A Bone‐Targeting Hydrogen Sulfide Delivery System for Treatment of Osteoporotic Fracture via Macrophage Reprogramming and Osteoblast‐Osteoclast Coupling

Abstract The demand for systemic treatment of osteoporotic fractures to reduce recurrence is increasing, but current anti‐osteoporosis medications exhibit unsatisfactory efficacy due to adverse events and limited effects on fracture healing. Herein, a bone‐targeting zeolitic imidazolate framework‐8 (ZIF)‐based hydrogen sulfide (H 2 S) delivery system (ZIF‐H 2 S‐SDSSD) is designed to simultaneously promote fracture healing and alleviate osteoporosis. With bone‐targeting peptide SDSSD grafted on the surface, ZIF‐H 2 S‐SDSSD nanoparticles release H 2 S in bone tissues without affecting the serum H 2 S level, thereby mitigating potential risks of systematic H 2 S delivery. Upon cellular uptake, the acidic environment in lysosomes drives the release of H 2 S from the encapsulated zinc sulfide in conjunction with the degradation of ZIF. The synergistic effects of released Zn 2+ and H 2 S promote macrophage metabolic reprogramming by suppressing succinate accumulation and mitochondrial reactive oxygen species (mtROS) production, and further regulate osteoblast‐osteoclast coupling. Overall, this strategy holds great promise in the clinical treatment of osteoporotic fractures and broadens the application of nanomedicine therapy for orthopedic diseases.