Neuroprotection and Axonal Regeneration via ECM-Mimetic Nanofibers Incorporating Metal-Phenolic Network Nanoparticles...

Spinal cord injury (SCI) triggers secondary pathological cascades, such as excitotoxicity, neuroinflammation, and glial scarring, creating a hostile injury microenvironment that exacerbates the death of spared neurons and inhibits axonal regeneration, thus impeding functional recovery. While aligned electrospun nanofibers (NFs) fabricated from decellularized extracellular matrix (dECM) can mimic topological and bioactive cues of native ECM to guide axonal regrowth, they fail to intervene in these secondary pathological cascades. To address this limitation, Mg²⁺ and epigallocatechin gallate (EGCG) molecules are initially self-assembled into nanoparticles (MPN NPs) via metal-phenolic coordination, and then integrated with dECM by electrospinning to form an aligned fibrous scaffold, MPN@dECM NFs. These MPN NPs undergo pH-responsive degradation in the acidic SCI microenvironment, releasing Mg²⁺ to alleviate excitotoxicity by blocking Ca²⁺ influx and EGCG to suppress neuroinflammation by reducing pro-inflammatory mediators. In the mouse SCI model, MPN@dECM NFs consistently attenuate neuroinflammation and glial scarring, and ameliorate the regeneration-inhibitory microenvironment, thereby not only protecting spared neurons from secondary degeneration but also enhancing dECM-mediated axonal regeneration. Ultimately, surviving neurons and regenerating axons synergize to facilitate motor function restoration. Collectively, this scaffold design synergistically promotes neuroprotection and axonal regeneration, demonstrating enhanced repair efficacy for SCI as a promising therapeutic strategy.