactivatable prodrugs. It works by exciting photosensitizers (PSs) to generate reactive oxygen species (ROS), thereby selectively destroying tumor tissue [1]. Compared to conventional therapies such as surgery and chemotherapy, PDT demonstrates significant advantages in treatment selectivity, safety, and systemic toxicity management [2,3]. However, the clinical application of current PSs remains limited due to low in vivo clearance rates, pronounced photobleaching, tendency to aggregate, and potential hepatotoxicity [[4], [5], [6]]. These limitations have prompted intensive efforts toward the development of next-generation PSs with improved performance. Research has revealed that transition metal ruthenium (Ru) complexes, particularly Ru(II) polypyridyl complexes, exhibit immense potential for PDT applications. These complexes not only feature facile synthesis and low toxicity to healthy tissues but also possess superior photophysical and photochemical properties, including strong absorption in the visible region, high ROS quantum yields, and remarkable photostability [[7], [8], [9], [10], [11], [12]]. Notably, the Ru(II)-based photosensitizer TLD1433 has advanced to Phase II clinical trials for the treatment of bladder cancer [13], underscoring the translational potential of this class of complexes.

Despite these merits, the clinical implementation of Ru(II) complexes in photodynamic therapy faces notable challenges. Many Ru(II)-based photosensitizers primarily operate via a Type II mechanism, where light-excited PS transfers energy to molecular oxygen to generate cytotoxic singlet oxygen (1O2) [[14], [15], [16], [17]]. This process critically depends on local oxygen concentration. However, many solid tumors develop hypoxic microenvironments due to rapid proliferation and insufficient blood supply, substantially compromising PDT efficacy [[18], [19], [20]]. To circumvent this limitation, photocatalytic cancer therapy has emerged as a promising, non-invasive alternative [[21], [22], [23], [24]]. In the development of metal-based photocatalytic anticancer drugs, nicotinamide adenine dinucleotide (NADH), a key redox coenzyme, serves as an important intracellular target [[25], [26], [27], [28], [29], [30], [31]]. Metal-based photocatalysts can be activated by light to catalyze the oxidation of NADH to NAD+via electron transfer reactions. This photoinduced process disrupts the intracellular redox balance and metabolic homeostasis, ultimately triggering cell death even under hypoxic conditions [[32], [33], [34]].

Recent findings on the intrinsic photocatalytic activity of Ru(II)-based PSs highlight their potential for dual-functionality [[35], [36], [37]]. By combining photodynamic and photocatalytic mechanisms, these agents may achieve enhanced antitumor efficacy while mitigating the challenges posed by tumor hypoxia. Moreover, this dual-action approach could lower the risk of therapeutic resistance, providing a promising strategy to overcome the current limitations of Ru-based photosensitizers.

Structural studies reveal that [Ru(dip)2(L)]2+-type complexes (dip = 4,7-diphenyl-1,10-phenanthroline and L = a bidentate ligand) serve as an ideal scaffold for Ru-based PS design. The extended π-conjugation system in dip enhances visible-light absorption, while its hydrophobic character facilitates cellular internalization and preferential nuclear localization [38,39]. In this work, we synthesized two Ru(II) polypyridyl complexes using dip as the ancillary ligand (Fig. 1): [Ru(dip)2(dppn)](PF6)2 (Ru1) and [Ru(dip)2(dpb)](PF6)2 (Ru2). The primary ligands dppn (benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine) and dpb (2,3-diphenylbenzo[ghi]perylene) were selected for their extended conjugation systems. Using the classical [Ru(bpy)3]2+ complex as reference, we systematically compared their in vitro antitumor activities and established structure-activity relationships between ligand architecture and PDT efficacy. Furthermore, we quantitatively evaluated their photocatalytic capabilities through NADH oxidation turnover frequency (TOF) measurements and hypoxic tumor cell killing efficacy assessments, providing possible mechanistic insights into their dual-action therapeutic potential.