Recent advances in cell-free protein synthesis technologies now enable the synthesis and assembly of virus-like particles (VLPs) in a reaction environment that is directly accessible. This, in turn, offers unprecedented control over the transcription, translation, protein folding, and particle assembly reactions. We have used this accessibility to introduce non-natural amino acids into lymphokines and single chain Fv antibody fragments and well as into the coat protein that forms the VLPs. These novel reagents were then used to assemble artificial, non-infectious viral mimics for use as personalized lymphoma vaccines. Multiple surface decorations were added to the VLP surface in a single, simple chemical reaction. We have also used the same accessibility to co-translationally load the VLPs with “cargo”. In this case, a small hairpin RNA (shRNA) was fused to a VLP internalization oligonucleotide, and this oligonucleotide was added to the cell-free reaction to produce VLPs containing the shRNA. These new capabilities provide the foundation for a broad variety of applications including more effective vaccines and custom-designed vehicles for the delivery of therapeutic agents to specifically targeted cells.

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