Akademska digitalna zbirka SLovenije - logo
E-resources
Peer reviewed Open access
  • Engineered virus-like parti...
    Banskota, Samagya; Raguram, Aditya; Suh, Susie; Du, Samuel W.; Davis, Jessie R.; Choi, Elliot H.; Wang, Xiao; Nielsen, Sarah C.; Newby, Gregory A.; Randolph, Peyton B.; Osborn, Mark J.; Musunuru, Kiran; Palczewski, Krzysztof; Liu, David R.

    Cell, 01/2022, Volume: 185, Issue: 2
    Journal Article

    Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery. Display omitted •Engineered virus-like particles (eVLPs) overcome three bottlenecks to protein delivery•DNA-free eVLPs efficiently deliver gene editing proteins with minimal off-target editing•Base editor eVLPs reduced serum Pcsk9 levels 78% following 63% liver editing in mice•Base editor eVLPs improved visual function in a mouse model of genetic blindness Engineered, DNA-free virus-like particles efficiently deliver gene editing proteins, have minimal off-target effects, can be applied in vivo to deliver base editors to multiple organs, and are used to improve visual function in a mouse model of genetic blindness.