ABSTRACT
The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS)
coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic with significant morbidity and mortality. Despite
widespread efforts, it's far from certain that an effective vaccine will be available soon. Therefore, developing
new therapeutics for this devastating disease is critically important. However, to date, no specific treatments
are recommended to prevent or treat COVID-19. Previous studies have demonstrated that SARS-CoV-2 infects
host cells through its viral spike glycoprotein interacting with cell-surface angiotensin-converting enzyme 2
(ACE2), which is a membrane-bound monocarboxypeptidase found in pulmonary alveolar epithelial type II
(AECII) cells in the lung. An important function of ACE2 is to degrade angiotensin II, which limits several
detrimental effects that result from angiotensin II binding to Angiotensin II type 1 (AT1) receptors, including
vasoconstriction, enhanced inflammation, and thrombosis. The entry of SARS-CoV-2 into cells markedly down-
regulates ACE2. Loss of ACE2 at the external site of the cell membrane results in increased pulmonary
inflammation and coagulation. Nanoparticles are increasingly being proposed as lung drug delivery vehicles.
Nanoparticles can also serve as imaging probes for theranostic strategies. Our long-term goal is to develop an
effective and efficient protocol for manufacturing a wide range of therapeutic drugs to treat pulmonary infectious
diseases using emerging siRNA and molecular imaging technologies. The overall objective of this project is to
design a novel approach for introducing ACE2 targeting nanotherapeutics into pulmonary AECII cells to prevent
interactions between SARS-CoV-2 and ACE2. These nanotherapeutics will also carry siRNA targeting the AT1
receptor to block the progression of inflammatory and thrombotic processes that local angiotensin II
hyperactivity triggers following SARS-CoV-2 infection. In addition, the nanotherapeutics will have a
superparamagnetic nanoparticle core, which can provide a way to non-invasively assess drug delivery using
magnetic particle imaging (MPI). MPI provides high sensitivity detection and depth-independent quantitation for
longitudinal studies. The output of this work will include a novel image-guided method for delivering nanodrugs
to the lungs. This is significant because these nanodrugs will be capable of targeting ACE2-expressing cells,
and preventing SARS-CoV-2 from entering the cells. These nanodrugs will also silence the expression of the
AT1 receptor to block the progression of inflammatory and thrombotic processes that are normally induced by
decreases in ACE2. This project will also demonstrate the utility of MPI for lung applications, such as evaluating
the efficiency and uniformity of aerosol delivery, and tracking the aerosolized nanodrugs in vivo.
