2. Academic Validation
  3. Designed bone-targeting ROS-responsive nanoplatform for precision glycolysis inhibition in postmenopausal osteoporosis

Designed bone-targeting ROS-responsive nanoplatform for precision glycolysis inhibition in postmenopausal osteoporosis

  • Bioact Mater. 2025 Nov 29:58:1-18. doi: 10.1016/j.bioactmat.2025.11.032.
Qihang Wu 1 2,  Jiansen Miao 1 2,  Yu Chen 1 2,  Yayun Yang 3,  Haibo Liang 1 2,  Chenxin Yu 2 4,  Chenyu Wang 2,  Yiting Tu 1 2,  Yinuo Wu 2,  Yining Xu 1 2,  Xiao Yang 3,  Kenny Yat Hong Kwan 5,  Changcan Shi 3,  Xiangyang Wang 1 2,  Jiake Xu 1 6 7,  Haiming Jin 1 7 2
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 2 The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 3 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325011, China.
  • 4 Department of Endocrinology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 5 Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 5/F Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong, China.
  • 6 Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518107, China.
  • 7 School of Biomedical Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
PMID: 41403870 DOI: 10.1016/j.bioactmat.2025.11.032
Abstract

Postmenopausal osteoporosis (PMOP) arises from estrogen deficiency, which disrupts bone remodeling by shifting the balance toward bone resorption over osteogenesis. Glycolytic regulation has emerged as a critical mechanism governing osteoclast differentiation and resorptive activity. Blocking lactate transport through monocarboxylate transporters (MCTs) suppresses glycolysis, thereby attenuating these processes and highlighting MCT inhibition as a potential therapeutic target. The MCT inhibitor AZD3965 blocks lactate transport, thereby downregulating NF-κB/MAPK signaling, increasing intracellular lactate levels, and ultimately suppressing osteoclast formation and bone resorption in vitro. To achieve targeted delivery and reduce off-target effects, a bone-targeted, Reactive Oxygen Species (ROS)-responsive nanocarrier (PH/DPA@A) was engineered by integrating a bone-affinitive DSPE-PEG-Asp8 (DPA) ligand with a ROS-cleavable phenylboronic acid pinacol ester-hyaluronic acid (PH) shell to encapsulate AZD3965. The nanoparticles exhibited a mean diameter of ∼179 nm, well-defined ROS-triggered drug release kinetics, and high in vivo bone-targeting efficiency. In vitro, PH/DPA@A inhibited osteoclast formation and resorptive activity at levels comparable to free AZD3965, indicating preserved pharmacological potency. In ovariectomized (OVX) mice, systemic PH/DPA@A administration increased femoral bone mineral density and improved trabecular number, thickness, and connectivity, as confirmed by micro-computed tomography. These findings demonstrate that the bone-targeting, ROS-responsive design enables efficient in vivo delivery and metabolic modulation in osteoporotic bone, supporting PH/DPA@A as a multifunctional nanoplatform with translational potential for postmenopausal osteoporosis therapy.

Keywords

Bone targeting; Glycolysis; Nanoparticle; Osteoclast; ROS.

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