Co-assembled polypeptides-adsorbing bridge molecules to enhance macrophage efferocytosis for the resolution of periodontitis inflammation.

Effective removal of apoptotic cells, namely efferocytosis, promotes inflammation resolution of periodontitis and tissue restoration. However, effective treatments to enhance macrophage efferocytosis in periodontitis are still lacking. Co-assembly of distinct building blocks is considered a versatile and effective method of modulating the structure and functionality of supramolecular materials. Herein, a biologically inert amphiphile peptide (PA) (C₁₆H₃₁ONNCCCCS, PAS) was designed based on a previous amphiphile peptide (C₁₆H₃₁ONNCCCCRRES(p), PARRES). We described those two peptides' co-assembly in modulating macrophage efferocytosis for periodontitis resolution. The results showed that individual PAS and PARRES co-assemble together and transform the secondary structure from α-helix to β-sheet pattern via hydrogen bonding. Compared with individual PAs, the composite PA adsorbed more "bridging molecules" that enhance apoptotic signal binding on macrophages. The enriched "bridging molecules" could bind to macrophages on one side via phagocytic receptors and attract the apoptotic cells on the other side, thus promoting efferocytosis. When injected into mice with periodontitis, composite PA promotes inflammation resolution and further promotes periodontal tissue regeneration. This study provided an easily adjustable supermolecular system that enhances efferocytosis for periodontitis and revealed insights into the relationship between physicochemical properties and biological effects of supermolecular materials. STATEMENT OF SIGNIFICANCE: Efferocytosis promotes periodontitis resolution and further tissue restoration. Nevertheless, high-performance therapeutics for promoting efferocytosis are still lacking. Peptides have desirable features, including biocompatibility and sequence-specific secondary structures. A biologically amphiphile peptide (PA) was designed with a similar structure to a previous PA. We described those PAs' co-assembly in modulating efferocytosis for periodontitis resolution. Specifically, those PAs co-assemble together and transform secondary structure from α-helix to β-sheet pattern. The composite PA adsorbs more "bridging molecules," enhancing apoptotic signals binding to macrophages and attracting apoptotic cells for promoting efferocytosis. In vivo, the composite PA promotes periodontitis resolution and regeneration. This study provided an easily adjustable supermolecular system enhancing efferocytosis and revealed insights into the relationship between physicochemical properties and biological effects.