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

• Published in: Advanced Materials 2021-12, Vol.33 (49), p.e2103471-n/a
• Main Authors: Xie, Feng, Su, Peng, Pan, Ting, Zhou, Xiaoxue, Li, Heyu, Huang, Huizhe, Wang, Aijun, Wang, Fangwei, Huang, Jun, Yan, Haiyan, Zeng, Linghui, Zhang, Long, Zhou, Fangfang
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin-Converting Enzyme 2; Animals; Biomedical materials; COVID-19; COVID-19 Drug Treatment; Extracellular vesicles; Extracellular Vesicles - metabolism; Materials science; Membranes; Mice; palmitoylation; Protein Binding; Proteins; SARS-CoV-2; Severe acute respiratory syndrome; Spike Glycoprotein, Coronavirus - chemistry; Thiolester Hydrolases - metabolism; Vesicles; Viral diseases
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202103471

Angiotensin converting enzyme 2 (ACE2) is a key receptor present on cell surfaces that directly interacts with the viral spike (S) protein of the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). It is proposed that inhibiting this interaction can be promising in treating COVID‐19. Here, the presence of ACE2 in extracellular vesicles (EVs) is reported and the EV‐ACE2 levels are determined by protein palmitoylation. The Cys141 and Cys498 residues on ACE2 are S‐palmitoylated by zinc finger DHHC‐Type Palmitoyltransferase 3 (ZDHHC3) and de‐palmitoylated by acyl protein thioesterase 1 (LYPLA1), which is critical for the membrane‐targeting of ACE2 and their EV secretion. Importantly, by fusing the S‐palmitoylation‐dependent plasma membrane (PM) targeting sequence with ACE2, EVs enriched with ACE2 on their surface (referred to as PM‐ACE2‐EVs) are engineered. It is shown that PM‐ACE2‐EVs can bind to the SARS‐CoV‐2 S‐RBD with high affinity and block its interaction with cell surface ACE2 in vitro. PM‐ACE2‐EVs show neutralization potency against pseudotyped and authentic SARS‐CoV‐2 in human ACE2 (hACE2) transgenic mice, efficiently block viral load of authentic SARS‐CoV‐2, and thus protect host against SARS‐CoV‐2‐induced lung inflammation. The study provides an efficient engineering protocol for constructing a promising, novel biomaterial for application in prophylactic and therapeutic treatments against COVID‐19. Engineered EVs enriched with palmitoylated ACE2 (PM‐ACE2) efficiently capture SARS‐CoV‐2 viruses and block their interaction with the cell surface ACE2, leading to reduced infection both in vitro and in vivo. This work identifies a novel palmitoylation‐dependent mechanism whereby human cells package ACE2 into EVs, meanwhile developing PM‐ACE2‐EVs as a novel candidate for prophylactic and therapeutic treatment against COVID‐19.