Nanoparticle-based drug delivery systems have the potential to revolutionize medicine,but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact.Nanoparticles deliver...Nanoparticle-based drug delivery systems have the potential to revolutionize medicine,but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact.Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system.However,very little is known about nanoparticle drug delivery at the fetal stage of development.In this report,using Ai9 CRE reporter mice,we demonstrate that lipid nanoparticle(LNP)mRNA complexes can deliver mRNA in utero,and can access and transfect major organs,such as the heart,the liver,kidneys,lungs and the gastrointestinal tract with remarkable efficiency and low toxicity.In addition,at 4 weeks after birth,we demonstrate that 50.99±5.05%,36.62±3.42%and 23.7±3.21%of myofiber in the diaphragm,heart and skeletal muscle,respectively,were transfected.Finally,we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero.These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero,which provides a promising strategy for treating a wide variety of devastating diseases before birth.展开更多
基金This work was in part supported by the California Institute for Regenerative Medicine(CIRM)grant DISC2-14097(A.W.)the National Institutes of Health grants UG3NS115599,R61DA048444-01,R01MH125979(N.M.),1R01NS100761 and 1R01NS115860(A.W.).
文摘Nanoparticle-based drug delivery systems have the potential to revolutionize medicine,but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact.Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system.However,very little is known about nanoparticle drug delivery at the fetal stage of development.In this report,using Ai9 CRE reporter mice,we demonstrate that lipid nanoparticle(LNP)mRNA complexes can deliver mRNA in utero,and can access and transfect major organs,such as the heart,the liver,kidneys,lungs and the gastrointestinal tract with remarkable efficiency and low toxicity.In addition,at 4 weeks after birth,we demonstrate that 50.99±5.05%,36.62±3.42%and 23.7±3.21%of myofiber in the diaphragm,heart and skeletal muscle,respectively,were transfected.Finally,we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero.These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero,which provides a promising strategy for treating a wide variety of devastating diseases before birth.
