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The development of therapeutic agents and strategies capable of responding to future outbreaks caused by emerging coronavirus variants remain an ongoing priority. Here, we engineered a single-stranded DNA aptamer (NApt8-3) that selectively binds to the conserved nucleocapsid (N) protein shared among multiple coronaviruses, including SARS-CoV-2 (wild-type, beta, omicron variant), SARS-CoV, MERS-CoV, HCoV-OC43 and HCoV-229E, and strongly inhibits N protein-induced inflammatory cytokine expression. Mechanistically, NApt8-3 effectively binds to the N protein and blocks its interaction with the NLRP3 inflammasome, a key mediator of coronavirus-induced inflammation. To enable intracellular delivery and evaluate its therapeutic potential, we developed a proof-of-concept anti\u2013SARS-CoV-2 agent\u2014circSASON, a circular trivalent aptamer\u2013antisense oligonucleotide (ASO) chimera\u2014combining NApt8-3, an antispike protein aptamer, and an ASO that silences the N gene. In vitro experiments demonstrated that circSASON effectively inhibits SARS-CoV-2 replication and suppresses N protein-induced cytokine expression in host cells. The intranasal administration of circSASON significantly decreased the level of SARS-CoV-2 and alleviated SARS-CoV-2-induced pulmonary inflammation and inflammatory cytokine expression in mice. Therefore, our findings highlight NApt8-3 as a broad-spectrum anti-inflammatory agent that targets the conserved coronavirus N protein. The therapeutic design strategy employed, together with the N aptamer developed in this study, may offer a framework for the rapid development of treatments to combat future pandemics caused by emerging coronavirus variants.<\/jats:p>","DOI":"10.1038\/s41392-025-02570-8","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:03:39Z","timestamp":1770941019000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting coronaviral inflammation: aptamer-based strategies for emerging threats"],"prefix":"10.1038","volume":"11","author":[{"given":"Yongyun","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfeng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duhan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longteng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongli","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-5589","authenticated-orcid":false,"given":"Jincun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajing","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"2570_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","volume":"17","author":"J Cui","year":"2019","unstructured":"Cui, J., Li, F. & Shi, Z.-L. 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