Controlled TPCA-1 delivery engineers a pro-tenogenic niche to initiate tendon regeneration by targeting IKKβ/NF-κB signaling

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. • NF-κB signaling activation involves in forming an inflammatory tendon niche after acute injuries. • An inflammatory niche inhibits tenogenesis and results in the pathological differentiation of stem cells. • Controlled TPCA-1 delivery engineers a pro-tenogenic niche for the transplanted hPDLSCs by targeting IKKβ/NF-κB signaling.