Research on the Combined Effects of miRNAs and Immunomodulatory Peptides on Bone Regeneration in an Inflammatory Bone Immunological Milieu.

Abstract

The development of bone regenerative substitutes capable of orchestrating osteogenesis within inflammatory immune microenvironments remains a critical challenge. This study investigates the dual-functional immunomodulatory peptide DP7-C as a microRNA (miRNA) co-delivery system to regulate osteogenic differentiation and macrophage polarization synchronously. Through systematic screening of DP7-C/miRNA nanocomplexes (miR-21, -26a, -29a, -34a, -124, -125a) in bone marrow mesenchymal stem cells (BMSCs) and RAW264.7 macrophages, we identified DP7-C/miR-124 as the optimal nanocomplex, demonstrating synergistic osteoimmunomodulatory effects. Results demonstrated that the DP7-C/miR-124 combination raised the expression of anti-inflammatory factors in inflammatory macrophages and decreased the expression of pro-inflammatory factors. It also stimulated the production of osteogenesis-related proteins BMP2 and Runx2 to promote BMSC osteogenesis. Mechanistic studies revealed bidirectional cellular crosstalk, where DP7-C/miR-124 enhanced IL-10-mediated anti-inflammatory macrophage polarization while reciprocally promoting BMSC differentiation through paracrine modulation. These findings establish DP7-C/miRNA nanocomplexes as next-generation osteoimmunomodulatory biomaterials that concurrently resolve inflammation and amplify bone regeneration through epigenetic-immune circuit regulation, offering a promising strategy for functionalized bone defect repair in inflammatory microenvironments.