Nanoencapsulated retinoic acid as a safe tolerogenic adjuvant for intranasal vaccination against cutaneous leishmaniasis.

Mucosal, but not peripheral, vaccination with whole Leishmania amazonensis antigen (LaAg) effectively protects mice against leishmaniasis, likely through a tolerogenic mechanism. Given the crucial role of retinoic acid (RA) in CD4+ Foxp3+ regulatory T cell (Treg) differentiation and mucosal tolerance, here we evaluated the capacity of RA to improve intranasal (i.n.) vaccination with LaAg. To prevent degradation and possible mucosa irritation, RA was encapsulated in solid lipid nanoparticles (RA-SLN). Thus, BALB/c mice were given two i.n. doses of LaAg alone or in association with RA-SLN (LaAg/RA-SLN) prior to challenge with L. amazonensis. No histological sign of irritation or inflammation was produced in the nasal mucosa after RA-SLN administration. LaAg/RA-SLN vaccine was more effective in delaying lesion growth and reducing parasite burdens than LaAg alone (96% and 61% reduction, respectively). At two months after challenge, both vaccinated groups displayed similar T helper (Th) 1-skewed in situ cytokine responses, different from early infection where both Th1 and Th2 responses were suppressed, except for transforming growth factor (TGF)-β mRNA, that was higher in mice given RA-SLN. At the mucosa, RA-SLN promoted enhanced expression of interleukin (IL)-10 and CD4+ Foxp3+ Treg population. In sum, these data show that RA-SLN is an effective and safe tolerogenic adjuvant for i.n. vaccination against leishmaniasis.