Carboxymethylated Laminarin-Decorated ZIF-8 Enables Macrophage-Targeted Quercetin Delivery with Superior Anti-Inflammatory Efficacy.

To address the limitations of quercetin (Qu), including low bioavailability, limited targeting, and insufficient synergistic enhancement, we developed a ZIF-8-based nanodelivery system (Qu-ZIF-8-CMLA) coated with a carboxymethyl laminarin (CMLA) layer. The platform was designed for macrophage-targeted delivery with potential for oral administration. Qu-ZIF-8-CMLA exhibited a hydrodynamic diameter of 151.5 nm, a drug loading capacity of 15.2%, and colloidal stability. Characterization confirmed CMLA coating of the Qu-ZIF-8 surface through electrostatic interactions and hydrogen bonding. The resulting nanoparticles maintained structural integrity and exhibited pH-responsive, controlled-release properties. In simulated gastric fluid, Qu-ZIF-8-CMLA released 23.54% of the Qu, whereas release reached 70.08% under simulated intestinal conditions, indicating a more sustained release profile than free Qu. Release kinetic analysis suggested a non-Fickian mechanism involving polysaccharide erosion and drug diffusion. In RAW264.7 macrophages, CMLA modification increased uptake by 6.35-fold, while competitive inhibition with free CMLA significantly attenuated this enhancement, supporting the involvement of CMLA-sensitive receptor-associated recognition in macrophage uptake. At high concentrations, Qu-ZIF-8-CMLA maintained higher RAW264.7 cell viability than Qu-ZIF-8 under the tested conditions. Anti-inflammatory activity was evaluated in LPS-stimulated RAW264.7 macrophages by measuring TNF-α, IL-1β, and IL-6 secretion using ELISA. Qu-ZIF-8-CMLA significantly reduced three pro-inflammatory cytokines compared with the LPS model group, and no statistically significant differences were detected between the Qu-ZIF-8-CMLA and untreated control groups (p > 0.05). Qu-ZIF-8-CMLA showed significantly greater anti-inflammatory activity than free Qu and Qu-ZIF-8. Collectively, these findings provide in vitro proof of concept for CMLA-modified, macrophage-targeted Qu delivery and support further investigation of this platform for oral anti-inflammatory applications.