A dual pH/ROS-responsive hyaluronan-gated hollow mesoporous silica nanoplatform with CD44-associated cellular interaction improves curcumin retention under serum challenge and attenuates TNF-α–driven inflammatory outputs in rheumatoid arthritis synov

Rheumatoid arthritis (RA) synovitis is driven in part by activated fibroblast-like synoviocytes derived from rheumatoid arthritis tissue (RA-FLS), which amplify inflammatory and oxidative pathways that contribute to progressive joint damage. Curcumin (CUR) is mechanistically relevant to these pathogenic processes; however, its therapeutic utility is constrained by poor aqueous solubility, low bioavailability, and non-selective exposure. Here, we developed a hollow mesoporous silica nanoparticle (HMSN)-based nanodelivery platform that integrates an HA outer gate with a dual pH/reactive oxygen species (ROS)-responsive interfacial design. Unlike passive HA-coated carriers, this system was designed to combine serum-phase CUR retention with condition-dependent HA gate remodeling and CD44-associated cellular interaction. The final HA-gated formulation preserved the hollow HMSN architecture, achieved high CUR incorporation (encapsulation efficiency 73.55 ± 3.06%; drug loading 18.39 ± 0.77% w/w), and showed reduced baseline leakage under neutral conditions with increased release under combined acidic/oxidative stimulation. HA shedding assays and bonding-mode controls further supported stimulus-selective gate detachment rather than simple adsorption-related loss. Under protein challenge, the HA-gated system reduced premature CUR leakage relative to ungated HMSNs. In RA-FLS, it increased cell-associated CUR signal in a CD44-associated manner and, at matched CUR-equivalent dosing, produced the strongest suppression of metabolic viability, DNA synthesis, TNF-α-induced inflammatory and matrix-associated mediators, and intracellular ROS, while showing improved tolerability in healthy synoviocytes compared with free CUR. These findings support this HA-gated dual pH/ROS-responsive HMSN system as an in vitro proof-of-concept nanodelivery platform for improving CUR retention and RA-FLS-directed functional activity under inflammatory microenvironment-relevant conditions.