抗体寡核苷酸偶联物的研究进展——抗体递送siRNA的可行性分析

Research Progress of Antibody-Oligonucleotide Conjugates—Feasibility Analysis of Antibody-Mediated siRNA Delivery

摘要: 抗体–寡核苷酸偶联物(AOC)作为新兴的靶向递送平台，通过将单克隆抗体的特异性靶向能力与治疗性寡核苷酸(如siRNA、ASO)的基因调控功能相结合，旨在系统性解决寡核苷酸药物，尤其是siRNA疗法在肝外组织递送中面临的体内不稳定、细胞摄取效率低及内体逃逸困难等核心瓶颈。本文聚焦于siRNA的有效递送及应用，详细阐述了AOC的三大组成部分：决定组织特异性的靶向抗体、执行基因沉默的有效载荷以及控制时空释放的连接子(Linker)，并剖析了其从靶向结合、内吞、内体逃逸到胞内发挥作用的完整递送路径与机制。目前，该领域已从概念验证快速进入临床开发关键期，全球竞争格局初显，代表的生物技术公司主导了针对罕见神经肌肉疾病的领先管线，其中部分候选药物已推进至临床后期。尽管面临内体逃逸效率低、生产工艺复杂等挑战，但AOC平台展现出的模块化设计优势和精准治疗潜力，为其未来拓展至心血管疾病、肿瘤免疫及中枢神经系统疾病等更广阔的治疗领域奠定了坚实基础，标志着精准基因药物治疗新时代的开启。

Abstract: Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging targeted delivery platform designed to systematically overcome the core challenges associated with oligonucleotide therapeutics, particularly the extrahepatic delivery of siRNA. By integrating the specific targeting capability of monoclonal antibodies with the gene-regulatory function of therapeutic oligonucleotides such as siRNA and ASOs, AOCs address critical bottlenecks including in vivo instability, inefficient cellular uptake, and the difficulty of endosomal escape. This article focuses on the efficient delivery and application of siRNA. It details the three fundamental components of AOCs: the targeting antibody, which confers tissue specificity; the therapeutic payload (e.g., siRNA), which executes gene silencing; and the linker, which controls spatiotemporal release. Furthermore, it dissects the complete delivery pathway and mechanism, encompassing target binding, internalization, endosomal escape, and subsequent intracellular action. The field has rapidly progressed from proof-of-concept to a critical phase of clinical development, with an emerging global competitive landscape. Leading biotechnology companies are driving pipelines focused on rare neuromuscular diseases, some of which have advanced to late-stage clinical trials. Despite persistent challenges such as low endosomal escape efficiency and complex manufacturing processes, the modular design and precise therapeutic potential of the AOC platform lay a solid foundation for its future expansion into broader therapeutic areas. These include cardiovascular diseases, cancer immunotherapy, and central nervous system disorders, heralding the dawn of a new era in precision genetic medicine.