Lu Fei, Ouyang Chengren, Yu Jielin, González-García Jorge, Wang Junping, Ou Guanrong, Teng Haixin, Yin Caixia, Zhou Chun-Qiong
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Instituto de Ciencia Molecular, Departamento de Química Inorgánica, Universidad de Valencia, Paterna 46980, Spain.
ACS Appl Mater Interfaces. 2025 May 28;17(21):30637-30652. doi: 10.1021/acsami.5c03956. Epub 2025 May 14.
Most photosensitizers face enormous challenges in tumor hypoxia, the redox microenvironment, and low immune efficacies for reactive oxygen species (ROS). Herein, dye SQ-580 was constructed by coupling the electron-donating indole and thiophenazine-thiophene with the electron-withdrawing dicyanovinyl squaraine. It exhibited a high generation of OH and O by decreasing Δ and acted as an excellent type I photosensitizer for conquering tumor hypoxia. The nanoplatform involving SQ-580, MnO, and a targeting peptide CREKA was constructed and targeted breast tumor. In the tumor microenvironment, MnO reacted with high-expressed GSH and produced Mn, which catalyzed HO to decompose into OH and induced chemodynamic therapy (CDT). The reduction of GSH inhibited the consumption of SQ-580 and maintained its high photodynamic therapy (PDT) efficacy. GSH depletion and ROS resulted in cell ferroptosis. Under the synergy of ferroptosis and ROS, Mn amplified immunogenic cell death (ICD). In the mouse models, SQ-580@MnO NPs showed NIRF/MR imaging-guided tumor targeting, effectively inhibited the growth of the primary and distant tumors, and amplified PDT and immune efficacies in the synergy of PDT, CDT, ferroptosis, and ICD. This study provides an effective strategy to design excellent type I photosensitizers and amplify the PDT and ICD efficacies utilizing valence metals and the tumor microenvironment.
大多数光敏剂在肿瘤缺氧、氧化还原微环境以及活性氧（ROS）的低免疫效力方面面临巨大挑战。在此，通过将供电子吲哚和噻吩嗪 - 噻吩与吸电子二氰基乙烯基方酸耦合构建了染料SQ - 580。它通过降低Δ表现出高的·OH和·O生成，并作为一种优异的I型光敏剂来克服肿瘤缺氧。构建了包含SQ - 580、MnO和靶向肽CREKA的纳米平台并靶向乳腺肿瘤。在肿瘤微环境中，MnO与高表达的谷胱甘肽（GSH）反应生成Mn²⁺，其催化H₂O₂分解为·OH并诱导化学动力疗法（CDT）。GSH的减少抑制了SQ - 580的消耗并维持其高光动力疗法（PDT）疗效。GSH耗竭和ROS导致细胞铁死亡。在铁死亡和ROS的协同作用下，Mn²⁺放大了免疫原性细胞死亡（ICD）。在小鼠模型中，SQ - 580@MnO纳米颗粒显示出近红外荧光/磁共振成像引导的肿瘤靶向性，有效抑制了原发性和远处肿瘤的生长，并在PDT、CDT、铁死亡和ICD的协同作用下放大了PDT和免疫疗效。本研究提供了一种有效的策略来设计优异的I型光敏剂，并利用价态金属和肿瘤微环境放大PDT和ICD疗效。
