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Unlike traditional RNA\u2010based methods that work post transcriptionally, PTRs interact with gene promoter regions to either activate or suppress gene transcription. This strategy offers a key advantage by enabling more stable and long\u2010lasting control of gene expression, since it acts directly at the level of chromatin and epigenetic regulation rather than only degrading RNA or blocking translation. Unlike CRISPR\u2010based methods, promoter\u2010targeted RNAs alongside traditional siRNAs and ASOs provide a reversible and finely tuned way to reprogram the chromatin accessibility and histone modifications without making permanent changes to the genome. This review explores the broadening spectrum of PTRs modalities, including small activating RNAs, small interfering RNAs, promoter\u2010targeted R\u2010loop inducers, peptide nucleic acids, RNA aptamers, and triplex\u2010forming RNAs. Several preclinical studies have demonstrated their ability to reactivate silenced tumor suppressor genes or downregulate oncogenes, offering targeted and reversible gene control. Notably, saRNAs like MTL\u2010CEBPA (Phase II) and RAG\u201001 (Phase I) have reached clinical evaluation for liver and bladder cancer, highlighting their translational potential. However, efficient nuclear delivery, off\u2010target effects, immune activation, and tumor heterogeneity remain the major concerns for clinical applications. Future progress in this field will depend on overcoming technical hurdles such as ensuring efficient nuclear delivery, improving chemical modifications to increase RNA stability, and designing delivery systems that combine tissue\u2010specific targeting with precise transcriptional regulation.<\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Regulatory RNAs\/RNAi\/Riboswitches &gt; Regulatory RNAs<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Regulatory RNAs\/RNAi\/Riboswitches &gt; RNAi: Mechanisms of Action<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Regulatory RNAs\/RNAi\/Riboswitches &gt; Biogenesis of Effector Small RNAs<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1002\/wrna.70043","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:03:04Z","timestamp":1777852984000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Promoter\u2010Targeting\n                    <scp>RNA<\/scp>\n                    Technologies: An Epigenetic Strategy for Gene Activation and Gene Silencing"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2328-2966","authenticated-orcid":false,"given":"Rajat","family":"Hegde","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology, Manipal School of Life Sciences Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam Abdul","family":"Ajees","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Manipal School of Life Sciences Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kedlaya Srikrishna H.","family":"Damodar","sequence":"additional","affiliation":[{"name":"Department of Public Health Genomics, Manipal School of Life Sciences Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esha","family":"Poojary","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Manipal School of Life Sciences Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Manipal College of Health Professions Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4158-3893","authenticated-orcid":false,"given":"Shama Prasada","family":"Kabekkodu","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Manipal School of Life Sciences Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010019\u20100196\u20103"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/polym15040858"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0299522"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14225546"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010021\u201000487\u20106"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2022.106348"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1230"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000000090"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658\u2010025\u201000736\u20104"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.751079"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.14304\/surya.jpr.v4n7.5"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms14046690"},{"key":"e_1_2_13_14_1","doi-asserted-by":"crossref","unstructured":"Coppola G. 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