Spatiotemporally adaptive metal-gas nanotherapy: Acid-triggered cascade release for osteoporosis treatment

The treatment of osteoporosis remains a critical challenge due to the limitations of current therapies in simultaneously restoring homeostasis of bone metabolism and modulating the chronic inflammation of bone microenvironment. While the acidic microenvironment greatly exacerbates bone resorption, it also lays the foundation for the application of responsive therapeutic nanoplatforms. Herein, inspired by the rocket-like responsive cascade release principle-defined by a “booster-payload” mechanism, in which a metal ion-doped mesoporous silica shell serves as an early-release booster and a calcium sulfide core acts as a sustained-release payload-a bone-targeted nanoplatform (CSM 3 P) was developed. This platform integrates calcium sulfide nanoparticles with magnesium/manganese-doped mesoporous silica for bone targeting. It leverages the pathological acidic microenvironment of osteoporosis to enable stimuli-responsive and stepwise release of multiple mineral ions (Mg 2+ /Mn 2+ /Ca 2+ ) and hydrogen sulfide (H 2 S), coordinates bone regeneration and regulation of the osteoimmunological microenvironment and thereby achieves metal-gas targeted therapy for osteoporosis. This acidic responsive and sequential ion/gas release model establishes a self-reinforcing therapeutic cycle, where the pathological acidity itself drives a synergistic and adaptive treatment regimen. Both in vitro and in vivo evaluations demonstrate the superior efficacy of CSM 3 P in ameliorating the inflammatory bone microenvironment and rebalancing bone remodeling. This work offers a novel paradigm for intelligent, feedback-driven nanotherapy against osteoporosis and other microenvironment-associated diseases. • A bone-targeting nanoplatform (CSM3P) triggers cascade release of H 2 S and therapeutic metal ions in acidic osteoporotic niches. • CSM 3 P integrates gas therapy and metal ion supplementation via a spatiotemporally adaptive mechanism. • CSM 3 P attenuates inflammation by suppressing cytokines and driving M2 macrophage polarization. • CSM 3 P rebalances bone remodeling by inhibiting osteoclastogenesis and enhancing osteogenesis.