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 (H2S) delivery system (ZIF‐H2S‐SDSSD) is designed to simultaneously promote fracture healing and alleviate osteoporosis. With bone‐targeting peptide SDSSD grafted on the surface, ZIF‐H2S‐SDSSD nanoparticles release H2S in bone tissues without affecting the serum H2S level, thereby mitigating potential risks of systematic H2S delivery. Upon cellular uptake, the acidic environment in lysosomes drives the release of H2S from the encapsulated zinc sulfide in conjunction with the degradation of ZIF. The synergistic effects of released Zn2+ and H2S 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.