TMEM16A Channel Blockade and Strontium/ROS Regulation by Carrier‐Free Nanoprodrug to Reconstruct Bone Homeostasis for Enhanced Osteoporosis Prevention and Treatment

Abstract Osteoporosis is a prevalent bone disorder caused by an imbalance between bone resorption and formation, leading to bone loss and increased fracture risk. Current clinical treatments primarily focus on inhibiting osteoclast activity but ignore restoring bone homeostasis. In this work, we developed a bone‐targeting and pH‐responsive carrier‐free nanoprodrug (HA–SrO 2 –TF NPs) to reconstruct bone homeostasis for osteoporosis prevention and treatment. Under the acidic bone resorption lacuna microenvironment (pH = 3–4), the HA–SrO 2 –TF NPs are completely decomposed to strontium ions, hydrogen peroxide, and theaflavin. Theaflavins downregulate osteoclast activity by inhibiting transmembrane protein 16A (TMEM16A) ion channel, which is identified as a novel drug target for osteoporosis in the previously studies. Concurrently, H 2 O 2 induces apoptosis of mature osteoclasts. Furthermore, Sr 2+ not only inhibits the differentiation of osteoclasts by enhancing the osteoprotegerin/receptor activator of nuclear factor‐κB ligand ratio, but also promotes osteoblast activity through the Wnt/β‐catenin signaling pathway. Through rebalancing bone resorption and formation, the HA–SrO 2 –TF NPs effectively enhance the trabecular bone mass volume and microstructure of osteoporotic ovariectomy mice. This study provides a biosafe therapeutic to target the ion channels and metal ions to reconstruct bone homeostasis for the prevention and treatment of osteoporosis.