{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:13:42Z","timestamp":1786115622437,"version":"build-2736575974"},"reference-count":138,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology"},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2025-02214129"],"award-info":[{"award-number":["RS-2025-02214129"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2022-NR075454"],"award-info":[{"award-number":["RS-2022-NR075454"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2025-02214129"],"award-info":[{"award-number":["RS-2025-02214129"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2022-NR075454"],"award-info":[{"award-number":["RS-2022-NR075454"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Diabetic foot ulcers (DFUs) affect 19\u201334% of diabetic patients with a five-year mortality rate of 50\u201370%. It is characterized by a high infection risk, chronic inflammation, oxidative stress, and poor angiogenesis, rendering existing therapies inadequate, which causes antimicrobial resistance and amputations. Bioactive compounds, such as curcumin, flavonoids, tannins, polyphenols, and proteins, found in natural product extracts (NPEs) have antibacterial, anti-inflammatory, antioxidant, and regenerative properties but are prone to variability and instability. Conventional drugs can be applied for targeted infection management and metabolic modulation, but lack regenerative capacity. The combined and synergistic potential of these two agents has not received much attention, especially when integrated into advanced drug delivery systems (DDSs), such as microneedles, hydrogels, nanofibers, and smart bandages. This review discusses NPEs, conventional drugs, combinations, and integration into DDSs, based on wound characteristics. These include depth, infection status, exudate level, and perfusion, as recommended by the 2023 IWGDF guidelines. Three combinations have shown promise in preclinical studies: propolis-charcoal bandages, propolis-oregano microneedles, and Centella-ZnO nanocomposites. However, none have yet been validated in clinical settings, and barriers to clinical adoption persist\u2014standardization, stability, and regulatory issues. This work aims to pave the way for more accessible, sustainable, and efficacious DFU therapeutics by bridging natural and conventional approaches.<\/jats:p>","DOI":"10.3390\/ijms27156997","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:15:22Z","timestamp":1785834922000},"page":"6997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Healing the Sole: Combining Natural Plant Extracts and Conventional Drugs in Wound Delivery Systems for Diabetic Foot Ulcer Treatment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8039-616X","authenticated-orcid":false,"given":"Raneille Quirsten","family":"Baligod","sequence":"first","affiliation":[{"name":"Department of Biomedical, Manufacturing, and Robotics Engineering, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4463-2221","authenticated-orcid":false,"given":"Izliah Grace Nicole","family":"Fabian","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Manufacturing, and Robotics Engineering, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1240-3812","authenticated-orcid":false,"given":"Kristine Margreth","family":"Repol","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Manufacturing, and Robotics Engineering, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8607-2073","authenticated-orcid":false,"given":"Heidi Lindt","family":"Sy","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Manufacturing, and Robotics Engineering, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jubert","family":"Marquez","sequence":"additional","affiliation":[{"name":"Department of Biology, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"},{"name":"Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University, Busan 47392, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6671-4079","authenticated-orcid":false,"given":"Joseph Rey","family":"Sta. Agueda","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Manufacturing, and Robotics Engineering, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"},{"name":"Center for Engineering and Sustainable Development Research, De La Salle University, 2401 Taft Avenue, Malate, Manila 1004, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2337\/dci22-0043","article-title":"Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers","volume":"46","author":"Mcdermott","year":"2023","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.15605\/jafes.036.02.14","article-title":"Predictors of Outcomes of Foot Ulcers among Individuals with Type 2 Diabetes Mellitus in an Outpatient Foot Clinic","volume":"36","author":"Felipe","year":"2021","journal-title":"J. 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