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In contrast, cutaneous leishmaniasis (CL) caused by <jats:italic>Leishmania (Viannia) braziliensis<\/jats:italic> is marked by an inflammatory response that, when uncontrolled, contributes to disease pathology. In this study, we evaluated the therapeutic potential of topical rSm29 in combination with meglumine antimoniate (Sb<jats:sup>v<\/jats:sup>) in experimental murine CL. First, rSm29 was functionalized onto spherical gold nanoparticles using a cysteamine linker (AuNPs-Cys-<jats:italic>Sm<\/jats:italic>29). Topical application of this formulation of rSm29 significantly decreased ear lesion thickness, and the combination of topical AuNPs-Cys-<jats:italic>Sm<\/jats:italic>29 plus intraperitoneal Sb<jats:sup>v<\/jats:sup> also significantly reduced ear lesion thickness, parasite load in the infection site, and the local inflammatory infiltrate when compared to mice treated with Sb<jats:sup>v<\/jats:sup> only. The production of IFN-\u03b3, TNF, and IL-10 was reduced in the draining lymph node, as well as the total number of CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>IFN<jats:sup>+<\/jats:sup> and CD3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>TNF<jats:sup>+<\/jats:sup> T cells in the infection site. This study demonstrated that combination therapy with topical AuNPs-Cys-<jats:italic>Sm<\/jats:italic>29\u2009+\u2009systemic Sb<jats:sup>v<\/jats:sup> reduced inflammation without compromising parasite clearance. These findings highlight the potential of AuNPs-Cys-<jats:italic>Sm<\/jats:italic>29 as a host-directed strategy in treating cutaneous leishmaniasis (CL).<\/jats:p>","DOI":"10.1371\/journal.pntd.0013510","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T17:31:57Z","timestamp":1758562317000},"page":"e0013510","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical AuNPs-Cys-Sm29 gel modulates the course of lesion development in experimental cutaneous leishmaniasis"],"prefix":"10.1371","volume":"19","author":[{"given":"Sayonara de M.","family":"Viana","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciana","family":"Cardoso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro 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