Targeted Intracellular Hydrogen Sulfide Delivery to Inflammatory Macrophages Reprograms Polarization and Mitigates Oxidative Stress in Osteoarthritis.

Osteoarthritis (OA) progression is driven by a chronic inflammatory microenvironment involving aberrant macrophage polarization and oxidative stress. Although the endogenous gasotransmitter hydrogen sulfide (H2S) possesses potent anti-inflammatory and antioxidant properties, its therapeutic application is hindered by rapid clearance, uncontrolled release profiles, and a narrow therapeutic window. Here, we present a macrophage-targeted and pH-responsive H2S delivery nanoplatform constructed by encapsulating acid-labile zinc sulfide within a zeolitic imidazolate framework-8 (ZIF-8) and functionalizing the nanoparticle surface with folate ligands (ZIF-H2S-FA). This strategy exploits the overexpression of folate receptors on pro-inflammatory M1 macrophages to ensure preferential cellular uptake. Following endocytosis, lysosomal acidity triggers framework degradation, sustaining the intracellular release of Zn2+ and H2S. These components synergistically scavenge reactive oxygen species (ROS) and suppress NF-κB signaling, effectively reprogramming macrophages from an inflammatory toward a regenerative M2 phenotype. In a rat OA model, intra-articular administration of ZIF-H2S-FA demonstrates prolonged joint retention, effective scavenging of oxidative stress, alleviation of cartilage destruction, and reduced osteoclast activity, without systemic toxicity. This study establishes a targeted H2S delivery strategy that enables precise immunomodulation, providing a feasible therapeutic approach for OA and other inflammation-associated disorders.