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A low-crosslinking hydrogel integrating prodrug nanoparticles modulates neuroinflammation and ECM deposition for enhanced spinal cord regeneration
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DOI：10.1016/j.biomaterials.2026.124526.png)
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Abstract
En 中文
Spinal cord injury (SCI) causes pathological extracellular matrix (ECM) deposition and tissue stiffening, impeding axonal regeneration and disrupting homeostasis. Galardin-mediated inhibition of matrix metalloproteinases reduces ECM deposition and promotes recovery, but systemic administration fails to adequately address local microenvironment deterioration. We therefore explore a localized biomaterial delivery strategy via regulating the crosslinking degree of hydrogel matrix, in which high-crosslinking density of hydrogel (HCGH) tends to exacerbate neuroinflammation via Piezo1 activation as well as Wwtr1-dependent macrophage reprogramming. Based on this, we fabricate an integrated therapeutic platform where pH-responsive curcumin-succinate self-assembled prodrug nanoparticles (co-loaded with Galardin and basic fibroblast growth factor, denoted as CrS-GF NPs) are encapsulated in a low-crosslinking hydrogel (LCGH). By thorough testing on the compression spinal cord injury model of mice, the LCGH@CrS-GF system not only modulates excessive ECM deposition and neuroinflammation, but also provides sufficient neurotrophic support, thereby facilitating smooth axonal regeneration and functional restoration of the damaged spinal cords in a collaborative manner. Our study highlights the importance of using hydrogels with tailored crosslinking density to deliver therapeutics for SCI repair by stimulating beneficial biological responses and manipulating ECM deposition.
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