Hyaluronan-bisphosphonate conjugate: A macromolecular anti-inflammatory agent and gas delivery system for neuroimmunomodulation in spinal cord injury

  • Int J Biol Macromol. 2025 Jul;318(Pt 1):144958. doi: 10.1016/j.ijbiomac.2025.144958.
Ranxi Chen  1 ,  Hexu Zhang  1 ,  Shan Pei  1 ,  Ya Li  1 ,  Zhiyan Wu  1 ,  Chaoyong He  1 ,  Runxiang Yao  1 ,  Lili Wang  2 ,  Tantai Zhao  3 ,  Liyang Shi  4
Affiliations
  • 1. State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, China.
  • 2. Department of Microbiology, College of Basic Medicine, Central South University, Changsha 410083, China.
  • 3. Department of Ophthalmology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4. State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, China. Electronic address: [email protected].
PMID: 40473155 DOI: 10.1016/j.ijbiomac.2025.144958
Abstract

Neuroinflammation-mediated secondary injury following Spinal Cord Injury (SCI) significantly exacerbates neuronal damage and impedes neurofunctional recovery. Hyaluronan-bisphosphonate (HA-BP) conjugates have emerged as a promising therapeutic agent with selective anti-inflammatory properties in bone and cartilage disorders, yet its potential in SCI remains unexplored. In this study, we highlight the unique role of HA-BP conjugates in modulating neuroinflammation. Our results show that HA-BP conjugates effectively reduce LPS-induced pro-inflammatory activation of microglia and Macrophages. Additionally, we developed an HA-BP-based macromolecular hydrogel via metal-ligand coordination, serving as a platform for therapeutic gas delivery. Cellular and animal studies demonstrated that HA-BP-based hydrogels without gas-releasing properties could suppress pro-inflammatory responses, while HA-BP hydrogels with gas-releasing capabilities not only further reduced reduced pro-inflammatory marker (iNOS) but also enhanced anti-inflammatory marker (CD206) expression. In a rat SCI model, the gas-releasing HA-BP hydrogel significantly reduced glial scar formation, promoted regeneration and survival of neurofilament- and class III β-tubulin-positive neurons, and improved motor functional recovery. This study underscores the therapeutic potential of HA-BP conjugates in neuroimmunomodulation, introducing a new application of HA-BP as both an anti-inflammatory agent and a gas-delivery platform for SCI treatment.

Keywords
Anti-inflammatory macromolecules; Gas-releasing platform; HA-BP conjugate; Neuroimmunomodulation; Spinal cord injury.