Self-assembling protein scaffolds known as virus-like particles (VLPs) are promising delivery vehicles for diagnostic and therapeutic applications. VLPs are easily produced in a bacterial expression system, are biocompatible, and have defined chemical handles that can attach targeting ligands. However, there are some key challenges to be solved. In particular, VLPs are highly stable and must come apart upon entry to the target cell. Moreover, it is difficult to control their size relative to other delivery platforms. Here, we engineered VLPs based on the MS2 bacteriophage by combining comprehensive codon mutagenesis, one-pot selections, and high-throughput sequencing to create protein fitness maps in a strategy we termed Systematic Mutagenesis and Particle Selection (SyMAPS). Using SyMAPS, we identified several mutations that confer a desired acid instability, as well as a single point mutation that uniformly alters the size and geometry of the VLP. We were intrigued by the mutation that alters the size of the VLP because size is a known characteristic that affects accumulation in tumors. Therefore we applied similar mutations to MS2 homologs to understand if the mutation’s effects were generalizable, and went on to identify alternative mutations that would confer the same size shift. Here, we present the detailed results of this suite of studies, and discuss the role of our engineered VLPs both for theranostic applications and as tools for investigating the role of particle size on tumor penetration.

Systematic engineering of virus-like particles to identify optimal characteristics for nanoparticle delivery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.