"Platelet-coated bullets" biomimetic nanoparticles to ameliorate experimental colitis by targeting endothelial cells.

ABSTRACT

Intestinal vascular impairment is critical to the recovery of inflammatory bowel disease (IBD), and targeting vascular endothelial cells is a promising emerging therapeutic option. Considering the natural homing properties of platelets to activated vascular endothelium, platelet membrane-mimetic nanoparticles are expected to achieve precise treatment of IBD. Patchouli alcohol (PA) has proven efficacy in experimental colitis, yet its pharmacochemical properties require improvement to enhance efficacy. The rationale for targeting vascular lesions in IBD was analyzed by network pharmacology, and PA-affecting pathways were predicted. PA-encapsulated bio-nanoparticles (PNPs) were constructed to investigate the efficacy of agents on mouse intestinal microvascular endothelial cells (MIMVEC) inflammation model and dextran sulfate sodium (DSS)-induced acute mouse colitis model. PNPs were endocytosed by MIMVEC in vitro and efficiently enriched in inflamed colon. PNPs significantly alleviated the symptoms of experimental colitis and improved neutrophil infiltration. PNPs down-regulated LPS-induced aberrant elevation of il1ß, tnfα and il6 mRNAs and reduced p65 phosphorylation in MIMVEC. Intracellular calcium expression, mitochondrial respiration and reactive oxygen species expression were also downregulated by PNPs. PNPs amplified the potency of PA as a calcium antagonist, restrained intracellular Ca2+ perturbations to prevent endothelial activation, which may block leukocyte recruitment in vivo to improve colitis.