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Elevated levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF), signaling through their respective receptors, glycoprotein 130 (GP130)\/interleukin-6 receptor (IL-6R) and tumor necrosis factor receptor 2 (TNFR2), are independent predictors of disease severity and mortality. To address this challenge, a series of bifunctional and trifunctional decoy receptor fusion proteins were developed by fusing the extracellular domains of TNFR2 and\/or GP130 to an engineered angiotensin-converting enzyme 2 (ACE2) protein, the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Five mutations (T27F, K31Y, L79W, R273Q, and N330Y) were introduced into the ACE2 domain to enhance its binding affinity and neutralizing activity against a broad range of SARS-CoV-2 variants, including the currently circulating JN.1 variant. The TNFR2 and GP130 domain confer strong binding to TNF and IL-6R-IL-6 complex, respectively, thereby effectively blocking pro-inflammatory signaling pathways. In a mouse model of acute lung inflammation induced by R848, treatment with the bifunctional and trifunctional fusion proteins markedly attenuated pulmonary pathology by dampening IL-6\u2013 and TNF\u2013mediated inflammation. These findings demonstrate a promising therapeutic strategy for severe COVID-19 and offer a framework for designing multifunctional biologics against emerging viral infections.<\/jats:p>","DOI":"10.1186\/s43556-025-00320-4","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T23:01:55Z","timestamp":1760482915000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of a trispecific fusion protein based on angiotensin-converting enzyme 2, glycoprotein 130, and tumor necrosis factor receptor 2 as a promising therapeutic for COVID-19"],"prefix":"10.1186","volume":"6","author":[{"given":"Yongfeng","family":"Qiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxiong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yarong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianmei","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbo","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhida","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"issue":"1","key":"320_CR1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s12933-020-01047-y","volume":"19","author":"C Sardu","year":"2020","unstructured":"Sardu C, Gargiulo G, Esposito G, Paolisso G, Marfella R. 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The studies were conducted in accordance with the local legislation and institutional requirements.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Competing interests Z.L., P.H., C.D., Y.Q., Y.H., H.H. and L.Z. have filed a patent for protecting a bifunctional therapeutic protein ACE2 (M)-Fc-GP130-TNFR2 for the treatment of patients with SARS-CoV-2 infection. Author Hong Hu is an employee in Ankerui (Shanxi) Biological Cell Co, but has no potential relevant financial or non-financial interests to disclose. The other authors have no conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"74"}}