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Holo\u2010Tf serves as the body's pool of ferric iron, facilitating transport from tissues such as the intestine, liver, spleen, and finally bone marrow, where iron is incorporated into erythropoiesis. In sickle cell disease (SCD), iron overload is primarily caused by chronic blood transfusions in patients at risk of stroke or frequent acute pain crisis. However, we have identified that pulmonary vascular iron accumulation, independent of transfusion, is a driver of pulmonary hypertension in SCD patients and murine models. Therefore, we hypothesize that intra\u2010pulmonary administration of apo\u2010Tf localizes the protein to sites of iron accumulation within the lung, where reactive iron\u2010driven pathology develops. This approach to therapeutic development focuses on optimizing administration using aerosol drug delivery, which can increase clinical compliance compared to subcutaneous or intravenous administration. The goal of this study was to purify apo\u2010Tf using a novel process, perform biochemical characterization on the material, and test the proof of concept that apo\u2010Tf protein can be delivered to lung regions where iron accumulation occurs in SCD pulmonary hypertension. We conclude that apo\u2010Tf can be isolated from plasma Cohn fraction IV paste using a simple process and that characterization of the material identified a high\u2010purity apo\u2010Tf product with functional iron binding properties. Further, this material was administered to SCD mice to target pulmonary anatomical regions where pathology occurs. This data suggests an intriguing approach to iron chelation applicable to a relevant clinical population.<\/jats:p>","DOI":"10.1002\/bit.70012","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T01:36:27Z","timestamp":1751333787000},"page":"2709-2723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transferrin Purification, Biophysical Characterization, and Lung Biodistribution in Sickle Cell Disease Mice"],"prefix":"10.1002","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-7820","authenticated-orcid":false,"given":"Shuwei","family":"Lu","sequence":"first","affiliation":[{"name":"William G. 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