SARS-CoV-2 virus is transmitted via both droplet and aerosols with saliva as a major contributor commonly in closed spaces by both vaccinated and unvaccinated people. Oral transmission of the virus is 3-5 orders higher in magnitude than the nasal route suggesting a decrease in oral viral load could have a substantial effect on virus transmission. SARS-CoV-2 spike protein enters the host cell via Angiotensin Converting Enzyme 2 (ACE2) receptor and ganglioside (GM1) co-receptor. Severe dental caries in children has been increasingly associated with pathogenic cross-kingdom biofilms complicating oral and systemic health. It is imperative to devise affordable mitigation strategies to curb oral transmission of pathogens and optimum oral health. A solution to address these challenges are plant engineered enzymes administered in an easy-to-use drug delivery platform to debulk SARS-CoV-2 in saliva and dental biofilm. We explore a novel topical chewing-based delivery approach using CTB (Cholera toxin B subunit)-ACE2, a plant based viral trap protein that will directly bind to the virus blocking its entry into the host cell by saturating both ACE2 and GM1 receptors. In addition, we investigate a combinatorial approach with new generation plant lipase and glucanohydrolases in chewing gums targeting extracellular polymeric substance (EPS) and microbes for disruption of oral biofilm. We describe necessary investigations in preparation of clinical grade drug substance (CTB-ACE2/Ang (1-7) for oral delivery that led to the regulatory approval of the topical drug product (ACE2 gum) – currently in Phase I/II Clinical trials. We assess clinical efficacy of oral ACE2/Ang (1-7) in MMVD dogs on background treatment with ACEI/ARB. We report the effect of ACEI/ARBs on RAS (Renin angiotensin system) metabolic pools in addition to the inhibitory effect of ACEI on both soluble and membrane ACE2 activity and adverse clinical outcome of increased mitral valve leakage due to excess Ang II by ARB. ACE2 is a pivotal link in RAS dysregulation and COVID-19 pathogenesis. Here, we unveil soluble ACE2 (sACE2) as a potential metabolic biomarker for Renin Angiotensin System (RAS) dysregulation in COVID-19 disease severity and recovery.