School of Biomedical Sciences Prof. Zhenzhen Wang has found that human lung spheroid cells derived exosomes (LSC-Exo) could bind and neutralize the SARS-CoV-2, providing prophylactic protection against virus. This finding was published Mar 12, 2024, by Nature Communications, entitled "Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2,"  Prof. Wang is the first author and corresponding author of this research and collaborate with Prof. Xiaojie Wang from Wenzhou Medical University and Prof. Ke Cheng from Columbia University.

The coronavirus disease 2019 (COVID-19) pandemic, provoked by SARS-CoV-2, presents a global health crisis to the public. Successful development of vaccines like BNT162b2 or mRNA-1273 has reduced the COVID-19 morbidity and mortality. However, an increasing number of SARS-CoV-2 variants of concern (VOC) altered SARS-CoV-2 pathogenesis, virulence, and transmissibility, but importantly raised severe concerns regarding current vaccines’ effectiveness against mutated viruses. Some variants, including B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants were highly resistant to BNT162b2 or mRNA-1273 vaccine-induced humoral immunity. Therefore, it is becoming undeniable evident that developing innovative and cost-effective interventions is necessary to prevent infection by SARS-CoV-2 and its variants.

SARS-CoV-2 primarily relies on the interaction between its spike (S) protein and the host cell receptor hACE2 to enter the host cells; thus, inhibiting this interaction is therefore a promising treatment strategy. Potent neutralizing monoclonal antibodies (mAbs) have been developed to target S protein for harnessing endogenous host defense mechanisms against SARS-CoV-2 infection. Similarly, recombinant human ACE2 protein (rhACE2) developed by APEIRON Biologics can bind with S-protein, reducing the adhesion and infectivity of SARS-CoV-2. Nevertheless, SARS-CoV-2 variants has led to decreased neutralizing activity of several mAbs. Moreover, the rapid degradation of free rhACE2 and the notoriously low efficiency of intravascular delivery across the plasma-lung barrier would greatly hamper its therapeutic efficacy against pulmonary infections.

Human lung spheroid cells (LSCs), composed of type I and II alveolar epithelial cells and mesenchymal cells, naturally express high levels of ACE2. Given that exosomes carry parental cell receptors, micro RNAs, and DNA and possess homing-target effect to recipient’s cell, Prof. Wang hypothesized that LSC-derived exosomes (LSC-Exo) would carry the parental cell’s ACE2, target lung, and confer protection against SARS-CoV-2.  

Subsequently, the authors evaluated the protection ability of LSC-Exo in preventing SARS-CoV-2 infection using Syrian hamsters as a model by inhalation. Compared to the HEK-Exo and PBS groups, inhaling aerosolized LSC-Exo significantly prevented weight loss caused by SARS-CoV-2 and reduced viral loads in oral swabs (OS) and bronchoalveolar lavage fluid (BAL), as depicted in Figure 1.

 Figure 1: Protective effect of LSC-Exo against authentic SARS-CoV-2 infection in Syrian hamsters

To investigate the protective mechanism of LSC-Exo, the authors performed the RNA-Seq analysis on lung tissues of infected hamsters (Figure 2). Principal component analysis (PCA) and Pearson correlation coefficient analyses revealed that the transcription profiles of hamsters receiving LSC-Exo were highly similar to those of sham group, with only 415 differentially expressed genes observed. Moreover, inhalation of LSC-Exo effectively restored a network of genes that center on cytokine signaling in the immune system, cytokine-cytokine receptor interaction, and regulation of cellular response to stress. The authors also discovered that SARS-CoV-2 mainly disrupts the redox balance of lung tissues through oxidative phosphorylation pathways, causing mitochondrial dysfunction. In contrast, inhaling LSC-Exo effectively reduced abnormal oxidative phosphorylation in lung tissue, restoring normal expression levels of multiple genes and maintaining the regulation of the lung tissue's oxidative defense system, thereby efficiently protecting the hamsters from SARS-CoV-2 infection.

 Figure 2: Protective mechanisms of LSC-Exo against SARS-CoV-2 infection

In summary, LSC-Exo expresses high levels of hACE2, can effectively neutralize SARS-CoV-2 and block the interaction between the virus and host cells, protecting the host from SARS-CoV-2 infection. Furthermore, LSC-Exo exhibits great potential in intercepting multiple SARS-CoV-2 variant strains from entering host cells and demonstrates favorable safety in vivo. Therefore, LSC-Exo could serve as a broad-spectrum protectant against existing and emerging virus variants.

Original Source: Zhenzhen Wang, et al. Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2. Nature Communications. 2024, DOI: 10.1038/s41467-024-45628-x.

Link: https://doi.org/10.1038/s41467-024-45628-x.