Transferosome Delivery Unlocks the Therapeutic Potential of Imiquimod for Experimental Cutaneous Leishmaniasis

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Abstract
Repurposing existing drugs offers an attractive strategy for neglected infectious diseases, but therapeutic efficacy may be limited by inadequate drug delivery to the site of infection. Imiquimod (IQ), a topical immunomodulatory agent, has shown potential against cutaneous leishmaniasis (CL); however, strategies to enhance its local therapeutic effect while minimizing drug exposure remain limited. Here, we developed IQ-loaded transferosomes (IQ-TFs) as nano-enabled topical delivery systems and evaluated their pharmaceutical performance, skin delivery properties, and antileishmanial efficacy against experimental CL caused by Leishmania (L.) amazonensis. IQ-TFs, prepared by thin-film hydration, showed a size of 596 ± 73 nm, low polydispersity (0.20 ± 0.02), zeta potential (−15.2 ± 1.8 mV), and high encapsulation efficiency (71.2 ± 18.7%). Encapsulation in transferosomes promoted sustained permeation and prolonged cutaneous retention of IQ, consistent with localized drug delivery. IQ-TFs markedly enhanced antileishmanial activity against both promastigotes and intracellular amastigotes. In vivo, topical IQ-TF significantly reduced parasite burden and improved infection-associated histopathological alterations. Notably, IQ-TFs achieved these effects using approximately 30-fold less IQ than the commercial 5% cream, with parasite control comparable to systemic deoxycholate amphotericin B. These findings highlight IQ transferosomes as a promising nanotechnology platform for transforming imiquimod into a more efficient low-dose topical therapy for cutaneous leishmaniasis.
Funding Information
  • São Paulo Research Foundation (2014/50315-0)
  • São Paulo Research Foundation (2022/15834-3)
  • São Paulo Research Foundation (2024/22230-2)
  • São Paulo Research Foundation (2023/01641-1)
  • São Paulo Research Foundation (2026/04102-2)
  • HCFMUSP-LIM50
  • Complutense University of Madrid
  • CNPq

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