Dual-engineered small extracellular vesicles targeted delivery miR-126 for reducing age-related bone loss

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Gerontology

Background:

• Age-related bone loss poses significant therapeutic challenges.
• Efficient delivery of nucleic acid therapeutics like microRNA (miRNA) is crucial for treating bone diseases.
• Current strategies for age-related bone loss often lack targeted delivery and efficacy.

Purpose of the Study:

• To develop an engineered small extracellular vesicle (sEV) platform for targeted delivery of miRNA to bone.
• To investigate the therapeutic potential of miR-126 loaded sEVs for age-related bone loss.
• To enhance bone regeneration and restore skeletal homeostasis in aged individuals.

Main Methods:

• Engineered small extracellular vesicles (sEVs) encapsulating miR-126 (m-sEV) were created.
• m-sEVs were functionalized with a bone-targeting peptide (DSS)6 to form bone-targeting engineered vesicles (Bm-sEV).
• In vitro and in vivo studies in aged rats (mandibular defect model, femur analysis) were conducted to evaluate therapeutic efficacy and mechanisms.

Main Results:

• Bm-sEVs achieved targeted delivery of miR-126 to bone tissue.
• Systemic administration of Bm-sEVs increased type H vascularization in the femur, improved bone microarchitecture, and reduced age-related bone loss.
• The therapeutic effect involved upregulation of endothelial Integrin β3 (ITGB3) and activation of the ITGB3/ERK2 signaling pathway.
• Osteoclastic activity in aged femurs was restored, re-establishing skeletal homeostasis.

Conclusions:

• Engineered sEVs provide a promising platform for targeted delivery of miRNA therapeutics for age-related bone loss.
• Bm-sEVs effectively promote vascularized bone regeneration and restore skeletal homeostasis by modulating angiogenesis-osteogenesis coupling.
• This approach offers a novel strategy for treating age-related bone diseases by combining sEVs, miRNA, and targeting peptides.