ACS Nano. 2025 Dec 27. doi: 10.1021/acsnano.5c19260. Online ahead of print.
ABSTRACT
Postmenopausal osteoporosis (POP) in women caused by estrogen deficiency leads to an increase in reactive oxygen species (ROS) within the osteoporotic microenvironment, thereby promoting osteoclastogenesis mediated by the receptor activator of the nuclear factor-κb ligand (RANKL)/receptor activator of the nuclear factor-κB (RANK) pathway and further enhancing bone resorption. Currently available therapies based on hormone replacement, bisphosphonates, or denosumab increase the risk of cardiovascular diseases and osteonecrosis of the jaw. Here, we utilized a straightforward and green templating method to synthesize an alendronate (Aln)-modified large mesoporous platinum nanoframework (Pt NF) encapsulated with the transmembrane protein 16A (TMEM16A) channel inhibitor (TF@Pt-Aln). Leveraging the robust hydroxyapatite-binding affinity of alendronate (Aln), TF@Pt-Aln demonstrates precise targeting capability toward bone tissues, effectively releases the TMEM16A inhibitor theaflavin (TF), leading to a decrease in hydrogen ions (H+) excretion and effectively inhibiting the activation of the RANKL-RANK pathway, and attenuates osteoclast activity. Concurrently, the inherent antioxidant properties of both Pt NF and TF scavenge a broad spectrum of ROS, alleviating the ROS-enriched POP microenvironment and further inhibiting osteoclast differentiation. In vivo experimental results have confirmed that TF@Pt-Aln can enhance the trabecular bone mass and microarchitecture by inhibiting abnormal bone resorption, thereby reversing the progression of osteoporosis in ovariectomized (OVX) mouse models. Furthermore, TF@Pt-Aln exhibits excellent biocompatibility and reduces the risk of osteonecrosis of the jaw, rendering it a promising candidate for the clinical treatment of POP.
PMID:41454887 | DOI:10.1021/acsnano.5c19260