基 于 近 红 外 聚 集 体 激 发 中 间 态 调 控 的 光 学 诊 疗 研 究（特 邀）

Significance Phototheranostics integrates diagnosis and therapy functions within a unified platform, thereby enhancing the precision of medical interventions. Its potential is greatly amplified by the use of near-infrared (NIR) photosensitizers (NIR-Ⅰ: 650 ‒ 950 nm; NIR-Ⅱ: 1000 ‒ 1700 nm), which leverage the biological optical windows characterized by maximal tissue transparency and deep penetration. This enables effective treatment of deeply embedded or bulky tumors. Nonetheless, conventional organic photosensitizers are hindered by aggregation-caused quenching (ACQ), photobleaching, and inadequate photostability. These limitations can be addressed through the formation of NIR aggregates via controlled molecular assembly, which enhances photostability and permits fine-tuning of photophysical properties via aggregation-induced emission or molecular packing modulation. Emerging studies have revealed that intermediate excited states within NIR aggregates act as energy-regulating hubs, determining photon energy dissipation pathways. This review briefly outlines the formation mechanisms, regulatory principles, and functional roles of these intermediate states, establishing structure-property relationships essential for the rational design of high-performance photosensitizers. Progress This review elucidates the formation mechanisms and regulatory strategies governing intermediate excited states in diverse NIR molecular aggregates, emphasizing their pivotal role in modulating phototheranostic performance. The analysis is structured around a systematic classification of aggregate types based on intermolecular interaction modes. We first examine aggregates formed via ground state interactions, specifically H-and J-aggregates, highlighting how distinct molecular stacking geometries give rise to divergent photophysical behaviors. Subsequently, we explore aggregates formed through excited state interactions, such as excimers and exciplexes, underscoring their transient characteristics and unique emission properties. Particular emphasis is placed on how molecular structure and supramolecular packing govern the formation, stability, and evolution of intermediate states. For photothermal therapy (PTT) applications, we demonstrate that rational aggregation design creates efficient non-radiative decay channels. A BODIPY-based dye (BDP) was developed that self-assembles into J-aggregates within nanoparticles, inducing an intermediate state with intermolecular charge-transfer (inter-CT) characteristic that facilitates ultrafast non-radiative decay (lifetime ~1.7 ps), elevating photothermal conversion efficiency (PCE) to 61% (Fig. 10). Furthermore, fluorine-substituted organic polymers were engineered to enhance π-π stacking, stabilizing excimer-type intermediates with exceptionally fast decay channels (~0.075 ps), resulting in a remarkable PCE of 81% (Fig. 11). For fluorescence imaging, we address the major challenge of ACQ through strategic intermediate state manipulation. An alkyl-doping strategy was employed in a perylene diimide derivative (OPE-PDI), where alkyl chains create hydrophobic microenvironments that suppress quenching-prone intermediate states and block intermolecular non-radiative channels. This approach enhanced fluorescence quantum yield by approximately 3-fold and enabled long-term in vivo tumor imaging (Fig. 12). Additionally, a fused-ring fluorophore (4F) exhibiting NIR-Ⅱ quenching due to dimeric intermediate states was optimized by modulating doping concentration, reducing dimer population from 73.5% to 64.3%, resulting in a fivefold increase in fluorescence efficiency and high-resolution vascular imaging in the NIR-Ⅱ region (Fig. 13). For photodynamic therapy (PDT), we developed perylenetetracarboxylic acid (PTA) nanoparticles (NPs) with semiconductor-like characteristics to overcome hypoxia-induced limitations. These aggregates facilitate photoinduced electron transfer, generating holes that oxidize water to produce O₂ in situ, which is subsequently converted into cytotoxic ¹O₂, establishing a self-sustaining oxygen supply effective under hypoxic conditions (Fig. 14). A zwitterionic photosensitizer (C3TH) was engineered to form nanoclusters undergoing photoinduced autoionization, generating radical cations and anions that effectively produce type Ⅰ ROS (·OH and O-₂ ·), exhibiting potent antibacterial activity at ultralow doses (Fig. 15). For phototheranostics, we designed a D-A-A’type aza-BODIPY molecule (SW8) forming aggregates capable of balancing fluorescence and heat generation through intermediate state mediation of both radiative decay for NIR-Ⅱ fluorescence (1230 nm) and ultrafast non-radiative decay (~0.07 ps) for PTT, achieving 75% PCE under 1064 nm laser excitation (Fig. 16). Further optimization through donor/side-chain engineering yielded a planar molecule (BETA), enhancing both NIR-Ⅱa fluorescence and photothermal performance, enabling complete tumor ablation in vivo (Fig. 17). Conclusions and Prospects Growing evidence indicates that intermediate excited states within NIR aggregates play a critical role in directing the flow of photoexcited energy. Through rational molecular design and precise control over aggregation, the formation and decay pathways of these states can be modulated to selectively enhance specific phototheranostic functions. The structural diversity of NIR aggregates—including J-and H-aggregates, excimers, and exciplexes—offers a versatile foundation for advanced excited state engineering. Despite impressive advances, the mechanistic understanding of intermediate state formation and dynamics remains incomplete. Future research integrating ultrafast spectroscopy, quantum chemical calculations, and artificial intelligence (AI) assisted materials discovery will be pivotal in establishing robust structure-property relationships. These efforts will catalyze the development of high-performance photosensitizers and accelerate their translation from fundamental research to clinical applications.