Abstract

Rationale Inflammatory bowel disease (IBD), known for its complexity and frequent relapses, urgently demands novel therapeutics due to the limited efficacy of current treatments. Cinnamaldehyde (CMA), a bioactive compound derived from Cinnamomum cassia Presl, has exhibited therapeutic potential for IBD. However, the therapeutic mechanism of CMA remains incompletely elucidated, and clinical translation is hampered by its poor oral pharmacokinetics. Methods Using RAW 264.7 cells stimulated with either LPS or IL-4, we evaluated the effects of CMA on macrophage polarization. Subsequently, the impact of CMA on glucose metabolism in M1 macrophages was analyzed. RNA sequencing identified the signaling pathways through which CMA inhibits M1 macrophage polarization, and this was further validated through genetic or pharmacological blockade. To overcome the pharmacokinetic challenges of CMA, macrophage membrane-biomimetic CMA-loaded nanoparticles (MM@CMANP) were designed, and their pharmacokinetics and targeting to intestinal inflammation sites were evaluated. Finally, the efficacy of MM@CMANP was assessed in DSS-induced IBD mice. Results CMA suppresses M1 macrophage polarization in vitro . Notably, CMA disrupted M1 macrophage glucose metabolic reprogramming, characterized by glycolysis suppression and enhanced oxidative phosphorylation. RNA sequencing demonstrated a clear association with mitophagy pathway following CMA treatment, and mechanistic studies verified that CMA promotes BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy activation. Crucially, CMA-induced inhibition of M1 macrophages was mitigated by BNIP3 knockdown or autophagy inhibitors. MM@CMANP enhanced CMA accumulation in inflamed colonic tissues. In IBD mice, MM@CMANP significantly alleviated epithelial barrier disruption and mucosal inflammation. Consistent with in vitro findi