Inhalation  with  ACE-2-Expressing-Lung-Exosomes  for  Prophylactic  Protection  and  Treating  SARS-CoV-2  Infection  and  Disease    

Inhalation  with  ACE-2-Expressing-Lung-Exosomes  for  Prophylactic  Protection  and  Treating  SARS-CoV-2  Infection  and  Disease    

Attapon  Cheepsattayakorn1,2,3,4*, Ruangrong  Cheepsattayakorn5, Porntep  Siriwanarangsun2


1. Faculty  of  Medicine  Vajira  Hospital, Navamindradhiraj  University, Bangkok, Thailand.

2. Faculty  of  Medicine, Western  University, Pathumtani  Province, Thailand.

3. 10th  Zonal  Tuberculosis  and  Chest  Disease  Center, Chiang  Mai, Thailand.

4. Department  of  Disease  Control, Ministry  of  Public  Health, Thailand.

5. Department  of  Pathology, Faculty  of  Medicine, Chiang  Mai  University, Chiang  Mai, Thailand.

Correspondence to: Attapon  Cheepsattayakorn, 10th  Zonal  Tuberculosis  and  Chest  Disease  Center, 143  Sridornchai  Road  Changklan  Muang  Chiang  Mai  50100  Thailand.


© 2024 Attapon  Cheepsattayakorn. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 28 March 2024

Published: 01 May 2024

Inhalation  with  ACE-2-Expressing-Lung-Exosomes  for  Prophylactic  Protection  and  Treating  SARS-CoV-2  Infection  and  Disease    

SARS-CoV-2  infectivity  depends  on  binding  its  S  protein  with  the  entry-receptor  “ hACE-2 ”  a  promising  strategic  treatment, therefore,  is  this  interaction  inhibition [1-3].  Some  SARS-CoV-2  variants, such  as  B.1.1.7 (Alpha), B.1.617.2 (Delta), and  B.1.1.529 (Omicron)  variants  were  highly  resistant  to  mRNA-1273   vaccine-induced  humoral  immunity or  BNT162b2 [4-6].  A  recent  study  demonstrated  that  in  a  female  mouse  model, inhalation  of  ACE-2-expressing-human-lung-spheroid-cells (LSC)-derived  exosomes (LSC-Exo) (Figure 1)  could  protect  the  host  throughout  the  whole  lung  by  biodistribution  and  deposition  against  COVID-19 (SARS-CoV-2)  infection  by  SARS-CoV-2  binding, blocking  the  interaction  of  host  cells  with  SARS-CoV-2, and  virus  neutralization  both  in  vitro  and  in  vivo [7].  This  study  also  revealed  decrease  of  viral  loads  and  protection  of  SARS-CoV-2-induced  disease [7].   Three  different  types  of  inhalation  devices  are  commonly  used; jet, ultrasonic, and  vibrating  mesh (all  are  nebulizer) (Figure  2) [8].   In  non-human  primates  and  rats  studies, when  nebulized  with  eFlow, human  immunoglobulin  preparations  were  deposited  into  the  airways  as  well  as  treated-lung  alveoli [9].   VR942, an  anti-interleukin (IL)-13  mAb  is  a  first-in-class  for  dry-powder  inhalers (DPIs) [10]. 


In  conclusion, ACE-2-expressing-human-lung-spheroid-cells-derived  exosomes  could  be  a  promising-broad-spectrum  bioprotectant  against  SARS-CoV-2  variants  and  other  emerging  virus  variants.  By  using  common  nebulizer  inhalation, it  can  be  administrated  other  therapeutic  agents  for  treating  the  patients’  lung  and  respiratory  system. 


Figure  1 :  A. Demonstrating  extraction scheme of LSC and LSC-Exo from healthy donors, created with B. Demonstrating  immunofluorescence staining and quantification analysis of ACE-2 on LSC and HEK. Scale bar: 50 μm. n = 3. C. Demonstrating  Western blot quantification of ACE-2 expression in LSC and HEK, which derived from the same experiments and processed in parallel. n = 3. D. Demonstrating  representative TEM images of LSC-Exo and HEK-Exo from 3 independent experiments. Scale bar: 100 μm. E. Demonstrating  measurements of size distribution of LSC-Exo and HEK-Exo via nanoparticle tracking analysis. Inset: 3-colar dSTORM image of CD63-Alexa Fluor®-488, PE-CD9, APC-CD81 of LSC-Exo or HEK-Exo. F. Demonstrating  quantification of ACE-2 expression on LSC-Exo and HEK-Exo by flow cytometry. n = 3 [7].


Figure 2 : Demonstrating  potential  therapeutic  approaches for respiratory delivery of passive immunotherapeutics against  SARS-CoV-2 (COVID-19) [8].



1. Lan  J, et  al.  Structure  of  the  SARS-CoV-2  spike  receptor-binding  domain  bound  to the  ACE-2  receptor.  Nature  2020; 581 : 215-220. 

2. Huang  X, et  al.  Nanotechnology-based  strategies  against  SARS-CoV-2  variants.  Nat  Nanotechnol  2022; 17 : 1027-1037. 

3. Zhang  L, et  al.  An  ACE-2  decoy  can  be  administered  by  inhalation  and  potently  targets  omicron  variants  of  SARS-CoV-2.  EMBO  Mol  Med  2022; 14 : e16109.   

4. Garcia-Beltran  WF, et  al.  Multiple  SARS-CoV-2  variants  escape  neutralization  by  vaccine-induced  humoral  immunity.  Cell  2021; 184 : 2372-2383.e2379. 

5. Pouwels  KB, et  al.  Effect  f  Delta  variant  on  viral  burden  and  vaccine  effectiveness  against  new  SARS-CoV-2  infections  in  the  UK.  Nat  Med  2021; 27 : 2127-2135. 

6. Hui  KPY, et  al.  SARS-CoV-2  Omicron  variant  replication  in  human  bronchus  and  lung  ex  vivo.  Nature  2022; 603 : 715-720.  

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