M2 macrophage extracellular vesicles in bone regeneration: Applications and challenges
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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M2 macrophage extracellular vesicles promote bone repair by reducing inflammation and stimulating blood vessel growth.
When combined with functionalized scaffolds, these vesicles significantly improve implant integration and defect healing.
Challenges remain in targeting, scalable production, and quality control for clinical use.
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ABSTRACT
Extracellular vesicles (EVs) can carry bioactive molecules and mediateintercellular communication. Among EVs from various sources, those derivedfrom M2 macrophages (M2-EVs) have attracted widespread attention in thefield of bone regeneration due to their inherent anti-inflammatory andosteogenic properties. M2-EVs promote osteogenic differentiation ofmesenchymal stem cells by delivering specific microRNAs and proteins thatactivate key signaling pathways, such as MAPK, TGF-β/Smad, AMPK-mTOR,and PI3K/Akt. They also modulate the osteoimmune microenvironment bysuppressing inflammation and inducing M2 polarization, while enhancingangiogenesis through VEGF and miR-21 transfer. In bone tissue engineering,M2-EVs can be integrated with various scaffolds—such as β-TCP, PCLfibrous scaffolds, and hydrogels—to improve osseointegration and bonedefect repair, as confirmed in preclinical models. However, clinical translationfaces challenges, including insufficient targeting, heterogeneity, isolationstandardization, and quality control. Despite these limitations, M2-EVsrepre-sent a promising cell-free therapeutic strategy for bone repair. Futureresearch may focus on engineering approaches to enhance their specificity,stability, and large-scale production, ultimately unlocking their full potential inregenerative medicine.-
Keywords:
- M2 macrophage /
- extracellular vesicles /
- bone regeneration /
- osteogenesis /
- immunomodulation /
- scaffolds
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REFERENCES
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Lu P., Luo F., Zhou Z., et al. (2026). M2 macrophage extracellular vesicles in bone regeneration: Applications and challenges. The Innovation Reviews 1:100003. https://doi.org/10.59717/j.tirv.2026.100003
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Lu P., Luo F., Zhou Z., et al. (2026). M2 macrophage extracellular vesicles in bone regeneration: Applications and challenges. The Innovation Reviews 1:100003. https://doi.org/10.59717/j.tirv.2026.100003
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Figure 1.
Extracellular vesicle biogenesis: Plasma membrane endocytosis internalizes cell surface and soluble proteins → early sorting endosomes (ESEs) → late sorting endosomes (LSEs) → multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs)
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Figure 2.
Classic extracellular vesicle isolation methods: high-speed centrifugation method; magnetic-activated cell sorting (MACS); size-exclusion chromatography (SEC); ultrafiltration (UF); microfluidics.
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Figure 3.
Osteogenic role of miRNAs: miR-378a positively regulates osteogenesis, promotes MSC osteogenic differentiation, and is highly enriched in M2-EVs
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Figure 4.
MAPK signaling pathway and TGF-β/Smad signaling pathway involved in osteogenesis
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Figure 5.
Comparative evaluation of bone defect repair for different biomaterial scaffolds loaded with various engineered extracellular vesicles
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Figure 6.
Preparation, characterization and bone regeneration of PTGFRN/IL-4-EV-modified Janus electrospun nanofibrous scaffolds
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Figure 7.
Histological and SEM characterization of EV-modified metal scaffolds and hydrogel biomaterials
