Singh Dilpreet, Singh Satvir, Tandon Nitin
School of Pharmaceutical Sciences, CT University, Punjab, India.
School of Applied Sciences, CT University, Punjab, India.
Nucleosides Nucleotides Nucleic Acids. 2025 Jun 26:1-19. doi: 10.1080/15257770.2025.2524468.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors, making it unresponsive to targeted hormonal and HER2-based therapies. Current treatment options, including chemotherapy and radiation, have limited efficacy and are associated with severe side effects, emphasizing the need for innovative therapeutic strategies. Aptamer-siRNA conjugates have emerged as a promising gene-silencing approach, leveraging the high specificity of nucleic acid aptamers to selectively deliver short interfering RNA (siRNA) to TNBC cells. Aptamers, single-stranded DNA or RNA molecules generated SELEX, exhibit nanomolar-range binding affinities (Kd ∼0.5-2.5 nM) for TNBC biomarkers such as EGFR, EpCAM, nucleolin, and MUC1, enabling receptor-mediated internalization of siRNA. Preclinical studies have demonstrated that aptamer-siRNA conjugates enhance cellular uptake by 5-10-fold, improve gene silencing efficiency (80-95%), and extend siRNA stability in circulation (from <2 h to 6-9 h). In xenograft models, aptamer-siRNA therapies have shown tumor volume reductions of 60-85%, outperforming non-targeted siRNA and chemotherapy. However, challenges such as nuclease degradation, immune responses, endosomal escape, and large-scale production remain significant hurdles to clinical translation. Recent advances in chemical modifications, lipid-based carriers, and artificial intelligence-driven aptamer design are addressing these limitations, paving the way for personalized, precision RNAi-based therapeutics. This review explores the mechanisms, recent advancements, challenges, and future directions of aptamer-siRNA therapeutics, providing a comprehensive analysis of their potential to revolutionize TNBC treatment by offering targeted, effective, and less toxic gene-silencing approaches.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，其特征是缺乏雌激素、孕激素和HER2受体，这使得它对靶向激素治疗和基于HER2的治疗无反应。目前的治疗选择，包括化疗和放疗，疗效有限且伴有严重副作用，这凸显了创新治疗策略的必要性。适体 - siRNA偶联物已成为一种有前景的基因沉默方法，利用核酸适体的高特异性将小干扰RNA（siRNA）选择性地递送至TNBC细胞。适体是通过指数富集的配体系统进化技术（SELEX）产生的单链DNA或RNA分子，对TNBC生物标志物如表皮生长因子受体（EGFR）、上皮细胞黏附分子（EpCAM）、核仁素和粘蛋白1（MUC1）表现出纳摩尔范围的结合亲和力（解离常数Kd约为0.5 - 2.5 nM），从而实现受体介导的siRNA内化。临床前研究表明，适体 - siRNA偶联物可将细胞摄取提高5至10倍，提高基因沉默效率（80 - 95%），并延长siRNA在循环中的稳定性（从<2小时延长至6 - 9小时）。在异种移植模型中，适体 - siRNA疗法已显示肿瘤体积缩小60 - 85%，优于非靶向siRNA和化疗。然而，核酸酶降解、免疫反应、内体逃逸和大规模生产等挑战仍然是临床转化的重大障碍。化学修饰、脂质载体和人工智能驱动的适体设计方面的最新进展正在解决这些局限性，为基于个性化、精准RNA干扰的治疗铺平道路。本综述探讨了适体 - siRNA治疗的机制、最新进展、挑战和未来方向，全面分析了它们通过提供靶向、有效且毒性较小的基因沉默方法来彻底改变TNBC治疗的潜力。
