The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Department of Emergency Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210002, China.
ACS Nano. 2024 Nov 12;18(45):31421-31434. doi: 10.1021/acsnano.4c11334. Epub 2024 Nov 4.
Hypoxia is one of the most typical features among various types of solid tumors, which creates an immunosuppressive tumor microenvironment (TME) and limits the efficacy of cancer treatment. Alleviating hypoxia becomes a key strategy to reshape hypoxic TME which improves cancer immunotherapy. However, it remains challenging to perform tumor precision therapy with controllable switches through hypoxia-activated gene editing and prodrugs to alleviate hypoxia. In this study, silica-coated second near-infrared window (NIR-II) emitting silver sulfide quantum dots are used as the carrier to load the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible factor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce the off-target effects in nontumor cells and better control safety risks, a TME-triggered cascade-activation nanodiagnostic and therapeutic platform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation of prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9 ribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic function of HIF-1α depletion by gene editing and TPZ activation. Importantly, targeting HIF-1α disrupts the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which effectively reshapes the immune-suppressive TME and activates T cell-mediated antitumor immunity. Taken together, we have provided a TME-triggered cascade-activation nanoplatform to alleviate hypoxia for improved cancer immunotherapy.
缺氧是各种实体瘤中最典型的特征之一，它会导致免疫抑制性肿瘤微环境（TME），并限制癌症治疗的效果。缓解缺氧成为重塑缺氧 TME 的关键策略，从而改善癌症免疫治疗。然而，通过缺氧激活基因编辑和前药来缓解缺氧，利用可控开关对肿瘤进行精确治疗仍然具有挑战性。在这项研究中，使用涂有二氧化硅的第二个近红外窗口（NIR-II）发射的硫化银量子点作为载体，负载 Clustered Regularly Interspaced Short Palindromic Repeats/Cas9（CRISPR/Cas9）系统，以靶向缺氧诱导因子-1（HIF-1α）并引导肿瘤靶向成像。为了减少非肿瘤细胞中的脱靶效应，并更好地控制安全风险，设计了一种 TME 触发级联激活纳米诊断和治疗平台（AA@Cas-H@HTS），该平台实现了前药替拉扎胺（TPZ）的缺氧激活和 CRISPR/Cas9 核糖核蛋白的时空释放。通过基因编辑和 TPZ 激活的协同作用，大大缓解了肿瘤缺氧。重要的是，靶向 HIF-1α 破坏了程序性细胞死亡 1/程序性细胞死亡配体 1（PD-1/PD-L1）信号通路，有效重塑了免疫抑制性 TME 并激活了 T 细胞介导的抗肿瘤免疫。总之，我们提供了一种 TME 触发级联激活纳米平台，用于缓解缺氧以改善癌症免疫治疗。
