Protein nanocage-scaffolded proteoliposomes: de novo design of a platform for bacterial vaccines

Pathogenic bacteria pose significant threats to the global healthcare and the economy.

Amid growing concerns over antimicrobial resistance, many healthcare programs have pivoted to vaccine development, while new vaccine platforms are in a high demand for disease control and swift responses in the case of health emergencies.

A major type of bacterial immunogen is transmembrane beta-barrel (TMB) proteins, which are found on the outer membrane of Gram-negative bacteria and play key roles in virulence.

The native folding and trafficking of TMBs requires specific machineries that do not exist in eukaryotic cell membranes. Consequently, there has been few vaccine platforms for TMB immunogens.

To address this need, I aim to construct protein nanocage-scaffolded proteoliposomes (PNC-PL) that can act as highly potent nanoparticle vaccine platforms for TMBs.

Such nanomaterial will be developed using two cutting-edge strategies in vaccine formulation: multivalent presentation and immune targeting.

Combining my strong background in PNC engineering and my host labs expertise in TMBs and their computation-assisted design, (1) I will multivalently present computationally engineered TMB immunogens on PNCs in a well-controlled manner, resulting in vaccines composed of PNC-PL nanoparticles that mimic the structures of enveloped viruses. (2) I will design transmembrane anchors using computation-assisted methods to host soluble protein ligands that recognize immune cells.

The resultant complexes will be subsequently co-presented with TMB immunogens on PNC-PLs for immune targeting, which will further increase the vaccine potency. (3) With my co-host labs rich immunological resources, I will assess immune cell activation induced by the vaccines as a criterion of potency.

This novel nanosystem will hold great promise to advance vaccine design with challenging immunogens and serve as a versatile technology for biomaterial design in drug delivery, artificial cells, and other applications.