Efficacy of benznidazole delivery during Chagas disease nanotherapy is dependent on the nanocarrier morphology.

The causative agent of Chagas disease, the protozoan Trypanosoma cruzi, is an obligate intracellular parasite that is typically treated with daily oral administration of Benznidazole (BNZ), a parasiticidal pro-drug with considerable side effects. Previously, we effectively targeted intracellular parasites using ∼100 nm diameter BNZ-loaded poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) vesicular nanocarriers (a.k.a. polymersomes) in a T. cruzi-infected mouse model, without causing the typical side effects associated with standard BNZ treatment. Here, we exploit the structural versatility of the PEG-b-PPS system to investigate the impact of nanocarrier structure on the efficacy of BNZ nanotherapy. Despite sharing the same surface chemistry and oxidation-sensitive biodegradation, solid core ∼25 nm PEG-b-PPS micelles failed to produce in vivo trypanocidal effects. By applying the Förster Resonance Energy Transfer strategy, we demonstrated that PEG-b-PPS polymersomes promoted sustained intracellular drug release and enhanced tissue accumulation, offering a significant advantage for intracellular drug delivery compared to micelles with the same surface chemistry. Our studies further revealed that the lack of parasiticidal effect in PEG-b-PPS micelles is likely due to their slower rate of accumulation into solid tissues, consistent with the prolonged circulation time of intact micelles. Considering the cardiac damage typically induced by T. cruzi infection, this study also investigated the contributions of cardiac cellular biodistribution and payload release for both nanocarriers to the treatment outcomes of BNZ delivery. Our findings emphasize the crucial role of cardiac macrophages in the parasiticidal effect of BNZ formulations and highlight the critical importance of nanobiomaterial structure during therapeutic delivery.