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Reducing the incidence of sepsis is of paramount importance. Given that sepsis-associated drugs largely fail in clinical trials, in this project, we devised and validated a novel long-acting C5a-blocking cyclic peptide drug (Cp1) via phage screening technology to block the upstream \u201cbottleneck molecule\u201d C5a-mediated amplification cascade of the inflammatory response. In the early stage of infection, we utilized the efficient neutralization of Cp1 against C5a to effectively curb the \u201cwaterfall effect\u201d of inflammatory factors and mitigate the progression to dysregulated systemic inflammation, thereby providing effective prevention and therapeutic intervention for sepsis. First, in vitro and in vivo studies collectively demonstrated the optimal binding affinity and blocking selectivity of Cp1. The excellent plasma stability of Cp1 further endows it with antibody-like systemic circulation. In the CLP-induced sepsis model, Cp1 significantly suppressed the expression of inflammatory factors and chemokines in both plasma and peritoneal lavage fluid (PLF). Additionally, Cp1 potently inhibited innate immune injury. Ultimately, after a single administration of Cp1, the CLP-induced septic mice presented a significant reduction in bacterial burden, evident amelioration of organ dysfunction, and notable prolongation of survival time. Overall, the novel cyclic peptide drug Cp1 developed in this study is a highly promising and cost-competitive therapeutic option for sepsis prophylaxis and therapy.<\/jats:p>","DOI":"10.1038\/s41392-025-02457-8","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T23:02:25Z","timestamp":1762297345000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A novel long-acting C5a-blocking cyclic peptide prevents sepsis-induced organ dysfunction via effective blockade of the inflammatory cascade"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-3004","authenticated-orcid":false,"given":"Zimiao","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichu","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyue","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8192-2693","authenticated-orcid":false,"given":"Zhaofan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"2457_CR1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer, M. et al. 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