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As antimicrobial resistance continues to rise, the clinical management of DFI persists as a major challenge, emphasizing the need for novel therapeutic approaches. In this study, we aimed to combine the dual antimicrobial and pro-healing properties of antimicrobial peptides (AMPs) with the intrinsic characteristics of the alginate polymer as an encouraging strategy to address the multifactorial etiology of chronic wounds. Using ionic cross-linking with calcium sulfate, we developed alginate-based hydrogels with a nanometric porous structure for the sustained delivery of the AMP human \u03b2-defensin-2 (hBD-2) to promote wound healing in conditions of diabetes. The effects of the produced hBD-2 hydrogels were assessed in a streptozotocin-induced diabetic mouse model with wounds infected by methicillin-resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (MRSA). Overall, hBD-2 hydrogels improved wound closure, by promoting re-epithelialization and tissue remodeling, ultimately restoring normal epidermal thickness. Moreover, hBD-2 hydrogels attenuated the wound MRSA load, while decreasing the inflammatory state. Lastly, hBD-2 hydrogels increased the number of Ki67\n                    <jats:sup>+<\/jats:sup>\n                    cells and CD31\n                    <jats:sup>+<\/jats:sup>\n                    cells, indicating improved cellular proliferation and angiogenesis, ultimately supporting the evidence of an early progression toward the final phases of wound healing. Despite the difficult MRSA-infected wound conditions, the findings underline the potential of hBD-2 hydrogels as a promising treatment for chronic wounds such as DFUs, owing to antimicrobial, anti-inflammatory, and tissue-regenerative properties.\n                  <\/jats:p>","DOI":"10.1007\/s10238-025-01798-6","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T14:48:40Z","timestamp":1752590920000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Alginate-based hydrogels loaded with human \u03b2-defensin-2 promote healing of MRSA-infected wounds in a diabetic model: a preclinical proof-of-concept study"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9305-4865","authenticated-orcid":false,"given":"Jessica","family":"Da Silva","sequence":"first","affiliation":[]},{"given":"Daniela","family":"Calheiros","sequence":"additional","affiliation":[]},{"given":"Teresa","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Eduardo A.","family":"Silva","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6264-3632","authenticated-orcid":false,"given":"Eug\u00e9nia","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-9861","authenticated-orcid":false,"given":"Ermelindo C.","family":"Leal","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"1798_CR1","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.chom.2019.03.006","volume":"25","author":"LR Kalan","year":"2019","unstructured":"Kalan LR, Meisel JS, Loesche MA, Horwinski J, Soaita I, Chen X, et al. 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