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This mutation drives the formation of hemoglobin S (HbS) polymers under deoxygenated conditions, causing erythrocyte sickling, vaso\u2010occlusive crises, and multi\u2010organ complications. Current therapies, such as hydroxyurea and voxelotor, provide only partial symptomatic relief, underscoring the urgent need for transformative strategies. This review highlights the molecular glue paradigm, a novel approach that repurposes hemoglobin itself as a therapeutic scaffold. By integrating high\u2010resolution structural insights from cryo\u2010electron microscopy and predictive modeling via artificial intelligence, engineered hemoglobin variants can be rationally designed to inhibit polymerization, stabilizing non\u2010pathogenic conformations and preventing fiber formation. These molecular glues, generated through gene editing or synthetic biology, offer a cell\u2010intrinsic, high\u2010concentration mechanism to counteract HbS polymerization, potentially overcoming the limitations of current therapies. We examine the key challenges in translating this paradigm, including precise structural characterization of polymerization intermediates, efficient intracellular delivery to erythrocytes, temporal regulation under hypoxic conditions, and the mitigation of immunogenicity.<\/jats:p>","DOI":"10.1002\/adhm.202504346","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:28:42Z","timestamp":1769750922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hemoglobin as a Molecular Glue: Toward Potent Inhibition of HbS Polymerization in Sickle Cell Disease"],"prefix":"10.1002","volume":"15","author":[{"given":"Mohammad","family":"Edrisi","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Biophysics (IBB) University of Tehran  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6945-8541","authenticated-orcid":false,"given":"Navid","family":"Rabiee","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Saveetha Dental College and Hospitals SIMATS Saveetha University  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.10"},{"issue":"20","key":"e_1_2_9_3_1","first-page":"2719","article-title":"Treating Sickle Cell Disease by Targeting HbS Polymerization. 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