Oral Colon- and Mitochondria-Targeted Nanoparticles Alleviate Ulcerative Colitis by Reeducating Macrophage Polarization via SIRT3/FOXO3a-Mediated Mitochondrial Restoration.

BACKGROUND AND AIM: Mitochondrial dysfunction in macrophages drives pro-inflammatory M1 polarization in ulcerative colitis (UC). We developed a colon-targeted, mitochondria-directed nanoplatform (KSF@SS31@S100Ns) to restore mitochondrial fitness and alleviate UC. METHODS: Kaempferol-loaded silk fibroin (SF) nanoparticles were conjugated with SS-31 peptide and coated with pH-sensitive Eudragit S100. Physicochemical properties, release profile, and uptake were characterized. Mitochondrial function, macrophage polarization, and SIRT3/FOXO3a signaling were assessed in LPS-stimulated RAW264.7 cells. Efficacy and mechanisms were evaluated in a DSS-induced colitis mouse model. RESULTS: Nanoparticles showed uniform size (~307 nm), high stability, and pH-dependent release. SS-31 enhanced macrophage uptake and mitochondrial localization. In vitro, KSF@SS31Ns restored mitochondrial membrane potential and ATP, reduced ROS, promoted mitophagy, and shifted macrophages toward the M2 phenotype via SIRT3/FOXO3a activation. In vivo, oral KSF@SS31@S100Ns accumulated in inflamed colons, reduced disease severity, suppressed pro-inflammatory cytokines, elevated IL-10, restored tight-junction proteins, and increased M2 macrophages. CONCLUSIONS: KSF@SS31@S100Ns effectively treats experimental colitis by restoring mitochondrial homeostasis, reprogramming macrophage polarization, and repairing the intestinal barrier, offering a translational nanotherapeutic strategy for UC.