RVG peptide-modified extracellular vesicles achieved superior brain delivery of siRNA compared to CPP.16-modified vesicles by redirecting internalized cargo into transcytotic pathways rather than enhancing cellular uptake.
Transcytosis, not uptakeBBB-crossing peptides work by rerouting EVs through transcytotic pathways, not by increasing how much cells absorb them
What the researchers found
RVG and CPP.16 modifications redirect sEVs into transcytotic rather than endocytic pathways. RVG-sEVs use clathrin-mediated endocytosis for superior BBB penetration and more efficient siRNA delivery to neurons and astrocytes in vivo.
Why it matters
Understanding how peptide modifications actually achieve brain delivery (transcytosis, not enhanced uptake) enables rational design of brain-targeting therapeutics for neurological diseases.
How the study worked
In vitro BBB model comparing RVG- and CPP.16-modified sEVs for internalization, transcytosis, pathway analysis, and gene silencing, with in vivo brain distribution studies in mice.
What this study cannot tell us
Mouse models; human BBB may respond differently. Only siRNA cargo tested. Long-term safety of repeated peptide-modified EV administration unknown.
How to read the evidence
Mechanistic study with in vitro BBB model and in vivo validation. Provides important design principles for brain-targeting peptide strategies.
When this study was published
Published in 2025.
The bigger picture
This study resolves a long-standing question about how RVG peptide enables brain delivery and provides design principles for the next generation of brain-targeting peptide-guided nanomedicines.
Questions still open
- Can RVG-modified EVs deliver larger therapeutic cargoes (proteins, mRNA) to the brain?
- Would combining RVG with other BBB-targeting strategies further improve delivery?
- Is the transcytosis mechanism conserved in human brain endothelial cells?
Common questions
How does the RVG peptide help deliver drugs to the brain?
Could this deliver gene therapies for brain diseases?
Read the original research
Selective peptide-guided transcytosis enhances extracellular vesicle-mediated siRNA delivery across the blood-brain barrier.
The Journal of biological chemistry, 302(1), 110942
Citation
Fang, Jingwen; Zhang, Lingzhu; Wang, Ye; Chen, Menghan; He, Yanqiu; Zhang, Chen-Yu; Zhang, Yujing; Jiang, Xiaohong; Li, Jing. (2026). Selective peptide-guided transcytosis enhances extracellular vesicle-mediated siRNA delivery across the blood-brain barrier.. The Journal of biological chemistry, 302(1), 110942. https://doi.org/10.1016/j.jbc.2025.110942