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.