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In response, drug delivery systems incorporated into biomaterial scaffolds have emerged as a promising strategy to enhance therapeutic efficacy and promote bone regeneration. This review provides a comprehensive overview of biodegradable natural polymer\u2010based scaffolds, focusing on their structural characteristics and drug delivery capabilities in bone tissue engineering. Four principal scaffold architectures\u2014sponges, nanofibers, hydrogels, and microspheres\u2014are examined with respect to their regenerative functionality, associated limitations, and recent engineering advancements. In particular, we discuss the use of four representative natural polymers\u2014collagen, cellulose, chitosan, and hyaluronic acid\u2014and their physicochemical properties that contribute to osteogenesis. Furthermore, recent strategies for enhancing scaffold performance can be broadly divided into two categories. First, nanostructured approaches that reinforce the intrinsic functionality of natural polymers, such as MXene\u2010polymer nanocomposites, halloysite nanotube\u2010loaded hydrogels, and nanocrystalline cellulose systems, have improved drug delivery efficiency and mechanical resilience. Second, advances in three\u2010dimensional (3D) scaffold fabrication\u2014including electrospinning, freeze\u2010drying, 3D printing, bioplotting, photolithography, and microfluidics\u2014have enabled precise control over scaffold architecture, porosity, and biomolecule positioning. Together, these strategies represent critical developments for designing next\u2010generation bone tissue engineering platforms.<\/jats:p>","DOI":"10.1002\/med.70039","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T06:39:43Z","timestamp":1774507183000},"page":"966-988","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biodegradable Natural Polymer\u2010Based Drug Delivery Systems for Bone Tissue Engineering"],"prefix":"10.1002","volume":"46","author":[{"given":"Hyejin","family":"Jo","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinwon","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Eun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inseon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9654-8577","authenticated-orcid":false,"given":"Seunghun S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2007.10.021"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-813259-3.00001-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252312766"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5152\/eurjrheum.2016.048"},{"key":"e_1_2_9_6_1","unstructured":"J. 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