Qin Zhen-Xin, Zuo Ling, Zeng Ziran, Ma Rongguan, Xie Wenyan, Zhu Xiao, Zhou Xiaorong
Department of Immunology, School of Medicine, Nantong University, Nantong, China.
The Second Affiliated Hospital, Guangdong Medical University, Zhanjiang, China.
Expert Opin Drug Deliv. 2025 Apr;22(4):455-469. doi: 10.1080/17425247.2025.2466767. Epub 2025 Feb 18.
Nucleic acid-based therapeutics have become a key pillar of the 'third wave' of modern medicine, following the eras of small molecule inhibitors and antibody drugs. Their rapid progress is heavily dependent on delivery technologies, with the development of N-acetylgalactosamine (GalNAc) conjugates marking a breakthrough in targeting liver diseases. This technology has gained significant attention for its role in addressing chronic conditions like chronic hepatitis B (CHB) and nonalcoholic steatohepatitis (NASH), which are challenging to treat with conventional methods.
This review explores the origins, mechanisms, and advantages of GalNAc-siRNA delivery systems, highlighting their ability to target hepatocytes via the asialoglycoprotein receptor (ASGPR). The literature reviewed covers preclinical and clinical advancements, particularly in CHB and NASH. Key developments in stabilization chemistry and conjugation technologies are examined, emphasizing their impact on enhancing therapeutic efficacy and patient compliance.
GalNAc-siRNA technology represents a transformative advancement in RNA interference (RNAi) therapies, addressing unmet needs in liver-targeted diseases. While significant progress has been made, challenges remain, including restricted targeting scope and scalability concerns. Continued innovation is expected to expand applications, improve delivery efficiency, and overcome limitations, establishing GalNAc-siRNA as a cornerstone for future nucleic acid-based treatments.
继小分子抑制剂和抗体药物时代之后，基于核酸的疗法已成为现代医学“第三次浪潮”的关键支柱。它们的快速发展在很大程度上依赖于递送技术，N-乙酰半乳糖胺（GalNAc）偶联物的开发标志着在治疗肝脏疾病方面取得了突破。这项技术因其在治疗慢性乙型肝炎（CHB）和非酒精性脂肪性肝炎（NASH）等慢性病中的作用而备受关注，这些疾病用传统方法治疗具有挑战性。
本综述探讨了GalNAc-siRNA递送系统的起源、机制和优势，强调了它们通过去唾液酸糖蛋白受体（ASGPR）靶向肝细胞的能力。所综述的文献涵盖了临床前和临床进展，特别是在CHB和NASH方面。研究了稳定化化学和偶联技术的关键进展，强调了它们对提高治疗效果和患者依从性的影响。
GalNAc-siRNA技术代表了RNA干扰（RNAi）疗法的变革性进展，满足了肝脏靶向疾病中未满足的需求。虽然已经取得了重大进展，但挑战依然存在，包括靶向范围受限和可扩展性问题。预计持续的创新将扩大应用范围，提高递送效率并克服局限性，使GalNAc-siRNA成为未来基于核酸治疗的基石。
