Cytosolic Delivery of a Bithiophene Derivative via Polymersomes Kills <i>Trypanosoma cruzi</i> Amastigotes and Modulates the Inflammatory Response

Chagas disease, caused by the protozoan <i>Trypanosoma cruzi</i>, is an infectious illness that progresses through acute, indeterminate, and chronic phases. The acute phase often presents mild symptoms, followed by an asymptomatic indeterminate phase. In some cases, the disease advances to chronic Chagas cardiomyopathy, driven by sustained inflammation. Current treatments, benznidazole and nifurtimox, have limited efficacy in this stage and are associated with significant toxicity, highlighting the need for better therapies. PEG-<i>b</i>-PPS loaded with <b>BTAc</b>, exhibited favorable physicochemical properties, including high stability and an average size of 120 nm, suitable for efficient uptake by phagocytic cells such as macrophages. <b>BTAc</b>-loaded polymersomes showed enhanced efficacy against intracellular amastigotes of three <i>T. cruzi</i> strains (CL Brener, Brazil and Y) with IC₅₀ values of 6.17, 24.01, and 30.68 μg/mL, respectively. The formulation simultaneously reduced proinflammatory cytokines to basal levels, suggesting an immunomodulatory potential. Importantly, Förster Resonance Energy Transfer analysis confirmed that <b>BTAc</b>-loaded polymersomes remain intact upon cellular uptake, escape the endosomal compartment, and release their payload directly into the cytosol, which is the intracellular niche where amastigotes persist during chronic infection. These findings underscore the potential of this nanocarrier system as an innovative approach that combines targeted antitrypanosomal therapy with enhanced immunomodulation, offering a promising strategy for the treatment of chronic Chagas disease.