Osteoclast-targeted delivery of anti-miRNA oligonucleotides by red blood cell extracellular vesicles
Limei Xu1, Xiao Xu1, Yujie Liang2
1Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial, Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China.
Abstract:
Osteoporosis (OP) affects millions worldwide but currently cannot be cured. Suppressing the level of miR-214 in osteoclasts by the anti-miRNA oligonucleotide (AMO) anti-miR-214 reverses bone absorption and provides a potential treatment. Here we report a peptide-guided delivery strategy using red blood cell extracellular vesicles (RBCEVs) as the vehicle to realize osteoclast-targeted delivery of anti-miR-214. A bi-functional peptide, TBP-CP05, which binds to both the CD63 on RBCEVs and receptors on osteoclasts, acts as the guide. TBP-CP05 binds with RBCEVs through CP05, displays the TRAP-binding peptide (TBP) on the surface of EVs, and endows RBCEVs with osteoclast-targeting capability both in vitro and in vivo. Intravenous injection of the osteoclast-targeting RBCEVs (OT-RBCEVs) led to the enrichment of EVs in the bone skeleton, significant inhibition of the osteoclast activity, elevated osteoblast activity, and improved bone density in osteoporotic mice. Altogether, this work demonstrates efficient guidance of drug-loaded EVs to the targeted cells in vivo using bi-functional fusion peptides, and showcases that targeted delivery of anti-miR-214 by OT-RBCEVs may be a viable method for OP treatment. SIGNIFICANCE STATEMENT. Surface functionalization of EVs endows these nanovesicles cell-specific targeting property which guides the drug cargos to specific tissues and cells with higher accuracy, longer retention, and minimal off-target effects. Methods to functionalize EVs with minimal procedures are highly desired for clinical applications. Here we present a facile method using a bifunctional fusion peptide to guide RBCEVs to osteoclasts. A simple incubation of the bifunctional peptide and RBCEVs results in osteoclast-targeting RBCEVs (OT-RBCEVs) that effectively deliver anti-miR-214 to osteoclasts in vivo in a mouse model of osteoporosis, bringing a potential therapy to osteoporotic patients. This is, to our knowledge, the first report on peptide functionalization of RBCEVs and osteoclast-targeted delivery using RBCEVs.
Insights
A novel peptide-guided strategy uses red blood cell extracellular vesicles (RBCEVs) to deliver anti-miR-214, effectively targeting osteoclasts. This approach shows promise for treating osteoporosis by inhibiting bone resorption and improving bone density in mice.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Drug Delivery Systems
Background:
- Osteoporosis (OP) is a widespread condition with no current cure.
- Current treatments aim to manage symptoms, but targeted therapies are needed.
- MicroRNA-214 (miR-214) plays a role in osteoclast activity and bone absorption.
Purpose of the Study:
- To develop a targeted delivery system for anti-miR-214 to osteoclasts.
- To utilize red blood cell extracellular vesicles (RBCEVs) functionalized with a peptide for enhanced targeting.
- To evaluate the efficacy of this strategy in a mouse model of osteoporosis.
Main Methods:
- Engineered a bifunctional peptide (TBP-CP05) to bind RBCEVs and osteoclasts.
- Functionalized RBCEVs with TBP-CP05 to create osteoclast-targeting RBCEVs (OT-RBCEVs).
- Administered OT-RBCEVs loaded with anti-miR-214 intravenously to osteoporotic mice.
Main Results:
- OT-RBCEVs successfully targeted osteoclasts in vitro and in vivo.
- Injected OT-RBCEVs accumulated in the bone skeleton.
- Demonstrated significant inhibition of osteoclast activity and enhanced osteoblast activity.
- Observed improved bone density in treated osteoporotic mice.
Conclusions:
- Peptide-guided functionalization of RBCEVs provides an effective method for targeted drug delivery.
- OT-RBCEVs loaded with anti-miR-214 represent a potential therapeutic strategy for osteoporosis.
- This approach offers enhanced accuracy, retention, and reduced off-target effects for drug delivery.
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