Hyaluronic acid-coated ROS-responsive mesoporous organosilica nanoparticles for enhanced curcumin delivery and redox remodeling in liver fibrosis

Liver fibrosis is associated with persistent oxidative stress, hepatic stellate cell (HSC) activation, and excessive extracellular matrix deposition. Here, we developed hyaluronic acid-coated, phenylboronic acid-modified mesoporous organosilica nanoparticles loaded with curcumin (MON-PBA@Cur@HA, MPCH) to improve curcumin delivery in liver fibrosis. The platform combined mesoporous organosilica-mediated drug loading, H 2 O 2 -responsive release, and HA-associated cellular uptake. MPCH nanoparticles exhibited good dispersion stability, and concentration-dependent H 2 O 2 -responsive release of intact curcumin. In TGF-β1-activated LX-2 cells, MPCH enhanced cellular uptake, reduced intracellular oxidative stress, and suppressed fibrogenic and activation-associated markers. Free HA competition markedly reduced MPCH uptake, supporting the involvement of CD44-associated interactions. In a CCl 4 -induced mouse model, MPCH produced stronger and more sustained liver-associated fluorescence than the HA-uncoated formulation and attenuated oxidative stress, inflammatory responses, collagen accumulation, and histopathological injury. Metabolomic and molecular analyses further indicated that these effects were associated with redox metabolic remodeling, NRF2-associated antioxidant responses, and modulation of autophagy-related signaling. Collectively, MPCH provides a microenvironment-responsive organosilica delivery strategy that improves the therapeutic performance of curcumin and may offer a useful basis for the delivery of other hydrophobic antifibrotic agents.