A dual-drug sequential delivery hydrogel for programmatic microglia/macrophage polarization and function recovery in spinal cord injury

Precisely modulating microglia/macrophage polarization to meet the dynamic needs of different stages after spinal cord injury (SCI) is a significant challenge due to the complexity of M1/M2 polarization processes. This study introduces a dual-drug sequential delivery hydrogel (DSDH) to modulate microglia/macrophage polarization through sequential-drug release. DSDH utilizes a hyaluronic acid-based hydrogel combined with fucoidan nanoparticles to deliver minocycline initially, suppressing M1 polarization during early acute inflammatory stage, and a biotin-streptavidin system to release interleukin-4 subsequently, promoting M2 polarization in late non-acute stage. In a rat model of SCI, DSDH programmatically modulated the inflammatory microenvironment, significantly reduced scar formation, and effectively enhanced neuron regeneration compared to dual-drug non-sequential delivery hydrogel (non-DSDH). Additionally, compared with non-DSDH, DSDH improved motor function, alleviated bladder dysfunction, and reduced lesion cavity. This study underscores the potential of temporal-controlled drug release for SCI immunotherapy, offering a promising strategy for addressing dynamic neuroinflammatory responses and improving functional recovery after SCI.