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This study evaluated the therapeutic potential of nanoformulated Walterinnesia aegyptia (WA) venom using hyaluronic acid-based (WA-HA) and silver-based (WA-Ag) nanoparticles. Nanoparticles were synthesized and characterized by scanning and transmission electron microscopy and energy-dispersive X-ray spectroscopy. The antipromastigote activity of crude WA venom was assessed by MTT assay, and apoptosis induction was analyzed using Annexin V-FITC\/propidium iodide flow cytometry. In vivo efficacy was evaluated in BALB\/c mice infected with Leishmania major, with outcomes assessed by lesion progression, biochemical markers, histopathology, and PCR-based parasite detection. WA venom exhibited potent dose-dependent cytotoxicity (IC50 = 26.73 \u00b5g\/mL) and induced predominantly apoptotic cell death. In vivo, nanoformulated WA significantly enhanced therapeutic outcomes compared with crude venom, with WA-HA achieving near-complete lesion resolution comparable to Amphotericin B. Treatment also reduced parasite burden, normalized liver enzyme levels, and restored hepatic and splenic architecture. These findings demonstrate that nanocarrier-based delivery markedly improves the therapeutic performance and systemic safety of WA venom, highlighting its potential as a promising nanotherapeutic strategy for cutaneous leishmaniasis.<\/jats:p>","DOI":"10.3390\/nano16100614","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:39:34Z","timestamp":1779295174000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nanoformulated Walterinnesia aegyptia Venom Enhances Therapeutic Outcomes in Experimental Cutaneous Leishmaniasis: A Comparative Study of Hyaluronic Acid and Silver Nanoparticles"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0118-2778","authenticated-orcid":false,"given":"Almaha","family":"Al-Aqil","sequence":"first","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4690-1050","authenticated-orcid":false,"given":"Ibrahim S.","family":"Al Nasr","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Qassim University, Buraydah 52571, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0790-0426","authenticated-orcid":false,"given":"Hana","family":"Hakami","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5430-9554","authenticated-orcid":false,"given":"Faten","family":"Abou El Fadl","sequence":"additional","affiliation":[{"name":"Polymer Chemistry Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, Nasr City, P.O. Box 7551, Cairo 11762, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Environmental Science and Engineering, Shaanxi University of Science and Technology, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Al-Shammari","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2150-6928","authenticated-orcid":false,"given":"Samiah","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohaialah","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0646-6488","authenticated-orcid":false,"given":"Afnan","family":"Al-Qurashi","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Al-Rashid","sequence":"additional","affiliation":[{"name":"Chair for Infectious Disease Vaccine Research, Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-9848","authenticated-orcid":false,"given":"Ebtesam","family":"Al-Olayan","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Singh, P., Tripathi, M.K., and Kumar, D. 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