Single-pore silica nanotherapeutic platform with pH-Responsive NO release for osteoporosis repair

Osteoporosis is a systemic bone disease with progressive deterioration of the bone microarchitecture. A key trigger for Osteoporosis is oxidative stress damage caused by reactive oxygen species (ROS). Nitric oxide (NO) can prevent excessive production of ROS in the bone microenvironment by regulating the abnormal opening of the mitochondrial permeability transition pore (mPTP). NO, as a highly active molecule, also plays an important role in bone regeneration and bone remodeling. However, its short half-life and unstable release severely limit its clinical application. Herein, a pH-responsive NO-releasing nanotherapeutic platform (GSCe NPs) was developed. Single-pore silica nanoparticles (SPMSNs) were synthesized via calcination of nano selenium core, enabling high loading of the NO donor S-nitrosoglutathione (GSNO). GSNO@SPMSN was aminated and coated with Cerium dioxide (CeO 2 ) to form GSCe NPs. The CeO 2 outer layer protected NO from premature release, scavenged ROS to prevent NO oxidation, and catalyzed acid-triggered NO generation in the osteoporotic microenvironment. Released NO suppressed mPTP opening, inhibiting ROS accumulation and apoptosis. In dibutyl phthalate (DBP) and dexamethasone (DEX) treated mouse osteoblastic cell lines (MC3T3-E1), GSCe NPs enhanced proliferation, calcium deposition, and alkaline phosphatase (ALP) expression while restoring mitochondrial function. In ovariectomized mice, GSCe NPs improved bone microstructure, increased bone mass, and upregulated osteogenic markers including collagen type I (Col-I), bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) with minimal toxicity. This pH-responsive NO-releasing platform offers a targeted strategy for osteoporosis repair by synergistically regulating ROS/NO/mitochondrial pathways.