{"doi":"10.7150/thno.66831","title":"An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages","abstract":"Rationale: Macrophages are the frontline immune cells in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Angiotensin-converting enzyme 2 (ACE2) serves as the binding receptor to SARS-CoV-2 Spike glycoprotein for fusion and internalization into the human host cells. However, the mechanisms underlying SARS-CoV-2-elicited macrophage inflammatory responses remain elusive. Neutralizing SARS-CoV-2 by human ACE2 (hACE2) decoys has been proposed as a therapeutic approach to ameliorate SARS-CoV-2-stimulated inflammation. This study aims to investigate whether an engineered decoy receptor can abrogate SARS-CoV-2-induced macrophage inflammation. Methods: hACE2 was biotinylated to the surface of nano-liposomes (d = 100 nm) to generate Liposome-human ACE2 complex (Lipo-hACE2). Lentivirus expressing Spike protein (D614G) was also created as a pseudo-SARS-CoV-2 (Lenti-Spike). Liposome-hACE2 was used as a decoy receptor or competitive inhibitor to inhibit SARS-CoV-2 or Lenti-Spike-induced macrophage inflammation in vitro and in vivo. Results: Both SARS-CoV-2 and Lenti-Spike stimulated strong inflammatory responses by inducing the expression of key cytokine and chemokines, including IL-1, IL-6, TNF, CCL-2, and CXCL-10, in murine and human macrophages in vitro, whereas Lipo-hACE2 decoy abolished these effects in macrophages. Furthermore, intravenous injection of Lenti-Spike led to increased macrophage and tissue inflammation in wild type mice, which was also abolished by Lipo-hACE2 treatment. Mechanistically, Spike protein stimulated macrophage inflammation by activating canonical NF-B signaling. RNA sequencing analysis revealed that Lenti-Spike induced over 2,000 differentially expressed genes (DEGs) in murine macrophages, but deficiency of IB kinase (IKK), a key regulator for NF-B activation, abrogated Lenti-Spike-elicited macrophage inflammatory responses. Conclusions: We demonstrated that the engineered Lipo-hACE2 acts as a molecular decoy to neutralize SARS-CoV-2 or Spike protein-induced inflammation in both murine and human macrophages, and activation of the canonical IKK/NF-B signaling is essential for SARS-CoV-2-elicited macrophage inflammatory responses.","journal":"Theranostics","year":2022,"id":249856,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":480472,"name":"Zhaojie Meng","orcid":"0000-0003-4857-3038","position":1,"is_corresponding":false},{"id":673939,"name":"Rebecca Hernandez","orcid":"0000-0003-4127-3323","position":2,"is_corresponding":false},{"id":564716,"name":"Susana Cavallero","orcid":"0000-0001-5402-8840","position":3,"is_corresponding":false},{"id":302275,"name":"Tong Zhou","orcid":"0000-0003-2361-1931","position":4,"is_corresponding":false},{"id":385049,"name":"Tzung K. Hsiai","orcid":"0000-0003-1734-0792","position":5,"is_corresponding":false},{"id":480474,"name":"Changcheng Zhou","orcid":"0000-0001-7649-0710","position":6,"is_corresponding":false},{"id":704718,"name":"Sandro Satta","orcid":"0000-0002-0827-8862","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:24:23.754337Z","pmid":"35401811","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}