Zhang Xi, Xu De-Zhong, Zhao Wen-Jing, Han Xin-Yue, Lu Zhong-Lin, Liu Rui
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, P.R. China.
Angew Chem Int Ed Engl. 2025 Jun 12:e202505041. doi: 10.1002/anie.202505041.
Gene therapy (GT) and photodynamic therapy (PDT) present promising approaches for cancer treatment. However, GT is frequently impeded by the lysosomal capture of nucleic acids, while PDT is constrained by low oxygen levels in tumors. Herein, we reported the design of a versatile block polyester vector, BFN, which comprises of a photosensitizer BODIPY (B), an oxygen carrying perfluorinated carbon chain (F) as well as a GSH-responsive, and RNA-condensing [12]aneN (N) moiety. In the presence of DOPE (D) and DSPE-PEG-iRGD (R), BFN is able to carry oxygen and condense HIF-1α siRNA efficiently and afford hybrid nanoparticles BFNDR/HIF-1α siRNA@O₂. These combined functionalities work together to reverse tumor hypoxia, remodel the tumor microenvironment, and allow for the efficient lysosomal escape of nucleic acids, thereby significantly boosting the efficacy of PDT and GT in solid tumors. In vitro and in vivo studies demonstrated that the BFN-DR/HIF-1α siRNA@O₂ nanoplatform significantly exhibited substantial inhibitory effects in 4T1 tumors with TGI up to 87%. This research marks the first-in-class integration of such multimodality therapeutic strategies within a single block polymeric vector, thus offering a novel perspective for developing effective oncological treatment paradigms.
基因治疗（GT）和光动力疗法（PDT）是很有前景的癌症治疗方法。然而，基因治疗常常受到核酸被溶酶体捕获的阻碍，而光动力疗法则受限于肿瘤中的低氧水平。在此，我们报道了一种多功能嵌段聚酯载体BFN的设计，它由一种光敏剂BODIPY（B）、一条携氧的全氟碳链（F）以及一个对谷胱甘肽有响应且能凝聚RNA的[12]aneN（N）部分组成。在存在二油酰磷脂酰乙醇胺（DOPE，D）和二硬脂酰磷脂酰乙醇胺-聚乙二醇-iRGD（DSPE-PEG-iRGD，R）的情况下，BFN能够有效地携带氧气并凝聚缺氧诱导因子-1α（HIF-1α）小干扰RNA（siRNA），形成混合纳米颗粒BFNDR/HIF-1α siRNA@O₂。这些组合功能协同作用，可逆转肿瘤缺氧，重塑肿瘤微环境，并使核酸有效地从溶酶体逃逸，从而显著提高光动力疗法和基因治疗在实体瘤中的疗效。体外和体内研究表明，BFN-DR/HIF-1α siRNA@O₂纳米平台在4T1肿瘤中显著表现出强大的抑制作用，肿瘤生长抑制率高达87%。这项研究标志着在单个嵌段聚合物载体中首次实现了此类多模态治疗策略的整合，从而为开发有效的肿瘤治疗模式提供了新的视角。
