FGF‐Mimicking Triphen[3]arene Peptide Self‐Assembly to Accelerate Muscle Regeneration and Repair

Abstract Bioactive peptides play crucial roles in the biomedicine fields including cancer therapy and regenerative medicine due to their favorable biocompatibility, low immunogenicity, and excellent biological activity. However, their low stability greatly limits their clinical application. Herein, a novel bioactive peptide delivery strategy is reported that utilizes triphen[3]arene polyvalent‐conjugated bioactive peptides to induce self‐assembly and form nanofibers to enhance the in vivo stability and bioactivity of bioactive peptides. Specifically, a water‐soluble triphen[3]arene (WTP3(YRSRK) 6 , Comp. 2 ) containing six FGF‐mimicking peptides, primarily comprising two components: triphen[3]arene serves as a skeleton molecule and an assembly motif with multiple customizable sites, while YRSRK is a pentapeptide with fibroblast growth factor 2 (FGF‐2) biological activity. Despite the presence of the inhibitor dexamethasone (Dex), Comp. 2 continued to enhance cell proliferation by 15% and rescued 17% of cells from apoptosis. The administration of Comp. 2 resulted in improved restoration of skeletal muscle atrophy and functional damage in mice. The mean grip strength increased by 42%, and the calf muscle volume increased by 17%. This innovative approach of utilizing macrocycle polyvalent conjugated bioactive peptides offers a universal method for enabling bioactive peptides to produce sustained and efficient biological effects, potentially advancing the development of promising peptide‐based nanomedicines.