biostudies-literatureUnknown22(1)Lyons FMTMalaria parasite fertilisation occurs within the Anopheles mosquito midgut. Interventions that inhibit parasite fertilisation prevent ongoing transmission and are important for malaria elimination efforts. Pfs48/45 and Pfs230 are two leading transmission-blocking vaccine candidates. Both proteins form a complex on the surface of sexual stage parasites and are essential for male fertility. Here we have identified nanobodies against Pfs48/45 that recognise gametocytes and have strong transmission-reducing activity. The crystal structure of our most potent nanobody in complex with Pfs48/45 reveals it binds a distinct epitope to TB31F, a leading transmission-blocking monoclonal antibody but to similar epitopes as RUPA-44 and RUPA-117. These results demonstrate the potential of nanobodies as a PLoS pathogense1013884https://www.ebi.ac.uk/biostudies/studies/S-EPMC12858062biostudies-literaturePfs48/45 nanobodies block Plasmodium falciparum transmission.PMC12858062Chmielewski JZeglinski KDietrich MHGouil QLyons FMTTong JAdair AGabriela MTham WHChan LJfalsePfs48/45 nanobodies block Plasmodium falciparum transmission.Malaria parasite fertilisation occurs within the Anopheles mosquito midgut. Interventions that inhibit parasite fertilisation prevent ongoing transmission and are important for malaria elimination efforts. Pfs48/45 and Pfs230 are two leading transmission-blocking vaccine candidates. Both proteins form a complex on the surface of sexual stage parasites and are essential for male fertility. Here we have identified nanobodies against Pfs48/45 that recognise gametocytes and have strong transmission-reducing activity. The crystal structure of our most potent nanobody in complex with Pfs48/45 reveals it binds a distinct epitope to TB31F, a leading transmission-blocking monoclonal antibody but to similar epitopes as RUPA-44 and RUPA-117. These results demonstrate the potential of nanobodies as a 2026-01-01T00:00:00Z2026 Jan2026-06-14T05:44:41.175Z2026-06-14T03:09:17.427ZS-EPMC128580624159213910.1371/journal.ppat.1013884