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

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.