Engineering Extracellular Vesicles Enriched with Palmitoylated ACE2 as COVID-19 Therapy

Area of Science:

• Biochemistry
• Virology
• Nanomedicine

Background:

• Angiotensin converting enzyme 2 (ACE2) is a critical host receptor for SARS-CoV-2 entry.
• Inhibiting the ACE2-spike protein interaction is a potential COVID-19 therapeutic strategy.
• ACE2 is found in extracellular vesicles (EVs), and its levels are regulated by protein palmitoylation.

Purpose of the Study:

• To engineer EVs enriched with ACE2 on their surface for potential COVID-19 treatment.
• To investigate the role of protein palmitoylation in ACE2 secretion into EVs.
• To evaluate the therapeutic efficacy of engineered EVs against SARS-CoV-2.

Main Methods:

• ACE2 was engineered with a palmitoylation-dependent plasma membrane targeting sequence.
• Extracellular vesicles enriched with surface ACE2 (PM-ACE2-EVs) were generated.
• In vitro and in vivo assays were used to assess the neutralization potency and therapeutic effects of PM-ACE2-EVs against SARS-CoV-2.

Main Results:

• Engineered PM-ACE2-EVs demonstrated high-affinity binding to the SARS-CoV-2 spike receptor-binding domain (RBD).
• PM-ACE2-EVs effectively blocked the interaction between SARS-CoV-2 and cell surface ACE2 in vitro.
• PM-ACE2-EVs neutralized pseudotyped and authentic SARS-CoV-2 in vivo, reduced viral load, and protected against lung inflammation.

Conclusions:

• Protein palmitoylation is crucial for ACE2 targeting to membranes and EV secretion.
• Engineered PM-ACE2-EVs represent a promising biomaterial for COVID-19 prophylaxis and therapy.
• This study provides an efficient protocol for developing novel EV-based therapeutics against SARS-CoV-2.