Photodynamic therapy (PDT) using oxygen-dependent type II photosensitizers is frequently limited by the hypoxic microenvironment of solid tumors. Type I photosensitizers show oxygen-independent reactive oxygen species (ROS) generation upon light irradiation but still face the challenges of aggregation-caused quenching (ACQ) and low efficiency to produce ROS. Herein, we first prepare an efficient type I photosensitizer from a perylene derivative via intramolecular donor–acceptor binding and sulfur substitution, which significantly enhance intersystem crossing between singlet and triplet states and electron transfer capability. After reaction with a type II photosensitizer, the covalent organic framework (COF) nanophotosensitizer is formed with alternated type I and II photosensitizer motifs in the same layer and staggered AB stacking between layers to avoid ACQ. The nanophotosensitizer exhibits high-efficiency generation of singlet oxygen (¹O₂) and superoxide anion radicals (O₂^•–) via type I and II mechanism under normoxia upon exposure to light irradiation. Under hypoxia, massive O₂^•– can be produced continuously. The potent ROS generation capability results in efficient cellular apoptosis and immunogenic cell death (ICD) efficiently. After combination with immune checkpoint inhibitors, tumor immunosuppressive microenvironment is reversed, which effectively ablates bulky hypoxic primary tumors and suppresses metastases via photodynamic immunotherapy. The COF nanophotosensitizers with staggered type I and II photosensitizer motifs represent a promising strategy to boost photodynamic immunotherapy of hypoxic tumors.

中文翻译：

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具有交错 I/II 型基序的强效共价有机框架纳米光敏剂，用于缺氧肿瘤的光动力免疫治疗


使用氧依赖性 II 型光敏剂的光动力疗法 （PDT） 经常受到实体瘤缺氧微环境的限制。I 型光敏剂在光照射下产生不依赖氧的活性氧 （ROS），但仍面临聚集引起的淬灭 （ACQ） 和低效率生产 ROS 的挑战。在此，我们首先通过分子内供体-受体结合和硫取代从苝衍生物制备了一种高效的 I 型光敏剂，这显着增强了单重态和三重态之间的系统间交叉和电子转移能力。与 II 型光敏剂反应后，共价有机框架 （COF） 纳米光敏剂与同一层中交替的 I 型和 II 型光敏剂基序形成，层与层之间交错 AB 堆叠以避免 ACQ。纳米光敏剂在常氧下通过常氧机制在光照射下表现出高效产生单线态氧 （¹O₂） 和超氧阴离子自由基 （O₂^•–）。在缺氧下，可以连续产生大量的 O₂^•–。有效的 ROS 生成能力可有效实现细胞凋亡和免疫原性细胞死亡 （ICD）。与免疫检查点抑制剂联合使用后，肿瘤免疫抑制微环境逆转，通过光动力免疫治疗有效消融大块缺氧原发性肿瘤并抑制转移。具有交错的 I 型和 II 型光敏剂基序的 COF 纳米光敏剂代表了一种很有前途的策略，可以促进缺氧肿瘤的光动力免疫治疗。