Li Xiaoyu, Hu Huanhuan, Wang Hailong, Liu Jia, Jiang Wenting, Zhou Feng, Zhang Jiantao
Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China.
Ningbo Cixi Institute of Biomedical Engineering, Ningbo, China.
Mater Horiz. 2025 Mar 4;12(5):1388-1412. doi: 10.1039/d4mh01158a.
Targeted therapy has emerged as a transformative breakthrough in modern medicine. Oligonucleotide drugs, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have made significant advancements in targeted therapy. Other oligonucleotide-based therapeutics like clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems are also leading a revolution in targeted gene therapy. However, hybridisation-dependent off-target effects, arising from imperfect base pairing, remain a significant and growing concern for the clinical translation of oligonucleotide-based therapeutics. These mismatches in base pairing can lead to unintended steric blocking or cleavage events in non-pathological genes, affecting the efficacy and safety of the oligonucleotide drugs. In this review, we examine recent developments in oligonucleotide-based targeted therapeutics, explore the factors influencing sequence-dependent targeting specificity, and discuss the current approaches employed to reduce the off-target side effects. The existing strategies, such as chemical modifications and oligonucleotide length optimisation, often require a trade-off between specificity and binding affinity. To further address the challenge of hybridisation-dependent off-target effects, we discuss DNA nanotechnology-based strategies that leverage the collaborative effects of nucleic acid assembly in the design of oligonucleotide-based therapies. In DNA nanotechnology, collaborative effects refer to the cooperative interactions between individual strands or nanostructures, where multiple bindings result in more stable and specific hybridisation behaviour. By requiring multiple complementary interactions to occur simultaneously, the likelihood of unintended partially complementary binding events in nucleic acid hybridisation should be reduced. And thus, with the aid of collaborative effects, DNA nanotechnology has great promise in achieving both high binding affinity and high specificity to minimise the hybridisation-dependent off-target effects of oligonucleotide-based therapeutics.
靶向治疗已成为现代医学中一项变革性的突破。寡核苷酸药物，如反义寡核苷酸（ASO）和小干扰RNA（siRNA），在靶向治疗方面取得了重大进展。其他基于寡核苷酸的疗法，如成簇规律间隔短回文重复序列（CRISPR）/CRISPR相关蛋白（Cas）系统，也正在引领靶向基因治疗的革命。然而，由于碱基配对不完全而产生的依赖杂交的脱靶效应，仍然是基于寡核苷酸疗法临床转化中一个重大且日益受到关注的问题。这些碱基配对中的错配可导致非病理基因中意外的空间位阻或切割事件，影响寡核苷酸药物的疗效和安全性。在本综述中，我们研究了基于寡核苷酸的靶向治疗的最新进展，探讨了影响序列依赖性靶向特异性的因素，并讨论了目前用于减少脱靶副作用的方法。现有的策略，如化学修饰和寡核苷酸长度优化，往往需要在特异性和结合亲和力之间进行权衡。为了进一步应对依赖杂交的脱靶效应这一挑战，我们讨论了基于DNA纳米技术的策略，这些策略在基于寡核苷酸的疗法设计中利用了核酸组装的协同效应。在DNA纳米技术中，协同效应是指单链或纳米结构之间的协同相互作用，其中多个结合会导致更稳定和特异的杂交行为。通过要求多个互补相互作用同时发生，核酸杂交中意外的部分互补结合事件的可能性应该会降低。因此，借助协同效应，DNA纳米技术在实现高结合亲和力和高特异性以最小化基于寡核苷酸疗法的依赖杂交的脱靶效应方面具有巨大潜力。
