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

  • Mater Today Bio. 2025 Sep 29:35:102365. doi: 10.1016/j.mtbio.2025.102365.
Ya Li  1  2 ,  Yuyun Liang  1 ,  Chaoyong He  1 ,  Runxiang Yao  1 ,  Ke Jian  1 ,  Liyang Shi  1
Affiliations
  • 1. College of Biology, Hunan University, Changsha, 410082, China.
  • 2. Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration, Xinxiang Medical University, Xinxiang, 453003, China.
PMID: 41080728 DOI: 10.1016/j.mtbio.2025.102365
Abstract

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.

Keywords
Dual-drug; Microglia/macrophages; Programmable polarization; Sequential release; Spinal cord injury.
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