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

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. © 2024 Wiley-VCH GmbH.