Erythropoietin, or Epo for short, is a notorious doping agent. It promotes the formation of red blood cells, leading thereby to enhanced physical performance — at least, that is what we have believed until now. However, as a growth factor, it also protects and regenerates nerve cells in the brain. Researchers at the Max Planck Institute of Experimental Medicine in Göttingen have now revealed how Epo achieves this effect. They have discovered that cognitive challenges trigger a slight oxygen deficit (termed ‘functional hypoxia’ by the researchers) in the brain’s nerve cells. This increases production of Epo and its receptors in the active nerve cells, stimulating neighbouring precursor cells to form new nerve cells and causing the nerve cells to connect to one another more effectively.

The growth factor erythropoietin is among others responsible for stimulating the production of red blood cells. In anaemia patients it promotes blood formation. It is also a highly potent substance used for illegal performance enhancement in sports.

“Administering Epo improves regeneration after a stroke (termed ‘neuroprotection’ or ‘neurogeneration’), reducing damage in the brain. Patients with mental health disorders such as schizophrenia, depression, bipolar disorder or multiple sclerosis who have been treated with Epo have shown a significant improvement in cognitive performance,” says Hannelore Ehrenreich of the Max Planck Institute of Experimental Medicine. Along with her colleagues, she has spent many years researching the role played by Epo in the brain.

Prolonged expression of the CRISPR-Cas9 nuclease and gRNA from viral vectors may cause off-target mutagenesis and immunogenicity. Thus, a transient delivery system is needed for therapeutic genome editing applications. Here, we develop an extracellular nanovesicle-based ribonucleoprotein delivery system named NanoMEDIC by utilizing two distinct homing mechanisms. Chemical induced dimerization recruits Cas9 protein into extracellular nanovesicles, and then a viral RNA packaging signal and two self-cleaving riboswitches tether and release sgRNA into nanovesicles. We demonstrate efficient genome editing in various hard-to-transfect cell types, including human induced pluripotent stem (iPS) cells, neurons, and myoblasts. NanoMEDIC also achieves over 90% exon skipping efficiencies in skeletal muscle cells derived from Duchenne muscular dystrophy (DMD) patient iPS cells. Finally, single intramuscular injection of NanoMEDIC induces permanent genomic exon skipping in a luciferase reporter mouse and in mdx mice, indicating its utility for in vivo genome editing therapy of DMD and beyond.