Cascade Therapy of Periodontitis via Sequential Release of Ribosome‐Targeting Antimicrobial Peptide and Irisin From a Multifunctional MOF‐Based System

ABSTRACT Surgical removal of bacterial plaque and antibiotic therapy have been widely used for the clinical treatment of periodontitis, which is driven by microbial dysbiosis and usually causes the loss of alveolar bone. However, key restrictions including drug resistance, poor anti‐inflammatory effects, and limited bone repair capacity exist in antibiotic therapy, presenting challenges for periodontitis treatment. Consequently, it is urgently required to develop novel systems to combat antimicrobial resistance and enhance bone regeneration ability. Here, a MOF‐based multicomponent system is developed, containing a cationic antimicrobial peptide GF for antimicrobial purpose and the adipomyokine Irisin for anti‐inflammation, antioxidation, and promoting bone regeneration. The obtained composite Irisin/GF@NH 2 ‐MIL‐101(Fe) exhibits pH‐responsive release of GF and irisin. In vitro and vivo experiments demonstrate this multicomponent system has robust antimicrobial activity and could attenuate inflammation while stimulating bone regeneration. Remarkably, the antimicrobial mechanism of GF is explored, revealing a distinct binding mode at the ribosomal A‐site, which establishes more stable interactions than tetracycline, thereby disrupting protein synthesis and effectively reducing the risk of antibiotic resistance. This study not only reveals a novel antibacterial mechanism of antimicrobial peptide, but also provides a novel cascade therapy for the treatment of periodontitis with multiple functions.