Triplet π-Conjugated Oligomer Nanoparticles with High Intersystem Crossing Efficiency for 808 nm Laser-Activated Photodynamic Therapy

Designing efficient organic near-infrared (NIR) photosensitizers (PSs) is crucial for improving photodynamic therapy (PDT) against tumors. However, their practical application is often hindered by suboptimal performance and an incomplete understanding of intersystem crossing (ISC) dynamics. Herein, we propose a terminal-group modulation strategy for constructing A-D-A'-D-A-type NIR PSs with an enhanced ISC efficiency. Three π-conjugated oligomers (O1-O3) were synthesized by integrating identical D-A'-D cores with distinct terminal acceptor units. The resulting nanoparticles (ONPs 1 - ONPs 3) exhibited comparable morphology, particle size, optical absorption, and emission profiles. Notably, ONPs 1 demonstrated substantially superior reactive oxygen species (ROS) generation compared with those of ONPs 2 and ONPs 3. Theoretical calculations revealed that the benzene terminal group in ONPs 1 significantly enhanced ISC efficiency (up to 28%), attributed to a reduced singlet-triplet energy gap (Δ<i>E</i>_ST), diminished oscillator strength (<i>f</i>), and an increased spin-orbit coupling (SOC) constant (λ). These features facilitate efficient conversion of singlet (S₁) excitons to triplet (T₁) states, thereby promoting either energy transfer to molecular oxygen or electron transfer to surrounding acceptors, ultimately boosting ROS production during PDT. Consequently, ONPs 1 achieved the highest ROS generation capability (6.8-fold higher than indocyanine green, ICG) and a markedly enhanced singlet oxygen (¹O₂) yield (2.2% vs 0.2% for ICG). In addition to ¹O₂, ONPs 1 was also confirmed to generate hydroxyl radicals (•OH). Collectively, these advantages enable ONPs 1 to achieve potent type-I and type-II synergistic PDT efficacy in both <i>in vitro</i> and <i>in vivo</i> models. This work provides a rational design guideline for developing high-performance organic NIR photosensitizers with enhanced ISC efficiency for advanced photodynamic cancer therapy.