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

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.