Retinoic acid-loaded nanoparticles enhance macrophage-mediated control of Leishmania infantum.

Abstract

Background/aim: Visceral leishmaniasis, primarily caused by Leishmania (L.) infantum, remains a major global health challenge due to limitations in current chemotherapeutic options, including toxicity and emerging drug resistance. Host-directed therapeutic approaches are increasingly recognized as promising alternatives. All-trans retinoic acid (ATRA) is an immunomodulatory molecule with host-dependent effects on macrophage function; however, its therapeutic use is hindered by instability and poor solubility. Solid lipid nanoparticles (SLNs) offer a controlled and biocompatible delivery platform capable of enhancing intracellular drug accumulation.

Materials and methods: ATRA-loaded SLNs were prepared and characterized for size, polydispersity index, zeta potential, and morphology. Their antileishmanial activity was evaluated against extracellular L. infantum promastigotes, noninfected RAW 264.7 macrophages, and L. infantum-infected macrophages using resazurin-based assays and xCELLigence real-time cell analysis.

Results: Neither free ATRA nor ATRA-loaded SLNs exhibited significant inhibitory activity against extracellular promastigotes at concentrations up to 75 μM. In contrast, both forms of ATRA demonstrated marked dose-dependent inhibition in infected macrophages, with a significantly enhanced intracellular response observed in the SLN formulation, while maintaining excellent biocompatibility in noninfected macrophages. Enhanced uptake and sustained intracellular release are likely contributors to the improved efficacy of the SLN system.

Conclusion: The findings reveal that ATRA exerts its antileishmanial activity primarily through host-dependent mechanisms that become apparent within infected macrophages, and that encapsulation into SLNs markedly amplifies this intracellular effect while preserving cell viability. ATRA-loaded SLNs thus represent a promising host-directed therapeutic strategy for the treatment of visceral leishmaniasis.