274: Sequence-Targeted Delivery Platforms: Responsive-Functionalized Hyaluronic Acid Coated Cyclodextrin Metal-Organic Framework Nanocubes for Precise Inflammation Targeting and Colitis Alleviation

Introduction

The interplay between intestinal immune homeostasis, mucosal barrier integrity, and microbiota composition is critical in the pathogenesis and progression of colitis. However, conventional first-line oral drug therapies for colitis often demonstrate limited efficacy and systemic off-target side effects due to a lack of multifunctional therapeutic management and targeted delivery.

Methods

To address these challenges, we developed a novel orally administered nanoplatform, QT-CMOF@HAS, featuring quercetin-loaded cyclodextrin metal-organic framework (CMOF) nanocubes encapsulated within a glutathione (GSH)-responsive hyaluronic acid shell (HAS). This system achieves sequential targeting, first to CD44-overexpressing inflammatory macrophages and subsequently to mitochondria, leveraging the mitochondrial-targeting properties of quercetin (QT).

Results

In both in vivo and in vitro studies, QT-CMOF@HAS demonstrated significant therapeutic benefits in colitis. It ameliorated the pro-inflammatory microenvironment and restored gut barrier integrity through multiple mechanisms, including oxidative stress reduction, promotion of type 2 macrophage polarization, and anti-inflammatory modulation via the TLR4/MyD88/NF-κB signaling pathway. Furthermore, QT-CMOF@HAS improved gut microbiota composition in colitis models, enhancing species uniformity, abundance, and diversity to achieve a healthier microbial state.

Significance

These findings highlight the potential of QT-CMOF@HAS as a multifunctional nanoplatform for targeted drug delivery and effective treatment of colitis, offering a promising avenue for advancing therapeutic strategies for inflammatory bowel disease.

Authors: Runan Zhao, Wenjun Wang, Beiwei Zhu, Donghong Liu, Jiangning Hu