Multilayer UiO-66-NH₂@CS/HA-PNIPAM Nanocomposite for Dual-Responsive Dexamethasone Delivery and Anti-Inflammatory Activity

Abstract

Dexamethasone (DEX) is an effective anti-inflammatory drug; however, its therapeutic application can be limited by rapid drug diffusion and insufficient control over the local release profile. In this study, a multifunctional DEX-loaded UiO-66-NH₂@chitosan/hyaluronic acid–poly(N-isopropylacrylamide) (UiO-66-NH₂@CS/HA-PNIPAM) nanocomposite was developed as a dual pH/temperature-responsive drug delivery platform. DEX was incorporated into porous UiO-66-NH₂ nanoparticles, followed by sequential coating with CS/HA and a thermoresponsive PNIPAM layer. The physicochemical properties, drug encapsulation, swelling behavior, temperature responsiveness, in vitro release, stability, cytocompatibility, and anti-inflammatory activity of the formulations were evaluated. The final F4 formulation exhibited an encapsulation efficiency of 86.7±2.0% and a particle size of 251.8±9.1 nm, with a polydispersity index of 0.26±0.03. F4 showed pronounced pH-dependent swelling, increasing from 48.7±3.5% at pH 5.5 to 82.6±4.8% at pH 7.4, while its particle size decreased from 251.8±9.1 nm at 25°C to 211.4±7.1 nm at 37°C, demonstrating temperature-responsive behavior. At pH 7.4 and 37°C, the 24-h cumulative DEX release from F4 was 43.5±2.1%, compared with 78.4±3.1% for the uncoated formulation. The nanocomposite-maintained cell viability above 90% at concentrations up to 100 μg/mL. In an LPS-induced inflammatory model, F4 reduced TNF-α and IL-6 concentrations to 108.6±7.5 and 82.3±6.9 pg/mL, respectively, compared with 286.7±14.8 and 238.5±12.6 pg/mL for the LPS control. The developed UiO-66-NH₂@CS/HA-PNIPAM nanocomposite provided controlled DEX release together with pH/temperature-responsive behavior, acceptable cytocompatibility, and enhanced anti-inflammatory activity, supporting its potential as a multifunctional platform for controlled anti-inflammatory drug delivery.