Structural precision meets bio-functionality: Virus-like delivery systems for genetic material

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The targeted delivery of genetic material is becoming increasingly important in therapeutic applications. Viruses are highly effective gene delivery systems but show restrictions in cargo size and cause significant immune responses in the human body. We herein propose the development of polymeric vectors that form virus-like particles upon condensation with genetic material. By using segmented bottle brush copolymers and advanced bioconjugation strategies, we will develop polyplexes featuring a core compartment (containing the cargo), a protective shell mimicking the viral capsid, and a protein corona enabling targeted interactions with cells. Due to their sterically confined nature bottle brush copolymers are ideally suited to mimic the protein-based supramolecular building blocks of a virus. By systematic investigation of polymer structure and composition, the size, shape, stability, and biological interaction profile of polyplexes will be tuned to enable efficient delivery. A new glycosylation strategy will be developed to couple protein ligands to the delivery system in a single-step and site-specific way. This will further fine-tune the interaction profile of the delivery system and enable targeted interactions with specific cell types, e.g., cancer cells. The developed polyplexes are functionally characterized in their mode of action using a reporter gene and a suicide gene in cell culture models and iteratively optimized in feedback loops. Proteins will be modified via genetic engineering to enable glycosyltransferase-based coupling of strained alkyne, which in turn can be coupled to polyplexes via strain promoted click chemistry. This project will enable access to advanced and structurally complex gene delivery systems via efficient and straight forward synthetic methods. In addition, fundamental knowledge about the design of virus-like polyplexes and their structure property relationships will be generated enabling adaption of this platform to various purposes.