Mucoadhesive gold nanoparticles enhance acetogenin binding to simplified protozoan membrane models

Annonaceous acetogenins are natural products with potent antiparasitic activity, but their poorly understood membrane interactions and limited aqueous solubility hinder their therapeutic development. Here, we investigated acetogenin 1–3 , isolated from Porcelia macrocarpa , using PE lipids Langmuir monolayers with mucins as simplified protozoan membrane models. Free acetogenins 1 and 3 showed weak interactions with PE monolayers, whereas acetogenin 2 exhibited stronger membrane affinity. Notably, the natural 1:1 mixture of acetogenin 1 and 2 displayed enhanced interaction, with a maximum insertion pressure above the range associated with physiological membrane lateral pressures. Acetogenin 1 was also encapsulated into ultrastable mucoadhesive gold nanoparticles, enabling controlled release and enhancing its interaction with mucin-containing membrane models. These findings provide physicochemical insights into acetogenin membrane interactions and highlight nanoparticle-based delivery as a promising strategy to improve their membrane activity and potential antiparasitic applications.