Inhalation of ACE2-expressing lung spheroid cell exosomes provides prophylactic protection against SARS-CoV-2

Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity pose the urgency for developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction is a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2 and protect the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates their deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protected hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercept the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and show comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as broad-spectrum protectant against existing and emerging virus variants. To To elucidate the underlying protection mechanisms of LSC-Exo against SARS-CoV-2 infection, the bulk RNA sequencing (RNA-seq) analysis on lung tissues of infected hamsters that received PBS or LSC-Exo treatment was performed.