Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS‐CoV‐2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can cause lethal pulmonary damage in humans. It contains spike proteins on its envelope that bind to human angiotensin‐converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS‐CoV‐2 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half‐life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2 h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS‐CoV‐2. Furthermore, mRNA‐generated hsACE2 binds to the receptor‐binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS‐CoV‐2 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA‐based nanotherapeutics can be potentially deployed to neutralize SARS‐CoV‐2 and open new treatment opportunities for coronavirus disease 2019 (COVID‐19).

Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination

“…Currently available intramuscularly administered vaccines induce circulating memory T cells, but not lung-resident, spike protein-specific T RM responses (35,74), highlighting an advantage of our mucosal PACE-mRNA delivery strategy. Although inhaled mRNA has been investigated for prophylactic therapeutics or decoy treatments to fight SARS-CoV-2 (48,(75)(76)(77)(78), this work is important because it describes de novo induction of protective immunity against SARS-CoV-2 with intranasal delivery of a nonviral vector mRNA vaccine.…”

Recent Advances in Site-Specific Lipid Nanoparticles for mRNA Delivery

“…Sahay’s group recently developed a liver-targeting LNP to deliver mRNA for SARS-CoV-2 . The mRNA encodes a soluble form of human angiotensin-converting enzyme 2 (hsACE2), which is the target for SARS-CoV-2 spike protein and mediates the endocytosis of SARS-CoV-2 into human airway cells. , The LNP composition was same to the formulation of Onpattro.…”

Microalgae as an Efficient Vehicle for the Production and Targeted Delivery of Therapeutic Glycoproteins against SARS-CoV-2 Variants

“…The human ACE2 is composed of three regions, namely, extracellular, transmembrane, and intracellular segments, among which the extracellular part contains a peptidase domain that participates in binding to the SARS-CoV-2 RBD [53]. The binding of S-glycoprotein to ACE2 is the initial step in the entry, replication, and subsequent pathogenesis of SARS-CoV-2.…”

“…In another approach, lipid nanoparticles were used to deliver transcribed messenger RNA into the mammalian cells to rapidly express ACE2. Different analyses revealed that the produced ACE2 was able to bind to the RBD of SARS-CoV-2 in mouse lung cells and strongly inhibited (more than 90%) the infection with SARS-CoV-2 pseudovirus [53]. However, the production of rhACE2 in human cells is a time-consuming and expensive process.…”

“…Blocking or reducing the binding reaction of the SARS-CoV-2 S-glycoprotein to the human ACE2 has presented an alternative approach for the treatment of patients with COVID-19 [121]. Given the large size of the human ACE2 receptor (740 amino acids) and concerns about immunogenic reactions, the potential of truncated forms of soluble rhACE2 was evaluated [53]. However, truncated forms of ACE2 are unstable, have a short half-life, and degrade rapidly resulting in a diminished ability to effectively trap the virus [121].…”