Development of a novel macroscopic regulation and microscopic intervention mode nanosystem for osteoporosis treatment.

Osteoporosis is a widespread global health issue characterized by progressive bone loss and impaired regeneration, largely due to an acidic bone microenvironment that suppresses osteoblast differentiation and fails to initiate effective osteogenesis. To address these challenges, we developed a novel bone-targeted nanosystem (RE@CR) based on rare-earth upconversion/downconversion nanoparticles (RENPs), integrating macroscopic environmental modulation with precise microscopic molecular-level intervention. RE@CR utilizes CaCO to neutralize local acidity, enhance osteoblast proliferation, and release Ca to support mineralization. Upon degradation, romosozumab is controllably released to inhibit sclerostin (SOST), while laser-triggered activation of endogenous nitric oxide (NO) stores suppresses Dickkopf-1 (DKK1). This dual-targeted activation of the Wnt/β-catenin pathway synergistically restores the osteogenic niche and promotes new bone formation. The system's efficacy has been validated in both and osteoporosis models. Our work presents a promising therapeutic platform that combines macro-regulation and micro-intervention to address the multifactorial pathology of osteoporosis and enable precise, efficient bone regeneration.