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Complement activation induces C5a production, which signals through the C5a<jats:sub>1<\/jats:sub> receptor (C5aR1) to drive inflammatory responses that may underlie IBD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We examined mucosal biopsies from ulcerative colitis patients and identified C5a<jats:sub>1<\/jats:sub> receptor up\u2010regulated in active lesions, supporting the C5a<jats:sub>1<\/jats:sub> receptor as a target for therapeutic intervention. Cyclic peptide C5a<jats:sub>1<\/jats:sub> receptor antagonists such as PMX205 are orally efficacious in preclinical colitis models; however, their clinical application may be limited by rapid metabolism. We therefore encapsulated PMX205 within pH\u2010sensitive polymers to target drug for colon delivery following oral administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>PMX205 nanoparticles were non\u2010toxic and released bioactive PMX205 in simulated colon fluid. In vivo imaging of Cy5\u2010labelled nanoparticles demonstrated rapid entry and persistence in the mouse colon for up to 48\u2009h. Next, we utilised the dextran sodium sulphate\u2010induced colitis model to examine efficacy of the C5a<jats:sub>1<\/jats:sub> receptor\u2010antagonist formulation. We show that oral administration of PMX205 nanoparticles every 2\u2009days from symptom onset significantly mitigated weight loss, clinical illness, colon length reduction and epithelial damage to a similar degree as C5a<jats:sub>1<\/jats:sub> receptor<jats:sup>\u2212\/\u2212<\/jats:sup> mice. Notably, unformulated PMX205 was markedly less effective in this dosing regimen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>This novel colon\u2010targeted formulation therefore offers a potent therapeutic strategy for translating C5a<jats:sub>1<\/jats:sub> receptor antagonists for IBD conditions such as ulcerative colitis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70056","type":"journal-article","created":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T19:30:01Z","timestamp":1745782201000},"page":"3852-3869","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Colon\u2010targeted complement C5a<sub>1<\/sub> receptor inhibition using pH\u2010sensitive nanoparticles ameliorates experimental colitis"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0534-027X","authenticated-orcid":false,"given":"Cedric 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