Sequential Targeted Enzyme‐Instructed Self‐Assembly Supramolecular Nanofibers to Attenuate Intervertebral Disc Degeneration

Abstract As an age‐related disease, intervertebral disc degeneration is closely related to inflammation and aging. Inflammatory cytokines and cellular senescence collectively contribute to the degradation of intervertebral disc. Blocking this synergy reduces disc extracellular matrix damage caused by inflammation and aging. In this study, drug‐loaded nanofibers with sequential targeting functions are constructed through intelligent response, hydrophilicity, and in situ self‐assembly empowerment of flurbiprofen. The peptide precursor responds to the cleavage of overexpressed MMP‐2 in the degenerative intervertebral disc microenvironment (intracellular and extracellular), resulting in the formation of self‐assembled nanofibers that enable the on‐demand release of flurbiprofen and COX‐2 response. In vitro, Comp. 1 (Flurbiprofen‐GFFYPLGLAGEEEERGD) reduces the expression of inflammation‐related genes and proteins and the polarization of M1 macrophages by competitively inhibiting COX‐2 and increases the expression of extracellular matrix proteins COL‐2 and aggrecan. Additionally, it can reduce the expression of Senescence‐Associated Secretory Phenotype and DNA damage in aged nucleus pulposus cells and promote the recovery of proliferation and cell cycle. In vivo, drug‐loaded nanofibers delay intervertebral disc degeneration by inhibiting inflammation and preventing the accumulation of senescent cells. Therefore, the sequentially targeted self‐assembled drug‐loaded nanofibers can delay intervertebral disc degeneration by blocking the synergistic effect of inflammatory cytokines and cellular senescence.