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

ABSTRACT Osteoarthritis (OA) progression is driven by a chronic inflammatory microenvironment involving aberrant macrophage polarization and oxidative stress. Although the endogenous gasotransmitter hydrogen sulfide (H 2 S) 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 H 2 S 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‐H 2 S‐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 Zn 2+ and H 2 S. 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‐H 2 S‐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 H 2 S delivery strategy that enables precise immunomodulation, providing a feasible therapeutic approach for OA and other inflammation‐associated disorders.