Antibiotic-free control of infectious osteoarthritis by ROS-responsive hydrogen sulfide nanodepots

Osteoarthritis (OA) is the most common degenerative joint disease in the elderly, which sometime accompanies with bacterial infection. Hydrogen sulfide (H₂S) gas delivery into cells has potential for treatment of infected OA. However, achieving controllable and sustained release of H₂S for infected OA therapy continues to pose considerable challenges, attributable to the high diffusivity and exceedingly short half-life of H₂S under physiological conditions. Herein, an injectable, pH-responsive, and multifunctional hydrogel (HSNP@HA) is constructed for dressing infected OA. The thioketal (TK)-linked dimeric dopamine conjugate and H₂S donor (HSD) was designed to form nanoparticles (HSNP) featuring ROS-responsibility, H₂S release as well as antibacterial property. HSNPs were further incorporated into a pH-responsive hydrogel based on Schiff base cross-linking, which can gradually degrade under the acidic microenvironment of infected OA and lead to controlled and sustained release of HSNPs. Guided by this design, the hemocompatibility and cytocompatibility, H₂S release and ROS quenching, antibacterial and anti-biofilm efficacy, macrophage polarization and inflammatory signaling were synergically achieved, giving rise to attenuates inflammatory cascades, preserves collagen II/proteoglycans, and normalizes subchondral microarchitecture in a bacteria-induced OA model. This work therefore provides a unified, translational strategy for infectious OA. STATEMENT OF SIGNIFICANCE: Joint infections worsen osteoarthritis and are hard to treat because antibiotics do not stay in the joint and biofilms resist drugs. We introduce a syringeable hyaluronic-acid hydrogel that forms a local depot for nanoparticles releasing the gasotransmitter hydrogen sulfide (H₂S) only when inflammatory oxidants are present. This antibiotic-free approach couples on-demand antibacterial action with reduction of oxidative stress and immune rebalancing, protecting cartilage and subchondral bone in rats. Compared with prior hydrogels or H₂S donors, our system provides sustained intra-articular delivery, biofilm disruption, and disease modification in one material. The platform shows how smart biomaterials can locally control infection and inflammation while limiting systemic exposure and resistance.