Dual Treatment of Chronic Chagasic Cardiomyopathy and Parasitic Burden via Combination Nanotherapy

In chronic Chagas disease, the persistence of the protozoan <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>) is associated with an extensive inflammatory response that impacts cardiac function. The standard treatment, oral benznidazole, effectively targets the parasitic burden but does not address the chronic inflammation nor prevent the progression of severe cardiomyopathies. This presents an inherent immunotherapeutic challenge, as implementing an anti-inflammatory approach can have the unwanted effect of inhibiting beneficial parasite-specific immunity. Here, we investigated a combination therapy approach using benznidazole and immunomodulatory rapamycin-loaded poly(ethylene glycol)-<i>b</i>-poly(propylene sulfide) polymersome nanocarriers in a chronic Chagas disease murine model with cardiac abnormalities. The combined treatment demonstrated effective management of both inflammation and parasitic burden at systemic and local levels. No systemic reactivation of <i>T. cruzi</i> infection was observed, along with cardioprotective immunomodulatory effects through the modulation of cytokines, management of parasitic burden, and improved cardiac function based on electrocardiography assessment. The combination treatment enhanced a protective cytokine response in the heart, characterized by increased anti-inflammatory IL-10 levels, achieving greater effects than standard benznidazole treatment, and normalized TNF-α levels. Localized immunomodulatory effects, along with parasitic burden control, extended to other solid tissues relevant to parasite pathology and reservoirs. These findings highlight the therapeutic potential of modulating the immune response in chronic Chagas disease with rapamycin polymersomes and emphasize the importance of precise treatment timing in the strategy's efficacy.