Biomimetic carboxymethyl β-glucan-ZIF-8 nanocarrier enhances structural stability, gastrointestinal release, and antioxidant efficacy of urolithin A via dectin-1-engaged mitophagy

The clinical translation of urolithin A (UA), an ellagitannin-derived metabolite with antioxidant and mitophagy-inducing properties, is hampered by its poor solubility, limited stability, and low oral bioavailability. To address these limitations, we developed a core-shell nanoplatform (UA@ZIF-8@CMG) comprising a ZIF-8 core for efficient encapsulation and a carboxymethyl β-glucan (CMG) shell for enhanced stability and potential targeting. The optimized formulation exhibited a high drug-loading capacity (12.65 %), markedly improved UA stability, and demonstrated pH-responsive release, with minimal leakage (22 %) under simulated gastric conditions followed by sustained release in the intestinal environment. In vitro studies revealed reduced cytotoxicity and a dual cellular uptake mechanism, involving putative Dectin-1-mediated endocytosis in macrophages and nonspecific uptake in intestinal cells. This uptake profile resulted in superior preservation of mitochondrial membrane potential and more effective ROS scavenging compared with free UA. The key innovation of this system lies in the synergistic ZIF-8@CMG architecture, which integrates robust protection, controlled release, and cell-type-specific uptake, thereby distinguishing it from previously reported delivery platforms. Collectively, this work presents a translatable strategy to enhance UA bioavailability and therapeutic performance, underscoring its promise for both nutraceutical and pharmaceutical applications.