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Conclusion
Opioids and opiates top the list of illicit drugs and cause the greatest burden of disease and drug-related deaths worldwide. This project aimed to develop a strategy that employed modified exosomes expressing the neuron-specific RVG peptide on the exosomal membrane surface to deliver MOR siRNA into the brain to treat opioid addiction and to prevent relapse. Here, we found that MOR siRNA could be efficiently packaged into RVG exosomes. Because the RVG peptide could mediate exosome transfer through the BBB via binding to the acetylcholine receptor expressed on the neuronal cell membrane, RVG exosomes bearing MOR siRNA were indeed found to effectively and specifically enter Neuro2A cells and the mouse brain, resulting in a great reduction of MOR gene expression both in vitro and in vivo. Interestingly, RVG exosomes did not allow the delivery of siRNA into cells lacking the acetylcholine receptor, further demonstrating that RVG exosomes represent a smart delivery system enabling targeted and selective uptake of siRNA by neurons. In the CPP test, knockdown of MOR by RVG exosome-delivered siRNA strongly blocked the morphine-induced CPP after re-exposure to morphine, indicating the therapeutic potential of exosome-based siRNA delivery to solve the addiction problems in the brain. In contrast, RVG exosomes loaded with MOR siRNA had no significant effect on the natural preference of the mice, suggesting that RVG exosome-delivered siRNA does not disrupt the normal reward system and is therefore safe and non-toxic.
This new strategy employing RVG exosome-delivered siRNA works by blocking the MOR in the brain and therefore blocks the effects of heroin and other opioids. People who are under this protection cannot achieve the “high” from using heroin. By all appearances, this new strategy has multiple advantages over existing therapeutic approaches: (1) This strategy neither produces euphoria nor creates a new addiction. Thus, it is not addicting and can be used in a variety of settings without concerns for abuse or diversion. For this reason this strategy is not a substitution therapy, when one addictive drug is changed for another (e.g., methadone maintenance treatment). (2) Due to absence of addictive properties, this strategy does not cause withdrawal symptoms when it is stopped taken. (3) This strategy does not generate obvious side effects. From this point of view, our new strategy may be an ideal choice for people who passed opioid detoxification and highly motivated to stay in recovery.
Project significance
(1) This project is highly innovative and has widespread impact. Opioid addiction poses serious social, medical and economic issues, but effective treatment remains limited. Our findings provide a brand new strategy to treat opioid addiction and to prevent relapse. This new approach is highly promising and may fill the void left by current methods for gene therapy of drug addiction.
(2) The development of a safe, tissue-specific delivery system for siRNA represents great progress in gene therapy. This project suggests that exosomes derived from engineered cells may realize the goal of delivering siRNA to a specific cellular environment with high efficiency and safety. Thus, exosomes compensate for the shortcomings of conventional siRNA delivery systems. This novel approach may open up new avenues for future therapeutic applications of siRNA.
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