We demonstrated that lung spheroid cell derived exosomes (LSC-Exo) carry the parental cell’s ACE2 that are able to target lung, intercept SARS-CoV-2 entry, confer protection against SARS-CoV-2 infection. This LSC-Exo prophylaxis paradigm would not be limited by viral evolution, showing great potential for emerged SARS-CoV-2 variants, including those that are yet to emerge.