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Here, we report the formation of bovine serum albumin (BSA) hydrogels generated through mild thermal aggregation (65 \u00b0C) without chemical cross-linkers, employing low protein concentrations (1\u20131.5%). The influence of the buffering environment (PBS vs Tris-HCl) on hydrogel architecture was identified as a key structural determinant. The resulting hydrogels were systematically characterized in terms of their structure, swelling behavior, water content, biodegradability, and morphology. Microscopic analyses revealed that Tris-HCl promoted the formation of a homogeneous and dense amyloid-like fibrillar network, whereas PBS led to more heterogeneous and irregular architectures. These structural differences affected the capacity to absorb and release model compounds with distinct physicochemical properties, producing sustained and matrix-dependent release profiles. In vitro assays demonstrated progressive degradation under physiological conditions, while in vivo murine models showed minimal immunological response.<\/jats:p>","DOI":"10.1021\/acsomega.5c11084","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:01:32Z","timestamp":1790888492000},"page":"60652-60667","source":"Crossref","is-referenced-by-count":0,"title":["Design and Characterization of Bovine Serum Albumin\nHydrogels: A Promising Platform for Controlled Drug Delivery"],"prefix":"10.1021","volume":"11","author":[{"given":"Eva M. M.","family":"Velez","sequence":"first","affiliation":[{"name":"Instituto de Investigacio\u0301n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucuma\u0301n (UNT), Ministerio de Salud Pu\u0301blica de Tucuma\u0301n - SIPROSA , Pasaje Dorrego 1080 , , ,","place":["San Miguel de Tucuma\u0301n, Tucuma\u0301n, Argentina, 4000"]},{"name":"Centro de Referencia para Lactobacilos (CERELA-CONICET) , Batalla de Chacabuco 145 , , ,","place":["San Miguel de Tucuma\u0301n, Tucuma\u0301n, Argentina, T4000ILC"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301a C.","family":"Maldonado Galdeano","sequence":"additional","affiliation":[{"name":"Centro de Referencia para Lactobacilos (CERELA-CONICET) , Batalla de Chacabuco 145 , , ,","place":["San Miguel de Tucuma\u0301n, Tucuma\u0301n, Argentina, T4000ILC"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosana","family":"Chehi\u0301n","sequence":"additional","affiliation":[{"name":"Instituto de Investigacio\u0301n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucuma\u0301n (UNT), Ministerio de Salud Pu\u0301blica de Tucuma\u0301n - SIPROSA , Pasaje Dorrego 1080 , , ,","place":["San Miguel de Tucuma\u0301n, Tucuma\u0301n, Argentina, 4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2003-9386","authenticated-orcid":true,"given":"Silvina","family":"Chaves","sequence":"additional","affiliation":[{"name":"Instituto de Investigacio\u0301n en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucuma\u0301n (UNT), Ministerio de Salud Pu\u0301blica de Tucuma\u0301n - SIPROSA , Pasaje Dorrego 1080 , , ,","place":["San Miguel de Tucuma\u0301n, Tucuma\u0301n, Argentina, 4000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026101315080627700_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2024.122718","article-title":"Biomedical\napplications of functional\nhydrogels: Innovative developments, relevant clinical trials and advanced\nproducts","volume":"312","author":"Zo\u0308ller","year":"2025","journal-title":"Biomaterials"},{"issue":"15","key":"2026101315080627700_cit2","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1016\/j.addr.2008.08.002","article-title":"Hydrogel nanoparticles\nin drug delivery","volume":"60","author":"Hamidi","year":"2008","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026101315080627700_cit3","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/j.msec.2017.05.096","article-title":"A mini review\non hydrogels classification and recent developments in miscellaneous\napplications","volume":"79","author":"Varaprasad","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"2026101315080627700_cit4","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.tifs.2020.05.025","article-title":"Edible polymers: An insight into\nits application in food, biomedicine and cosmetics","volume":"103","author":"Kouhi","year":"2020","journal-title":"Trends Food Sci. Technol."