School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou, 450001, China.
Adv Mater. 2022 Sep;34(37):e2204585. doi: 10.1002/adma.202204585. Epub 2022 Aug 10.
Virus-based immunotherapy is a promising approach to treat tumor. Closely mimicking the structure and sequential infection processes of natural viruses is highly desirable for effective tumor immunotherapy but remains challenging. Here, inspired by the robust innate immunity induced by herpesvirus, a herpesvirus-mimicking nanoparticle (named Vir-ZM@TD) is engineered for tumor therapy by mimicking the structure and infection processes of herpesvirus. In this biomimetic system, DNAzyme-loaded manganese-doped zeolitic imidazolate framework-90 (ZIF-90) nanoparticles (ZM@TD) mimic the virus nucleocapsid containing the genome; the erythrocyte membrane mimics the viral envelope; and two functional peptides, RGD and HA2 peptides, resemble the surface glycoprotein spikes of herpesvirus. Vir-ZM@TD can both effectively evade rapid clearance in the blood circulation and closely mimic the serial infection processes of herpesvirus, including specific tumor targeting, membrane fusion-mediated endosomal escape, and TFAM (transcription factor A, mitochondrial) deficiency-triggered mitochondrial DNA stress, as well as the release of manganese ions (Mn ) from organelles into the cytosol, ultimately effectively priming cGAS-STING pathway-mediated innate immunity with 68% complete regression of primary tumors and extending by 32 days the median survival time of 4T1-tumor-bearing mice.
基于病毒的免疫疗法是治疗肿瘤的一种很有前途的方法。为了实现有效的肿瘤免疫治疗，非常需要紧密模拟天然病毒的结构和连续感染过程，但这仍然具有挑战性。在这里，受疱疹病毒诱导的强大先天免疫的启发，通过模拟疱疹病毒的结构和感染过程，设计了一种疱疹病毒模拟纳米颗粒（命名为 Vir-ZM@TD）用于肿瘤治疗。在这个仿生系统中，负载 DNAzyme 的锰掺杂沸石咪唑骨架-90（ZIF-90）纳米颗粒（ZM@TD）模拟包含基因组的病毒核衣壳；红细胞膜模拟病毒包膜；两个功能肽，RGD 和 HA2 肽，类似于疱疹病毒表面糖蛋白刺突。Vir-ZM@TD 既能有效地在血液循环中逃避快速清除，又能紧密模拟疱疹病毒的连续感染过程，包括特异性肿瘤靶向、膜融合介导的内体逃逸以及 TFAM（线粒体转录因子 A）缺陷触发的线粒体 DNA 应激，以及从细胞器向细胞质释放锰离子（Mn ），最终有效地引发 cGAS-STING 通路介导的先天免疫，使原发肿瘤完全消退率达到 68%，并将 4T1 荷瘤小鼠的中位生存时间延长 32 天。
