De novo protein design to formulate smart mRNA delivery systems

• Applicant: Danny Wilbie, Ph.D.
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Biomaterials ; Pharmacy
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 579428459

Safe delivery of nucleic acids through cell membranes has not only become possible but even instrumental in human health in recent years, as demonstrated by the lipid nanoparticle-based mRNA vaccine against SARS-CoV-2. Efficacy of such medicines is however hampered by heterogeneous cargo encapsulation, a lack of understanding over the interaction with cell membranes, control over specific tissue targeting and efficient intracellular delivery of intact mRNA. Here we propose to integrate protein design and engineered cell membranes to engineer mRNA delivery vehicles of previously unachievable modularity. More specifically, we will combine computational de novo design methods, with biophysical and in cell characterization to: (WP1) design protein self-assembling building-blocks that specifically recognize and oligomerize only in the presence of a target mRNA bound by a natural mRNA binding domain; (WP2) engineer and purify cellular membranes to extracellularly display mini-binders targeting specific cell receptors alongside natural surface markers and potential additional functional proteins; and (WP3) creating high-quality membrane coated protein-nanocages for mRNA delivery. If successful, our approach will allow us to better understand the biophysical principles guiding mRNA-dependent protein self-assembly and the receptor-mediated mechanisms of uptake of hybrid delivery vehicles, but also result in novel vehicles for synthetic biology and biomedical applications.

• DFG Programme: Position