},{"key":"2026101315080627700_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpx.2025.100387","article-title":"Recent advances in albumin-based\nnanoparticle drug delivery systems for intestinal disease treatment","volume":"10","author":"Lin","year":"2025","journal-title":"Int. J. 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Sci."},{"issue":"9","key":"2026101315080627700_cit32","doi-asserted-by":"publisher","first-page":"3528","DOI":"10.1039\/b919449p","article-title":"Rheological properties\nof peptide-based hydrogels for\nbiomedical and other applications","volume":"39","author":"Yan","year":"2010","journal-title":"Chem. Soc.\nRev."},{"issue":"3","key":"2026101315080627700_cit33","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.171562","article-title":"Mechanical characteristics of beta\nsheet-forming peptide hydrogels are dependent on peptide sequence,\nconcentration and buffer composition","volume":"5","author":"Koch","year":"2018","journal-title":"R. Soc.\nOpen Sci."},{"key":"2026101315080627700_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2021.130912","article-title":"Gel properties of heat-induced transparent hydrogels from ovalbumin\nby acylation modifications","volume":"369","author":"Hu","year":"2022","journal-title":"Food Chem."},{"key":"2026101315080627700_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molliq.2021.115753","article-title":"The influence of sodium phosphate\nbuffer on the stability\nof various proteins: Insights into protein-buffer interactions","volume":"331","author":"Pavani","year":"2021","journal-title":"J. Mol. Liq."},{"issue":"10","key":"2026101315080627700_cit36","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1021\/acs.jpcb.0c10339","article-title":"Effect of Buffer on Protein Stability\nin Aqueous Solutions:\nA Simple Protein Aggregation Model","volume":"125","author":"Brudar","year":"2021","journal-title":"J. Phys.\nChem. 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Food Chem."},{"issue":"13","key":"2026101315080627700_cit44","doi-asserted-by":"publisher","DOI":"10.3390\/polym15132908","article-title":"A Comprehensive\nReview of Polysaccharide-Based Hydrogels as Promising Biomaterials","volume":"15","author":"Berradi","year":"2023","journal-title":"Polymers"},{"issue":"4","key":"2026101315080627700_cit45","doi-asserted-by":"publisher","DOI":"10.3390\/gels10040262","article-title":"Advances in\nHydrogel-Based Drug Delivery Systems","volume":"10","author":"Liu","year":"2024","journal-title":"Gels"},{"issue":"11","key":"2026101315080627700_cit46","doi-asserted-by":"publisher","DOI":"10.3390\/gels11110896","article-title":"Preparation of Hydrogel\nby Crosslinking and Multi-Dimensional\nApplications","volume":"11","author":"Bhuyan","year":"2025","journal-title":"Gels"},{"issue":"5","key":"2026101315080627700_cit47","doi-asserted-by":"publisher","DOI":"10.3390\/polym18050633","article-title":"Glutaraldehyde-Crosslinked Bovine\nSerum Albumin Hydrogels for Efficient Cu2+, Ni2+, and Co2+ Removal\nfrom Water","volume":"18","author":"Lancheros-Ayala","year":"2026","journal-title":"Polymers"},{"issue":"4","key":"2026101315080627700_cit48","doi-asserted-by":"publisher","DOI":"10.3390\/gels11040293","article-title":"Advancements and Prospects of pH-Responsive Hydrogels in Biomedicine","volume":"11","author":"Gao","year":"2025","journal-title":"Gels"},{"key":"2026101315080627700_cit49","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/978-1-4939-8793-1_3","article-title":"Measuring\nProtein Concentration with Absorbance, Lowry, Bradford Coomassie Blue,\nor the Smith Bicinchoninic Acid Assay Before Electrophoresis","volume":"1855","author":"Goldring","year":"2019","journal-title":"Methods Mol. 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