抗体偶联核酸药物研究进展与挑战

Research Advances and Challenges in Antibody-Conjugated Nucleic Acid Drugs

摘要: 核酸药物凭借其从基因层面干预疾病的独特优势，已成为生物医药领域的研究热点。然而，其在体内递送过程中面临稳定性差、靶向性不足及跨膜效率低等核心瓶颈，限制了广泛应用。抗体偶联核酸药物(AOCs)通过将治疗性寡核苷酸与特异性抗体共价连接，整合了抗体的高靶向性与核酸的基因调控功能，为克服上述挑战提供了创新平台。文章系统综述了核酸药物的发展现状与瓶颈，总结了AOCs的基本概念、设计原则、偶联化学与酶学策略，并重点分析了其基于受体介导内吞的递送机制及内体逃逸这一关键限速环节。同时对AOCs临床应用所面对的挑战作一定的阐述。最后，展望了AOCs在递送效率提升、结构均一性控制、组织特异性靶向及免疫原性优化等方面的未来发展方向，为该领域的深入研究与临床转化提供参考。

Abstract: Nucleic acid drugs have become a research hotspot in the field of biomedicine because of their unique advantages of intervening in diseases at the genetic level. However, its delivery in vivo faces core bottlenecks such as poor stability, insufficient targeting, and low transmembrane efficiency, which limit its wide application. Antibody-linked nucleic acid drugs (AOCs) combine the high targeting of antibodies and the gene regulation function of nucleic acids by covalently linking therapeutic oligonucleotides to specific antibodies, and provide an innovative platform to overcome the above challenges. This article systematically reviews the development status and bottlenecks of nucleic acid drugs, summarizes the basic concept, design principles, coupling chemistry, and enzymatic strategies of AOCs, and focuses on the receptor-mediated endocytosis-based delivery mechanism and endosomal escape, the key rate-limiting link. At the same time, the challenges faced by the clinical application of AOCs are described. Finally, we prospected the future development direction of AOCs in terms of improving delivery efficiency, structural homogeneity control, tissue-specific targeting, and immunogenicity optimization, so as to provide a reference for in-depth research and clinical translation in this field.