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ACE2-Decoy-Conjugated PLGA-PEG Nanoparticles Loaded with Nafamostat for Potent Antiviral Activity
Shulin Hou1, Yunyun Zhang1,2, Xin Zheng1,2
1Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Shanxi Medical University, Taiyuan 030001, China.
None:
Angiotensin-converting enzyme 2 (ACE2) is a key mediator of SARS-CoV-2 host cell entry, making it an attractive target for drug delivery strategies. Nafamostat (NM), a multifunctional agent with antiviral and anti-inflammatory properties, holds promise for COVID-19 treatment. In this study, we developed PLGA-PEG nanoparticles encapsulating NM (NM-PP NPs) and further conjugated them with specific ACE2 decoys (CTC-445.2d or SI5α) to generate NM-PP-Pro/Pep NPs. Both unmodified and ACE2-decoy-modified NPs exhibited uniform size distributions (diameter < 200 nm) and negative surface charges, as confirmed by dynamic light scattering and zeta potential measurements. The nanoparticles maintained structural integrity for at least 18 days at 4 °C and room temperature. In vitro release studies revealed sustained and controlled NM release kinetics. Notably, NM-PP-Pro NPs displayed potent antiviral activity, with an IC50 < 0.05 nM against wild-type SARS-CoV-2 and remained effective against the D614G variant (IC50 = 2 nM). These results underscore the potential of NM-PP-Pro NPs as a versatile nanotherapeutic platform for targeting SARS-CoV-2 and its emerging variants.
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