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Illegal drugs are highly addictive and pose serious health risks. Addiction to drugs is a painful battle for the addict as well as for those individuals around him or her. Opioids and opiates top the list of problem drugs and cause the greatest burden of disease and drug-related deaths worldwide. The goal of this project was to develop a strategy to treat opioid addiction and to reduce relapse. Because opioids act primarily as Mu-opioid receptor (MOR) agonist to activate the reward pathway in the brain, leading to the euphoric effect of opioid drugs and ultimately the opioid-dependent state, blockage of the expression and function of MOR would theoretically have therapeutic value in the treatment of opioid dependence. Thus, this project selected MOR as a therapeutic target for the treatment of opioid addiction and for the prevention of a relapse to opioid use.
siRNAs are emerging as promising therapeutic drugs against a wide array of diseases. The key obstacle for successful clinical application of siRNA is to develop a safe and effective delivery system directed at the target tissues only. Current techniques for small RNA transfer use viruses or synthetic agents as delivery vehicles. The replacement of these delivery vehicles with a low toxicity and high target-specific approach is essential for making siRNA therapy feasible. Because exosomes have the intrinsic ability to traverse biological barriers and to naturally transport functional small RNAs between cells, exosomes potentially represent a novel and exciting delivery vehicle for the field of siRNA therapy. As therapeutic delivery agents, exosomes will potentially be better tolerated by the immune system because they are natural nanocarriers derived from endogenous cells. Furthermore, exosomes derived from cells engineered to express siRNAs and surface proteins may be capable of delivering these small RNAs to the target cells. Thus, exosome-based delivery of siRNAs may provide an untapped source of effective delivery strategy to overcome impediments such as inefficiency, unspecificity and immunogenic reactions.
In this project, we constructed a plasmid expressing the neuron-targeting peptide RVG and employed HEK293 cells as donor cells to acquire exosomes expressing RVG on the surface. We also proposed a strategy of using RVG exosomes to encapsulate MOR siRNA and specifically deliver them to the brain. As a consequence, RVG exosome-delivered MOR siRNA can reversibly block or attenuate the effects of opioids, thereby functions as therapeutics for the prevention of relapse to opioid dependence following detoxification.
Fig1总的效果
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