Inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis involve chronic gastrointestinal inflammation. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) drives IBD pathogenesis. Anti-TNF-α therapies using monoclonal antibodies (mAbs) like infliximab (INF) help treat IBD but have limitations. We developed inflammation-targeting polyphenol-poloxamer nanoparticles loaded with the anti-inflammatory mAb INF (INF@PPNP) as a novel IBD therapy. Characterization showed that INF@PPNP had favorable stability and purity. Radiolabeling INF@PPNP with 89Zr enabled tracking localization with positron emission tomography (PET) imaging. Rectal administration of 89Zr-INF@PPNP led to colon delivery with remarkably reduced systemic exposure versus intravenous INF revealed by non-invasive PET imaging. 89Zr-INF@PPNP retention at inflamed foci indicated prolonged INF@PPNP action. INF@PPNP rectally achieved similar anti-inflammatory effects as intravenously injected INF, demonstrating the high therapeutic potential. Our findings support the use of nanoparticle-based rectal administration for localized drug delivery, prolonging drug activity and minimizing systemic exposure, ultimately offering an effective approach for treating IBD.