Jinliang Xu , Xiaoxiao Liu , Junqiang Ding , Hanchang Zhang , Tingting Yao , Sha Li , Rong Yang , Nianhui Yu , Qi Yue , Changyou Zhan , Xihui Gao
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引用次数: 0
摘要
肿瘤溶解性腺病毒(OA)具有选择性溶解肿瘤细胞和激活免疫反应的独特能力,是治疗胶质母细胞瘤(GBM)的有前途的疗法。然而,OA受体的低表达导致的细胞内化受限以及抗病毒反应导致的OA增殖受限往往阻碍了它们的治疗潜力。在这项工作中,通过用装载 siRNA 的超支化聚合物对病毒表面进行功能化,开发出了一种新型 OA,命名为纳米增效剂工程 OA(nsOA)。纳米增效剂不仅增强了OA的感染性,还促进了病毒复制,最终提高了其溶瘤功效。我们发现,病毒复制的增强是由信号转导和激活转录-3的下调启动的,信号转导和激活转录-3抑制了干扰素刺激基因的转录,最终规避了肿瘤细胞的抗病毒防御。此外,研究还发现 OA 破坏内体膜的先天能力可改善纳米增效剂的内体逃逸,从而产生协同效应,扩大治疗效果。单剂量的 nsOA 能显著增加后代病毒的产生,延长小鼠的存活时间。总之,这些结果为设计 OA 提供了一种有效而有价值的策略,可能为各种癌症带来创新的免疫疗法。
Nanosynergist-engineered oncolytic adenovirus enhancing immune-virotherapy efficacy for glioblastoma via interrupting antiviral responses
Oncolytic adenoviruses (OA) are promising therapeutics for glioblastoma (GBM) due to their unique capability of selectively lysing tumor cells and activating the immune response. However, their therapeutic potential is often impeded by limited cellular internalization caused by low expression of OA receptors, as well as restricted OA proliferation due to antiviral responses. In this work, a novel type of OA, named nanosynergist-engineered OA (nsOA), was developed by functionalizing the viral surface with siRNA-loaded hyperbranched polymers. The nanosynergist not only enhanced the infectivity of OA but also augmented virus replication, ultimately potentiating their oncolysis efficacy. We revealed that the enhanced replication of the virus was initiated by the downregulation of signal transducer and activator of transcription-3, which suppressed the transcription of interferon-stimulated genes, ultimately circumventing the antiviral defense of tumor cells. Furthermore, the innate ability of OA to disrupt endosomal membranes was found to improve the endosomal escape of the nanosynergist, creating synergistic effect that amplified the therapeutic benefits. A single dose of nsOA markedly increased the production of progeny viruses and prolonged the survival of mice. Collectively, these results provide an effective and valuable strategy to engineer OA, which may lead to innovative immunotherapies for various cancers.
期刊介绍:
Nano Today is a journal dedicated to publishing influential and innovative work in the field of nanoscience and technology. It covers a wide range of subject areas including biomaterials, materials chemistry, materials science, chemistry, bioengineering, biochemistry, genetics and molecular biology, engineering, and nanotechnology. The journal considers articles that inform readers about the latest research, breakthroughs, and topical issues in these fields. It provides comprehensive coverage through a mixture of peer-reviewed articles, research news, and information on key developments. Nano Today is abstracted and indexed in Science Citation Index, Ei Compendex, Embase, Scopus, and INSPEC.