β-Sheet-Assisted Fabrication of Drug-Loaded Gelatin/Silk Fibroin Nanoparticles for Spinal Cord Injury Treatment

Spinal cord injury (SCI) is a serious neurological disease accompanied by neuroinflammatory responses. Recently, nanosized drug delivery systems have attracted attention for SCI treatment by improving solubility and bioavailability and providing sustained drug release. Protein-based nanoparticles can be biocompatible but often require chemical cross-linkers for structural stability, raising biosafety concerns. Here, we introduce a β-sheet-driven physical cross-linking approach to fabricate nanoparticles without chemical cross-linkers, namely by employing gelatin (Gel) and silk fibroin (SF) as proteins. This coassembly approach ensures structural integrity, enables enzyme-responsive degradation, and allows precise size control with narrow size distributions. Gel/SF particles can load dexamethasone (DEX) with a high drug loading (∼72%), exhibiting long-term stability and enzyme-triggered release. <i>In vitro</i>, these nanoparticles suppress pro-inflammatory cytokines and promote M2 phenotype microglial polarization, suggesting their neuroinflammation-regulating potential. Gel/SF particles may be a biocompatible, cross-linker-free protein-based drug delivery system, offering a promising platform for SCI treatment and broader applications in neuroinflammatory disorders.