Design Strategies and Emerging Applications of Electrospun Silk Fibroin Nanofibers for Tissue Engineering.

Electrospun silk fibroin nanofibers (SFNFs) combine exceptional biocompatibility, tunable mechanical properties, and a native extracellular matrix (ECM)-mimetic architecture, making them compelling scaffolds for tissue engineering. Despite rapid progress, current research often pursues isolated material enhancements, lacking a cohesive strategy that aligns scaffold design with the complex biophysical and biochemical microenvironments of targeted tissues. To bridge this gap, this review presents a "design-application coupling" framework that systematically integrates SFNF composition, processing, and surface modifications with tissue-specific regenerative demands. Rather than exhaustively detailing basic manufacturing, we concisely distill advanced electrospinning modalities and targeted functionalization strategies─such as inorganic reinforcement and immunomodulation─that dictate mechanical robustness and bioactivity. Crucially, we map these engineered properties directly to their emerging clinical applications, comprehensively analyzing SFNF performance in the regeneration of bone, skeletal muscle, cardiovascular, neural, and skin tissues. Finally, we discuss critical challenges to clinical translation, including scalability and regulatory standardization, and propose future directions toward smart, bioresponsive materials. This framework provides a systematic pathway from bench-side innovation to bedside application, guiding the next generation of SFNF-based regenerative scaffolds.