Orally administered metal–organic framework nanocubes for sequence-targeted quercetin delivery in colitis alleviation

Inflammatory bowel disease (IBD) management is often hindered by limited efficacy and significant systemic side effects of traditional oral medications, owing to their lack of targeted delivery and multifunctional capabilities. This study introduces a novel orally sequence-targeted delivery system, QT-CMOF@HAS nanocube, based on hydrophobic cross-linked CD-MOF (CMOF) for the precise delivery of quercetin (Qu) to the inflamed colonic lesions. To enhance the mitochondrial targeting capabilities of Qu, a mitochondrial-functionalized Qu-(5-carboxypentyl) (triphenyl) phosphonium bromide (TPP) precursor complex (QT) was initially synthesized and loaded into the CMOF. A chitosan/glutathione-responsive hyaluronic acid (HAS) shell was subsequently coated onto the CMOF, forming the QT-CMOF@HAS nanoplatform to further enhance the gastrointestinal tolerance. Our results demonstrated that QT-CMOF@HAS significantly alleviated colitis symptoms by modulating the repolarization of pro-inflammatory M1 macrophages to anti-inflammatory M2 phenotypes and deactivation of the TLR4/MyD88/NF-κB pathway, thus reducing the production of inflammatory cytokines. Furthermore, the integrity of the intestinal mucosal barrier and the gut microbiota were enhanced. This study highlights the potential of QT-CMOF@HAS nanocube as a promising therapeutic tool for IBD treatment, offering a multifaceted approach to tackle inflammation and support mucosal healing in a targeted and controlled manner.