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Engineered ACE2 decoy in dry powder form for inhalation: A novel therapy for SARS-CoV-2 variants

Takaaki Ito,Tatsuya Suzuki,Sakai Yusuke,Keisuke Nishioka,Yumi Itoh,Kentarou Sakamoto,N. Ikemura,Satoaki Matoba,Yasunari Kanda,J. Takagi,Toru Okamoto,Kohei Tahara,Atsushi Hoshino

Published 2025 in Molecular Therapy: Methods & Clinical Development

ABSTRACT

The persistent threat of SARS-CoV-2 and the emergence of new variants has prompted the development of a novel, easily administered modality that can overcome viral mutations. The engineered ACE2 decoy shows neutralizing activity comparable to monoclonal antibodies and is broadly effective against SARS-CoV-2 variants and ACE2-utilizing sarbecoviruses. In addition to intravenous administration, this decoy has shown antiviral efficacy through nebulized aerosol inhalation in murine and primate models, offering a dose-sparing advantage. Clinically, dry powder formulation is ideal for convenience and storage but poses challenges for protein biologics. This study developed a freeze-dried spray formulation of the ACE2 decoy for inhalation. The trehalose and leucine-based excipient maintained neutralizing activity and prevented aggregate formation. The dry powder showed aerodynamic distribution from bronchi to alveoli, aiding protection against SARS-CoV-2 infections. Neutralizing activity, structural stability, and powder dispersibility were preserved after 6 months of storage. In a mouse model of SARS-CoV-2 infection, significant reductions in viral replication and lung pathology were observed with intratracheal administration 24 h post-infection. The ACE2 decoy retained activity against recent JN.1 and current KP.3 strains, confirming its robust efficacy against viral mutations. This ACE2 decoy powder inhalant is a self-administered, next-generation treatment addressing the ongoing immune-evading evolution of SARS-CoV-2.

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