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We previously established that miR\u201029b induces fetal haemoglobin (HbF) in Townes sickle cell anaemia (SCA) mice using a continuous infusion mini\u2010osmotic pump. Herein, we expanded the scope of our work to determine the ability of intermittent subcutaneous cholesterol\u2010conjugated miR\u201029b (Chol\u2010miR\u201029b) to induce HbF expression in SCA mice. Blood was collected for automated complete blood counts with differential, reticulocyte count and <jats:italic>\u03b3\u2010globin<\/jats:italic> and <jats:italic>\u03b2<jats:sup>S<\/jats:sup>\u2010globin<\/jats:italic> mRNA levels quantified by reverse transcription\u2010quantitative PCR; flow cytometry measured the percentage of HbF\u2010positive cells (F\u2010cells). Methylation assays determined 5\u2010methylcytosine levels, and RNA sequencing changes in gene expression for different treatment conditions. SCA mice receiving Chol\u2010miR\u201029b exhibited normal behaviour and weight gain without peripheral blood count toxicity. The <jats:italic>\u03b3\u2010globin<\/jats:italic> mRNA levels significantly increased, and F\u2010cell percentages were enhanced after Chol\u2010miR\u201029b treatment. Subsequently, spleen tissue confirmed decreased DNMT3A protein and 5\u2010methylcytosine levels in the <jats:italic>\u03b3\u2010globin<\/jats:italic> gene promoter. RNA\u2010seq analysis supports oncogene silencing and tumour suppressor gene activation by Chol\u2010miR\u201029b. These data demonstrate that a daily subcutaneous dose of Chol\u2010miR\u201029b induces HbF expression, highlighting its potential for clinical development in SCA.<\/jats:p>","DOI":"10.1111\/bjh.20107","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:08:09Z","timestamp":1746403689000},"page":"1786-1795","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cholesterol\u2010conjugated miR\u201029b induces fetal haemoglobin expression via <i>\u03b3\u2010globin<\/i> promoter demethylation in the Townes mouse model for sickle cell anaemia"],"prefix":"10.1111","volume":"206","author":[{"given":"Chithra D.","family":"Palani","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pediatrics Augusta University  Augusta Georgia 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