pH/ROS dual-responsive injectable hydrogel based on an oxidized hyaluronic acid/carboxymethyl chitosan-phenylboronic acid dynamic network for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, aberrant immune activation, and progressive joint destruction. Its pathological progression is closely associated with synovial microenvironment acidification, excessive reactive oxygen species (ROS) accumulation, and sustained release of pro-inflammatory mediators. Developing localized therapeutic systems with microenvironment responsiveness and prolonged intra-articular retention is critical for improving RA treatment outcomes. In this study, we developed a pH/ROS-dual-responsive injectable hydrogel drug delivery system with sustained release capability. It was formed by crosslinking carboxymethyl chitosan-grafted phenylboronic acid (CMCS-PBA) and oxidized hyaluronic acid (OHA) through dynamic Schiff base and boronic ester bonds, and was co-loaded with dexamethasone sodium phosphate (DSP) and rosemarinic acid encapsulated in sialic acid-modified liposomes (RosA-SAL). The prepared hydrogel exhibited favorable injectability, self-healing capability, and biocompatibility, while enabling sustained drug release in response to the acidic and ROS-rich microenvironment. The in vitro release study showed that the cumulative release rates of DSP and RosA reached 95% and 67%, respectively, after 14 days under simulated RA microenvironment conditions. Additionally, in vitro studies demonstrated that RosA-SAL/DSP@Gel effectively reduced inflammatory cytokine expression and suppressed inflammation-related responses. Furthermore, in vivo experiments confirmed that the hydrogel system significantly alleviated joint inflammation in adjuvant-induced arthritis (AIA) rats, attenuated cartilage damage and bone erosion, and provided substantial protection to joint structures. Overall, this study presents an intelligent microenvironment-responsive drug delivery strategy for localized intra-articular therapy of RA.