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Extracellular vesicles (EVs) from Trypanosoma cruzi have been shown to modulate host immune responses, often favoring parasite persistence. In this study, we characterized EVs derived from the non-pathogenic trypanosomatids Trypanosoma rangeli and Phytomonas serpens and evaluated their potential as immunogens capable of inducing cross-protection against T. cruzi infection. Isolated EVs were characterized by Nanoparticle Tracking Analysis (NTA) and electron microscopy. A comparative proteomic analysis of EVs was performed using Mass Spectrometry-Based Proteomic Analysis (LC-MS\/MS). The effects of EVs on immunomodulation and T. cruzi infection were assessed through in vitro and in vivo assays, using peripheral blood mononuclear cells (PBMCs) and BALB\/c mice. The proteomic analysis identified shared proteins between the EVs of T. rangeli, P. serpens, and T. cruzi, including immunogenic candidates such as calpain-like cysteine peptidase and elongation factor 2. In vitro, pre-stimulation with the T. rangeli EVs reduced infection rates of the host cells by T. cruzi. In vivo, immunization with the EVs from T. rangeli and P. serpens led to a significant reduction in parasitemia in the BALB\/c mice challenged with T. cruzi, though this did not translate into improved survival compared to controls. Interestingly, the EVs from T. cruzi also reduced parasitemia but did not confer protection against mortality. These findings suggest that while non-pathogenic trypanosomatid EVs exhibit potential immunogenic properties and can reduce parasitic load, their efficacy in preventing disease progression remains limited. Further research is needed to explore the mechanisms underlying these effects and to optimize EV-based strategies for protective immunity against Chagas disease.<\/jats:p>","DOI":"10.3390\/ijms26041544","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T06:06:06Z","timestamp":1739340366000},"page":"1544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Trypanosomatid Extracellular Vesicles as Potential Immunogens for Chagas Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Juliana Bernardi","family":"Aggio","sequence":"first","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f4nica Vit\u00f3ria","family":"Vedam","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"},{"name":"Laborat\u00f3rio de Biologia Celular e Protozoologia, Universidade Estadual de Ponta Grossa, Ponta Grossa 84030-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edndice Mitie","family":"Nisimura","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"},{"name":"Grupo de Imunologia Molecular, Celular e Intelig\u00eancia Artificial, Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosiane Valeriano","family":"da Silva","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"},{"name":"Laborat\u00f3rio de Imunopatologia Experimental, Departamento de Imunologia, Parasitologia e Patologia Geral, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Izabel","family":"Lovo-Martins","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"},{"name":"Laborat\u00f3rio de Imunopatologia Experimental, Departamento de Imunologia, Parasitologia e Patologia Geral, Centro de Ci\u00eancias Biol\u00f3gicas, Universidade Estadual de Londrina, Londrina 86057-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Santana","family":"Borges","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ-PR), Curitiba 81350-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Alves","family":"M\u00f6rking","sequence":"additional","affiliation":[{"name":"Instituto Carlos Chagas, 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