Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
J Immunotoxicol. 2021 Dec;18(1):61-73. doi: 10.1080/1547691X.2021.1902432.
There is a large, unmet medical need to treat chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis and other respiratory diseases. New modalities are being developed, including gene therapy which treats the disease at the DNA/RNA level. Despite recent innovations in non-viral gene therapy delivery for chronic respiratory diseases, unwanted or adverse interactions with immune cells, particularly macrophages, can limit drug efficacy. This review will examine the relationship between the design and fabrication of non-viral nucleic acid nanoparticle (NP) delivery systems and their ability to trigger unwanted immunogenic responses in lung tissues. NP formulated with peptides, lipids, synthetic and natural polymers provide a robust means of delivering the genetic cargos to the desired cells. However NP, or their components, may trigger local responses such as cell damage, edema, inflammation, and complement activation. These effects may be acute short-term reactions or chronic long-term effects like fibrosis, increased susceptibility to diseases, autoimmune disorders, and even cancer. This review examines the relationship between physicochemical properties, i.e. shape, charge, hydrophobicity, composition and stiffness, and interactions of NP with pulmonary immune cells. Inhalation is the ideal route of administration for direct delivery but inhaled NP encounter innate immune cells, such as alveolar macrophages (AM) and dendritic cells (DC), that perceive them as harmful foreign material, interfere with gene delivery to target cells, and can induce undesirable side effects. Recommendations for fabrication and formulation of gene therapies to avoid adverse immunological responses are given. These include fine tuning physicochemical properties, functionalization of the surface of NP to actively target diseased pulmonary cells and employing biomimetics to increase immunotolerance.
目前，治疗慢性阻塞性肺疾病、哮喘、特发性肺纤维化和其他呼吸系统疾病存在着巨大的、未满足的医疗需求。新的治疗方法正在开发中，包括在 DNA/RNA 水平治疗疾病的基因疗法。尽管最近在慢性呼吸道疾病的非病毒基因治疗传递方面有了创新，但与免疫细胞（尤其是巨噬细胞）的不想要或不良反应的相互作用可能会限制药物的疗效。这篇综述将探讨非病毒核酸纳米颗粒（NP）传递系统的设计和制造与其在肺部组织中引发不想要的免疫反应能力之间的关系。用肽、脂质、合成和天然聚合物制成的 NP 为将遗传 cargos 递送到所需细胞提供了一种强大的方法。然而，NP 或其成分可能会引发局部反应，如细胞损伤、水肿、炎症和补体激活。这些影响可能是急性短期反应，也可能是慢性长期影响，如纤维化、增加对疾病的易感性、自身免疫紊乱，甚至癌症。这篇综述考察了物理化学性质（如形状、电荷、疏水性、组成和刚度）与 NP 与肺部免疫细胞之间相互作用的关系。吸入是直接给药的理想途径，但吸入的 NP 会遇到先天免疫细胞，如肺泡巨噬细胞（AM）和树突状细胞（DC），它们将其视为有害的外来物质，干扰基因向靶细胞的传递，并可能引起不良的副作用。文中给出了避免不良免疫反应的基因治疗制造和配方建议。这些建议包括微调物理化学性质、NP 表面的功能化以主动靶向患病的肺部细胞以及采用仿生学来增加免疫耐受性。
