Chemotaxis-driven hybrid liposomes recover intestinal homeostasis for targeted colitis therapy

Abstract

Inflammatory bowel disease (IBD) is closely linked to the dysregulation of intestinal homeostasis, accompanied by intestinal epithelial barrier destruction, dysbiosis of gut microbiota, subsequent inflammatory factor infiltration, and excessive oxidative stress. Conventional therapeutics focus on suppressing inflammation and often suffer from metabolic instability as well as limited targeting, thereby leading to suboptimal remission rates and severe side effects. Here, we designed bacterial outer membrane vesicle (OMV, from Stenotrophomonas maltophilia)-fused and borneol-modified liposomes (BO/OMV-lipo@LU) for targeted delivery of luteolin to recover intestinal homeostasis by alleviating inflammation and modulating dysregulated intestinal epithelial barrier, redox balance, and gut microbiota in IBD. In a Caco-2/HT29-MTX monolayer model, the OMV and borneol-bifunctionalized liposomes enhanced the uptake efficiency of unfunctionalized liposomes with a 2-fold increase. Owing to the chemotaxis-driven colon-targeting ability of OMVs and the ability of borneol to promote intestinal epithelial uptake, the hybrid liposomes successfully targeted the inflamed colon. In a colitis mouse model, BO/OMV-lipo@LU exhibited enhanced efficacy following oral administration. The BO/OMV-lipo@LU treatment increased the colon length and body weights of mice suffering colitis by 40 % and 15 %, respectively, with values comparable to the healthy control group. Notably, BO/OMV-lipo@LU alleviated proinflammatory markers, modulated redox balance, and restored the intestinal epithelial barrier. In addition, the formulation increased the abundance of beneficial microbiota while decreasing the abundance of harmful microbiota. These results demonstrated that this biomimetic nanoplatform could be exploited as a safe and effective gut-targeted delivery system in IBD treatment.