Bone-Targeting Peptide and RNF146 Modified Apoptotic Extracellular Vesicles Alleviate Osteoporosis
Linyuan Gui1, Qingyuan Ye2, Lu Yu3
1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
Background:
Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment.
Methods:
We conjugated a bone-targeting peptide, (Asp-Ser-Ser)6 ((DSS)6), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)6-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)6-ApoEVs and (DSS)6-ApoEVsRNF146 were measured in vitro and in vivo.
Results:
Our study successfully synthesized bone-targeting and gained functional (DSS)6-ApoEVsRNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model.
Conclusion:
To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)6-ApoEVsRNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.
Insights
Engineered extracellular vesicles (ApoEVs) with bone-targeting peptides show promise for osteoporosis treatment. These modified ApoEVs enhance bone regeneration and targeting, offering a potential alternative to current therapies.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Orthopedics
Background:
- Osteoporosis is a prevalent condition causing fractures and motor function loss.
- Current osteoporosis drugs have significant side effects.
- Bone marrow mesenchymal stem cell (BMSC)-derived apoptotic extracellular vesicles (ApoEVs) promote bone regeneration but lack bone-targeting capabilities.
Purpose of the Study:
- To enhance the bone-targeting and bone-promoting functions of ApoEVs for osteoporosis treatment.
- To develop engineered ApoEVs with improved therapeutic potential.
Main Methods:
- Conjugated a bone-targeting peptide ((Asp-Ser-Ser)6 or (DSS)6) to ApoEVs using carbodiimide chemistry.
- Loaded ApoEVs with ubiquitin ligase RING finger protein146 (RNF146) via adenovirus transduction.
- Evaluated bone-targeting and osteogenesis-promoting abilities in vitro and in vivo using mouse models.
Main Results:
- Successfully synthesized bone-targeting and functional engineered ApoEVs ((DSS)6-ApoEVsRNF146).
- Engineered ApoEVs demonstrated enhanced osteogenesis in vitro.
- In vivo studies showed significant bone-targeting and osteogenesis-promoting effects, alleviating osteoporosis in a mouse model.
Conclusions:
- Engineered ApoEVs ((DSS)6-ApoEVsRNF146) significantly promote osteogenesis and alleviate osteoporosis.
- These modified ApoEVs offer a promising new therapeutic strategy for osteoporosis treatment.
- The study provides a novel method for enhancing ApoEVs' therapeutic efficacy in bone regeneration.
