Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing colon inflammation. Side effects and drug resistance limit current therapies. Andrographolide (AG), an NF-κB pathway inhibitor, shows promise in UC treatment but suffers from poor oral bioavailability. In this study, Paederia scandens-derived exosome-like nanoparticles (P-ELNs) were used as a delivery system to enhance the therapeutic efficacy of AG in UC. P-ELNs were extracted from Paederia scandens leaves and characterized for size, zeta potential, and morphology using transmission electron microscopy (TEM) and nanoparticle tracking analysis. AG was loaded into P-ELNs (AG-P-ELNs), and the complex was characterized for encapsulation efficiency using high-performance liquid chromatography (HPLC). The anti-inflammatory effects of AG, P-ELN, and the AG-P-ELNs complex were assessed in LPS-stimulated RAW264.7 macrophages (in vitro) and in a dextran sulphate sodium (DSS)-induced colitis mouse model (in vivo). According to the results, AG-P-ELNs demonstrated a high encapsulation efficiency of 38.64 % and a stable dispersion system with a zeta potential of -38.55 mV, indicating good colloidal stability. In vitro, AG-P-ELNs significantly reduced the production of pro-inflammatory cytokines IL-1β, IL-6, IL-18 and TNF-α, promoting M1 macrophage polarized to M2. In vivo, AG-P-ELN treatment ameliorated DSS-induced colitis, normalized colon length, and mitigated inflammatory cell infiltration. The AG-P-ELN group showed the lowest NF-κB, NLRP3, and iNOS expression, suggesting a synergistic therapeutic effect in modulating macrophage polarization and inflammation. P-ELNs effectively enhance the bioavailability and therapeutic efficacy of AG in treating UC by improving its solubility, stability, and cellular uptake while modulating macrophage polarization and inflammation. This study provides a novel approach for the delivery of AG and highlights the potential of plant-derived nanoparticles in inflammatory bowel disease management.