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Tendon repair remains challenging due to its poor intrinsic healing capacity, and stem cell therapy has emerged as a promising strategy to promote tendon regeneration. Nevertheless, the inflammatory environment following acute tendon injuries disrupts stem cell differentiation, leading to unsatisfied outcomes. Our study recognized the critical role of NF-κB signaling in activating inflammation and suppressing tenogenic differentiation of stem cells after acute tendon injury via multiomics analysis. TPCA-1, a selective inhibitor of IKKβ/NF-κB signaling, efficiently restored the impaired tenogenesis of stem cells in the inflammatory environment. By developing a microsphere-incorporated hydrogel system for stem cell delivery and controlled release of TPCA-1, we successfully engineered a pro-tenogenic niche to initiate tenogenesis for tendon regeneration. Collectively, we recognize NF-κB signaling as a critical target to tailor a pro-tenogenic niche and propose the combined delivery of stem cells and TPCA-1 as a potential strategy for acute tendon injuries.

Silk fibroin (SF), the core structural protein derived from Bombyx mori silk, is extensively employed in tissue engineering and regenerative medicine due to its exceptional mechanical properties, favorable biocompatibility, tunable biodegradability, and versatile processing capabilities. Despite these advantages, current research predominantly focuses on SF biomaterials as structural scaffolds or drug carriers, often overlooking their potential role in modulating cellular behavior and tissue regeneration. This review aims to present a comprehensive overview of the inherent biological effects of SF biomaterials, independent of any exogenous biomolecules, and their implications for various tissue regeneration. It will cover in vitro cellular interactions of SF with various cell types, including stem cells and functional tissue cells such as osteoblasts, chondrocytes, keratinocytes, endothelial cells, fibroblasts, and epithelial cells. Moreover, it will summarize in vivo immune responses, cellular responses, and tissue regeneration following SF implantation, specifically focusing on vascular, bone, skin, cartilage, ocular, and tendon/ligament regeneration. Furthermore, it will address current limitations and future perspectives in the design of bioactive SF biomaterials. A comprehensive understanding of these cellular interactions and the biological effects of SF is crucial for predicting regenerative outcomes with precision and for designing SF-based biomaterials tailored to specific properties, enabling broader applications in regenerative medicine., (© 2024 Wiley‐VCH GmbH.)