Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, Pennsylvania, USA.
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2023 Mar;15(2):e1856. doi: 10.1002/wnan.1856. Epub 2022 Sep 30.
Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
合成载体用于治疗性核酸递送，由于其免疫原性降低、大载量能力以及在符合 GMP 规范的标准下易于制造，目前正在与病毒载体显著竞争。脂质型 siRNA 治疗药物 Onpattro 的批准，以及 Pfizer-BioNTech 和 Moderna 的两种基于脂质的 COVID-19 疫苗的临床成功，预示着脂质型系统在所有其他合成核酸载体中的特定优势。具有不同载药的脂质型系统 - 质粒 DNA (pDNA)、反义寡核苷酸 (ASO)、小干扰 RNA (siRNA)、微小 RNA (miRNA)、小激活 RNA (saRNA) 和信使 RNA (mRNA) - 现已成为一种成熟的技术，在临床上的影响越来越大。四十多年的研究确定了决定这些多组分系统治疗成功的关键因素。在这里，我们讨论了主要的核酸技术，介绍了它们的作用机制、它们面临的输送障碍、有效载荷的结构特性以及调节物理化学性质、药代动力学和生物分布、效力和毒性的成分脂质。我们进一步详细介绍了制剂参数、产生可重复和可扩展输出的制造技术的演变，以及控制所得粒子物理化学性质的关键制造方面。随后讨论了其中一些制剂的临床前应用，这些制剂已从体外研究成功转化为动物模型。最后，从 1993 年至今，在对脂质型核酸递送系统的全面文献综述中，强调了这些系统的临床成功和失败。本文属于以下类别： 治疗方法和药物发现 > 新兴技术 治疗方法和药物发现 > 用于肿瘤疾病的纳米医学 毒理学和纳米医学中的监管问题 > 纳米材料的毒理学。
