(110f) Rational Design Approaches & Engineering Effective & Stable Targeted Delivery Systems & Formulations for RNA Therapeutics

RNA therapeutics enable personalised medicine and effective treatments for rare, infectious and life-threatening diseases. A milestone of RNA therapeutics was the clinical approval of messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, administered for combating COVID-19. The greatest failure of current vehicles is achieving effective targeted delivery of RNA therapeutics, thus, limiting RNA agents from exerting the desired therapeutic effect at the intended target site.

I develop approaches for rationally designing and engineering effective and stable therapeutic delivery formulations. My developed approaches require systematically accounting and defining the key biological barriers that a therapeutic delivery system encounters and ought to overcome, from the point of administration to target-site arrival. Currently, my research focus is to overcome obstacles including nonspecific distribution, cellular uptake, and escape from endolysosomal pathway. Additional areas of focus include improving therapeutic thermostability and opening-up novel avenues for site-specific localisation of therapeutics.

To date, implementing my developed rational design strategies has enabled (i) increasing the cellular uptake, transfection efficiency, and shelf life of self-amplifying RNA COVID-19 vaccines; (ii) improving the thermostability of effective virus-like particles for distribution in low- and middle-income countries; (iii) the scalable manufacturing of stable polyethylene glycol (PEG) free LNPs, eliminating concerns related to the presence of anti-PEG antibodies; (iv) the formation of stable injectable hydrogels for localised delivery; and (v) enhancing the targeted delivery of therapeutics across the blood-brain barrier in vivo.^1,2 Systematic experimental studies and molecular dynamic simulations revealed fundamental insight into the mechanisms of stabilisation and suppressed aggregation of proteins in strategically developed formulations.^3,4 This along with my coined methods for predicting the thermodynamic parameters of protein therapeutics will be shown, which could advance designs of stable therapeutic delivery formulations.

References

1. Shmool, T. A.; Hallett, J. P.; Bhamra, A. K.; Chen, R. Stable Composition. PCT/GB2022/051392, WO 2022/254209.
2. Shmool, T. A.; Constantinou, A. P.; Jirkas, A. et al. Chem. 2022, 13, 2340-2350.
3. Shmool, T. A.; Martin, L. K.; Bui-Le, L. et al. Sci. 2021, 12, 9528-9545.
4. Shmool, T. A.; Martin, L. K.; Matthews, R. P. et al. JACS Au 2022, 2, 2068-2080.