Adipose-Derived Extracellular Vesicles Mitigate Experimental Cutaneous Leishmaniasis Through an IL-10 Dependent Mechanism

de Almeida, D. B.; Fernandez, C.; Amaral, A.; Bittencourt, I.; Romano, J.; Praxedes, H.; Manhaes, N.; Trabach, R.; Toja de Miranda, B.; Covre, L.; Martins, A.; Gomes, D.; Ferreira Cruz, F.; Diniz Ramos, T.; Rocco, P.; de Matos Guedes, H. L.

doi:10.64898/2026.02.02.703256

bioRxiv · 10.64898/2026.02.02.703256

Adipose-Derived Extracellular Vesicles Mitigate Experimental Cutaneous Leishmaniasis Through an IL-10 Dependent Mechanism

de Almeida, D. B.·Fernandez, C.·Amaral, A.·Bittencourt, I.·Romano, J.·Praxedes, H.·Manhaes, N.·Trabach, R.·Toja de Miranda, B.·Covre, L.·Martins, A.·Gomes, D.·Ferreira Cruz, F.·Diniz Ramos, T.·Rocco, P.·de Matos Guedes, H. L.

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Abstract

Leishmaniasis, a neglected tropical disease caused by protozoa of the Leishmania genus, is characterized by an imbalanced immune response that promotes parasite survival while inducing tissue damage. We previously showed that adipose-derived mesenchymal stem cells (AD-MSCs) limited lesion progression in C57BL/6 mice infected with Leishmania amazonensis. In the current study, we examined whether extracellular vesicles released by AD-MSCs (AD-MSC-EVs) reproduce these therapeutic effects. AD-MSC-EVs were purified, expanded, and characterized, confirming their typical morphology and EV-associated surface markers. In vitro, treatment of infected macrophages with AD-MSC-EVs 4 hours post-infection reduced parasite load through the induction of reactive oxygen species (ROS), independent of nitric oxide (NO). However, treatment 24 hours post-infection failed to reproduce this effect. In vivo, intralesional administration of AD-MSC-EVs significantly reduced lesion size without altering parasite load, while also decreasing levels of specific IgM and IgG for Leishmania amazonensis antigens. AD-MSC-EV therapy also reduced proinflammatory cytokines production by CD4 and cytotoxicity CD8 T cells, while increasing IL-10 production by {gamma}{delta} T cells. Moreover, combined therapy with pentavalent antimonial further reduced lesion size but did not affect parasite load. Notably, AD-MSC-EVs failed to control lesions in IL-10-deficient mice, suggesting that their therapeutic effect is dependent on IL-10. In conclusion, these findings showed that AD-MSC-EVs modulated the host immune response to attenuate L. amazonensis-induced cutaneous pathology and may represent a promising adjunct or alternative therapy for cutaneous leishmaniasis. Significance StatementCutaneous leishmaniasis is a neglected tropical disease with limited therapeutic options and significant immunopathology. This study demonstrates that extracellular vesicles derived from adipose-derived mesenchymal stem cells (AD-MSC-EVs) can modulate host immune responses and reduce lesion severity in Leishmania amazonensis infection. Rather than directly eliminating parasites, AD-MSC-EVs attenuate tissue damage through IL-10 dependent immunoregulation, highlighting a novel host-directed therapeutic strategy. These findings advance understanding of EV-mediated immune modulation and support AD-MSC-EVs as a promising adjunct or alternative approach for treating cutaneous leishmaniasis and potentially other inflammatory infectious diseases.

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de Almeida, D. B., Fernandez, C., Amaral, A., Bittencourt, I., Romano, J., Praxedes, H., Manhaes, N., Trabach, R., Toja de Miranda, B., Covre, L., Martins, A., Gomes, D., Ferreira Cruz, F., Diniz Ramos, T., Rocco, P., de Matos Guedes, H. L.. 2026-02-03. Adipose-Derived Extracellular Vesicles Mitigate Experimental Cutaneous Leishmaniasis Through an IL-10 Dependent Mechanism. https://doi.org/10.64898/2026.02.02.703256

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