Ultrasound-triggered biomimetic ultrashort peptide nanofiber hydrogels promote bone regeneration by modulating macrophage and the osteogenic immune microenvironment

The immune microenvironment plays a vital role in bone defect repair. To create an immune microenvironment that promotes osteogenesis, researchers are exploring ways to enhance the differentiation of M2-type macrophages. Functional peptides have been discovered to effectively improve this process, but they are limited by low efficiency and rapid degradation in vivo. To overcome these issues, peptide with both M2 regulatory and self-assembly modules was designed as a building block to construct an ultrasound-responsive nanofiber hydrogel. These nanofibers can be released from hydrogel in a time-dependent manner upon ultrasound stimulation, activating mitochondrial glycolytic metabolism and the tricarboxylic acid cycle, inhibiting reactive oxygen species production and enhancing M2 macrophage polarization. The hydrogel exhibits advanced therapeutic potential for bone regeneration by triggering M2 macrophages to secrete BMP-2 and IGF-I, accelerating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts. Thus, modularly designed biomimetic ultrashort peptide nanofiber hydrogels provide a novel strategy to rebuild osteogenic immune microenvironments for bone repair. [Display omitted] •To achieve effective M2 type differentiation of macrophages for bone repair, an ultrashort peptide with both M2 regulatory and self-assembly modules was designed as a building block to construct an ultrasound-responsive nanofiber hydrogel. Compared to peptide monomer, enhanced stability was achieved upon self-assembly. In addition, such ultrasound-responsive peptide nanofiber hydrogel could achieve desired bone defect filling and controlled release capability. Upon ultrasound stimulation at the bone defect site, peptide nanofibers were responsively released from hydrogels to regulate the M2 macrophage formation and promoting bone defect regeneration. The released peptide nanofibers both inhibit the release production of reactive oxygen species by activating macrophage mitochondrial energy metabolism, and induce M2 macrophages to accelerate the osteogenesis differentiation of bone marrow mesenchymal stem cells by secreting BMP-2 and IGF-I.