**6.4 Stem cells route of delivery**

In most clinical trials investigating the MSC treatments of SARS-CoV-2 infection so far, MSCs are delivered via the intravenous route by infusion. The direct target of the intravenous route is not the lungs, that is why the inhalation route delivering the cells directly to lungs could be theoretically more effective. However, the inhalation route has the risk of not able to manage the uniform delivery of cells to lungs [202]. The evidence is being more and more visible to suggest that the curative potential of MSCs is attributed mostly to their secreted EVs via paracrine effects [203].

As evident from several clinically available inhaled medications for chronic lung disease, the inhalation route of delivering therapeutics to the lungs is a more direct route with lower the number of adverse effects, compared to the intravenous route. However, it must be appropriately managed for inhaled administration of a treatment in COVID-19 patients in the hospital setting. Many studies have showed the

feasibility of delivering stem cells via spray for direct pulmonary delivery with high viability [204]. Inhalation route of stem cell administration is an opportunity for efficient delivery of stem cells directly to the lungs, yet it needs further research and proof of concept.
