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PfPIMMS43, a surface protein of <jats:italic>P. falciparum<\/jats:italic> ookinetes and sporozoites, is critical for this transition and aids the parasite in evading mosquito immune responses. Previous studies demonstrated that polyclonal PfPIMMS43 antibodies reduced <jats:italic>P. falciparum<\/jats:italic> infection in <jats:italic>Anopheles<\/jats:italic> mosquitoes. Here, building on these findings, we have developed high-affinity single-domain VHH antibodies (nanobodies) derived from llama heavy-chain-only antibodies. We have shown that these nanobodies bind both recombinant and endogenous PfPIMMS43 produced by <jats:italic>P. falciparum<\/jats:italic> ookinetes in the mosquito midgut. Importantly, they significantly reduce infection intensity and prevalence of laboratory and field strains of <jats:italic>P. falciparum<\/jats:italic> in <jats:italic>An. coluzzii<\/jats:italic> and <jats:italic>An. gambiae<\/jats:italic>, respectively. Epitope mapping has revealed that the nanobodies target conserved regions in the second half of PfPIMMS43, with homology modelling confirming epitope accessibility. These findings establish PfPIMMS43 as a promising transmission-blocking target. To enhance malaria control and elimination efforts, we propose an innovative strategy in which genetically modified mosquitoes express PfPIMMS43-specific nanobodies in their midguts and spread this trait in wild mosquito populations via gene drive technology.<\/jats:p>","DOI":"10.1038\/s42003-025-08033-8","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T01:25:10Z","timestamp":1745976310000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes"],"prefix":"10.1038","volume":"8","author":[{"given":"Chiamaka Valerie","family":"Ukegbu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mgeni","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1346-5945","authenticated-orcid":false,"given":"Astrid","family":"Hoermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prisca A.","family":"Kweyamba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dickson Wilson","family":"Lwetoijera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-1165","authenticated-orcid":false,"given":"Nikolai","family":"Windbichler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-6654","authenticated-orcid":false,"given":"Sarah","family":"Moore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3323-1687","authenticated-orcid":false,"given":"George K.","family":"Christophides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-3014","authenticated-orcid":false,"given":"Dina","family":"Vlachou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"8033_CR1","unstructured":"World malaria report 2023: Geneva: World Health Organization. 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