Kavli Affiliate: Robert Hawkins
| Authors: Wenchao Gu, Sijin Luozhong, Ketaki Londhe, Nadine Elkasri, Simian Cai, Robert Hawkins, Zhefan Yuan, Kai Su-Greene, Margaret Cruz, Yu-Wei Chang, Patrick McMullen, Chunyan Wu, Changwoo Seo, Akash Guru, Wenting Gao, Tara Sarmiento, Chris Schaffer, Nozomi Nishimura, Richard Cerione, Melissa Warden, Robert Langer and Shaoyi Jiang
| Summary:
Abstract Systemic delivery of mRNAs into neurons is limited by the blood-brain-barrier (BBB) preventing the entry of carriers into the brain. Leukocyte-derived extracellular vesicles (EVs) can cross the BBB, emerging as promising carriers to target the brain. However, efficient mRNA encapsulation into EVs and their neuronal uptake remain challenges. We incorporated inside EVs the endogenous retrovirus-like Arc protein capsids, stabilized by RNA elements, Arc 5’UTRs, enabling effective cargo loading and delivery. Equipped with adhesion molecules from donor leukocytes, EVs extravasate BBB at inflammatory sites. Arc components promote endocytosis and cargo release, due to their native roles in transferring mRNAs inter-neuronally. Produced from self-derived leukocytes, engineered retrotransposon Arc EVs (eraEVs) are immunologically inert with minimal clearance. Possessing high effectiveness like viral vectors and biocompatibility as naturally occurring vesicles, eraEVs can be produced from virtually all donor cell types, potentially leading to the development of future clinical therapies for a range of diseases. Figure Download figureOpen in new tab Competing Interest Statement The authors have declared no competing interest.