MSC-mimicking nanovesicle embedded bio-adhesive hydrogel for dual immunomodulation and osteogenesis to promote maxillofacial bone regeneration

Significant efforts to utilize artificial soft materials in developing tissue engineering scaffolds show considerable promise for maxillofacial bone regeneration. However, most biological materials cannot simultaneously satisfy the multiple requirements of robust adhesive strength under masticatory environments, pathological immune regulation, and efficient cell-specific targeting therapy, ultimately compromising the repair process. Herein, a tissue-adhesive hydrogel loaded with mesenchymal stem cells-derived nanovesicles (PEG-pp@nMSC@MT) is introduced with inflammation regulation and cell-specific targeting as an all-in-one tool for maxillofacial bone repair. Relying on the quick amidation reaction between active ester groups of PEG-SG and amine groups of PEG-NH2 polymers, the uniform networks are rapidly formed with easy injection, favorable biocompatibility, and robust adhesive strength, which is capable of resisting frequent masticatory force in oral cavity. The incorporation of a matrix metalloproteinase 2 (MMP2)-cleavable peptide allows the hydrogel to respond to elevated protease levels at defect sites, enabling on-demand release of encapsulated nanovesicles while concurrently attenuating excessive MMP2 activity. Of note, the efficient transport of therapeutic melatonin to the intended BMMSCs enhances their osteogenic and immunomodulatory functions. Collectively, the reduction of MMP2, secretion of anti-inflammatory factors by BMMSCs, and immunomodulatory effects of nMSC@MT synergistically promote macrophage polarization toward M2 phenotype and facilitate bone regeneration. The therapeutic effect of PEG-pp@nMSC@MT displays superior biodegradability and osteo-inductive capacity compared with Bio-Oss, a first-line grafting material used in maxillofacial bone defect in current clinical treatment. Thus, this innovative hydrogel platform combines precise immunomodulation with cell-specific targeting, representing a promising therapeutic strategy for the effective repair of maxillofacial bone defects.