Glucose-Functionalized Piperlongumine-Encapsulated Nanoparticles Selectively Target Schistosomal Tegument and Enhance the Anti-schistosomiasis Effect

Abstract The therapeutic potential of piperlongumine (PL) against schistosomiasis and hepatic injury is limited by its poor water solubility. Herein, well-defined, monodisperse, surface glucose-functionalized, and PL-encapsulated nanoparticles (PL-NPs) with uniform size (hydrodynamic diameter: ∼264 nm) were synthesized via a nanoprecipitation protocol. These PL-NPs possessed excellent stability in various media (>120 h) and controlled-release profiles in vitro in Roswell Park Memorial Institute 1640 (t1/2 = 2.4 h) and phosphate-buffered saline (t1/2 = 12 h). Cytocompatibility assessments and organ toxicity studies confirmed that PL-NPs possessed excellent biocompatibility. In vivo and ex vivo fluorescence imaging revealed the perfect schistosoma-targeting capability of PL-NPs via the specific recognition and binding property of tegumental schistosome glucose transporter protein 4 toward the glucose molecule. PL-NPs (containing 10 μM PL) achieved an in vitro worm mortality of ∼95%, which was approximately 2.7-fold higher than that of PL alone (∼35%) with the same dosage. The enhanced worm-killing activity of PL-NPs compared to that of PL alone was attributed to a greater ability to disrupt the schistosomal tegument and a more pronounced impairment of the worm’s internal antioxidant capacity. After PL-NPs treatment, in vivo worm burden and hepatic and intestinal egg burden were significantly decreased by approximately 56%, 44%, and 37%, respectively, representing 1.9-, 2.0-, and 2.1-fold greater reductions than those observed with the PL group. Concurrently, PL-NPs obviously attenuated hepatic liver function impairment and fibrosis progression by decreasing the intrahepatic number of granulomas (∼75%, 1.7-fold lower than PL), granuloma size (∼50%, 3.6-fold lower than PL), and lipid peroxidation and restoring intrahepatic antioxidant capacity to near-normal levels. Thus, these PL-NPs, which were characterized by controlled release, specific schistosoma-targeting, potent anti-schistosomal efficacy, and hepatoprotective activity, offer a promising therapeutic strategy for schistosomiasis.