{"title":"Aptamer-directed siRNA delivery systems for triple-negative breast cancer therapy.","authors":"Dilpreet Singh, Satvir Singh, Nitin Tandon","doi":"10.1080/15257770.2025.2524468","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>via</i> 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.</p>","PeriodicalId":19343,"journal":{"name":"Nucleosides, Nucleotides & Nucleic Acids","volume":" ","pages":"1-19"},"PeriodicalIF":1.1000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nucleosides, Nucleotides & Nucleic Acids","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/15257770.2025.2524468","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 via 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.
期刊介绍:
Nucleosides, Nucleotides & Nucleic Acids publishes research articles, short notices, and concise, critical reviews of related topics that focus on the chemistry and biology of nucleosides, nucleotides, and nucleic acids.
Complete with experimental details, this all-inclusive journal emphasizes the synthesis, biological activities, new and improved synthetic methods, and significant observations related to new compounds.