1:45 PM - SB09.02.02
Designer Protein Chimeras for Next-Generation Cell Therapies
University of Bristol1
Adoptive cell therapies for in vivo tissue engineering are an exciting prospect, but are often limited by poor pharmacokinetics and pharmacodynamics. This can manifest as accumulation of transplanted cells in tissue sinks (e.g., lungs and spleen), leading to the formation of emboli and a poor prognosis. Accordingly, reengineering cells to improve their efficacy is key for the next generation of advanced cell therapies. In practise, this can be achieved through the synthesis of hybrid materials comprising highly cooperative biological and synthetic parts, which can be used to attenuate cell-target tissue interactions and provide compatible extracellular matrix components. Accordingly, we describe an emerging research programme that spans the fields of synthetic biology, nanomedicine, and regenerative medicine. Here, artificial membrane binding protein (AMBP) chimeras are designed and synthesised using a two-step process: protein supercharging to generate a supercationic plasma membrane binding anchor motif, followed by the electrostatic assembly of a membrane active polymer surfactant corona. Significantly, the resulting constructs spontaneously self-assemble at the plasma membrane of stem cells, providing resistance to hypoxia during cartilage tissue engineering.1 Moreover, the methodology can be readily adapted to display a modified thrombin on stem cell, giving rise to plasma membrane nucleated fibrin hydrogels,2 utilised to produce bacterial adhesin fusion constructs that direct stem cells to the myocardium,3 or applied to increase adhesion of stem cells on damaged articular cartilage via peptide display.4
1. Armstrong, J. P. K.; Shakur, R.; Horne, J. P.; Dickinson, S. C.; Armstrong, C. T.; Lau, K.; Kadiwala, J.; Lowe, R.; Seddon, A.; Mann, S.; Anderson, J. L. R.; *Perriman, A. W.; *Hollander, A. P., Artificial membrane-binding proteins stimulate oxygenation of stem cells during engineering of large cartilage tissue. Nature Communications 2015, 6.
2. Deller, R. C.; Richardson, T.; Richardson, R.; Bevan, L.; Zampetakis, I.; Scarpa, F.; *Perriman, A. W., Artificial cell membrane binding thrombin constructs drive in situ fibrin hydrogel formation. Nature Communications 2019, 10.
3. Xiao, W. J.; Green, T. I. P.; Liang, X. W.; Delint, R. C.; Perry, G.; Roberts, M. S.; Le Vay, K.; Back, C. R.; Ascione, R.; Wang, H. L.; Race, P. R.; *Perriman, A. W., Designer artificial membrane binding proteins to direct stem cells to the myocardium. Chemical Science 2019, 10 , 7610.
4. Delint, R.C., Day, G.J., Macalester, W.J., Kafienah, W., Xiao, W., and *Perriman, A.W., An artificial membrane binding protein-polymer surfactant nanocomplex facilitates stem cell adhesion to the cartilage extracellular matrix. Biomaterials, 2021, 276, 120996.