ACE2 Receptor‐Targeted Inhaled Nanoemulsions Inhibit SARS‐CoV‐2 and Attenuate Inflammatory Responses

Abstract Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin‐converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor‐binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug‐targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE‐AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation‐delivered remdesivir nanoemulsion (termed RDSV‐NE‐AYQ) effectively inhibits the infection of target cells by both wild‐type and mutant viruses. The RDSV‐NE‐AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti‐inflammatory drugs (TPCA‐1‐NE‐AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.