A low-crosslinking hydrogel integrating prodrug nanoparticles modulates neuroinflammation and ECM deposition for enhanced spinal cord regeneration

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.