Supramolecular Lipid Nanoparticle Functionalisation Platform for Targeted Delivery of Nucleic Acids

Our research looks at how we can apply Supramolecular Chemistry in Biological settings. Supramolecular Chemistry is the study of intermolecular, non-covalent interactions. These non-covalent interactions are critical to protein folding, DNA base pairing, and cellular signalling. Supramolecular Chemistry applies these same principles to create artificial systems capable of performing complex tasks. [1-3]

We will develop a host-guest conjugation system for the modular functionalisation of lipid nanoparticles (LNPs) to enable precise, targeted delivery of nucleic acid therapeutics (NATs). We will use supramolecular interactions analogous to high-affinity biological interactions which include protein-ligand (e.g. biotin-streptavidin) complexes and antigen-antibody binding. LNPs have emerged as the delivery vehicle of choice for nucleic acid therapeutics due to their biocompatibility and tuneable properties, along with their ability to protect payloads from degradation, facilitate cellular uptake, and promote endosomal escape. Furthermore, they support scalable clinical grade manufacturing, as proven by their success in mRNA vaccines. The major current limitation of LNPs is their limited tissue specificity beyond the liver, as their natural biodistribution favours hepatic accumulation. LNP functionalisation involves the conjugation of targeting groups to the surface of LNPs and promises increased precision and targeting scope beyond the liver.

Despite advances in LNP technology, precise targeting and control of biodistribution remain significant challenges. Overcoming the inherent hepatotropism of LNPs,[4] which would increase the scope of accessible targets, has proved challenging. Passive targeting strategies, involving modulation of the lipid composition, have had limited success in redirecting LNPs to the lungs or spleen.[5] While sufficient for some applications (i.e. immunotherapies) many diseases require specific targeting beyond the reach of current LNPs. To realise the potential of NATs, delivery vehicles that precisely target a range of tissues and organs are essential.

Surface functionalisation allows LNPs to be actively targeted, overcoming the intrinsic bias of the protein corona, and has yielded exceptional results in research settings. Translation of these functionalised LNPs from the lab to the clinic has proved challenging primarily due to limitations with existing conjugation techniques. Current options, both chemical and biological, are generally low yielding, low throughput, and limit researchers to small libraries suitable only for proof-of-principle studies.

This PhD Project will develop novel supramolecular approaches to targeted lipid nanoparticle generation, enabling robust, high-throughput, and purification-free generation using supramolecular chemistry to attach targeting groups to lipid nanoparticles. These will then be investigated by a range of cutting-edge analytical techniques (i.e. NanoFCM) and in subsequent biological studies.

Figure 1: General project plan and approach. Key benefit is in differentiation of a single stable intermediate LNP to many targeted LNPs, allowing rapid optimisation and successful targeted delivery.

Candidate background

This project would suit candidates with a background in chemistry or biochemistry, and an interest in working at the interface between disciplines. An interest in organic synthesis would be an asset, as would a willingness to learn new techniques. Working across King's College and Crick, the student will be trained in organic synthesis, supramolecular chemistry, and peptide synthesis in the McTernan group. They will gain skills to create compounds, purify them by HPLC, flash chromatography and crystallisation. They will learn to collect and interpret NMR, mass spectrometry, SPR, and ITC data, and so to identify the products of their reactions. They will develop skills in nanoparticle synthesis and analysis, cell culture, and microscopy. The student will benefit from the wider Crick PhD development programme, and will also be encouraged to make close connections to the STPs, whose skills will be leveraged to accelerate the project.

Lab-specific question

Looking at the research undertaken in our lab, what aspect would you be most interested in exploring further? Drawing on your own research experience, what perspective, skill or approach would you bring to investigating it?

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £27,715 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Beeren, S.R., McTernan, C.T. and Schaufelberger, F. (2023) The mechanical bond in biological systems. Chem 9: 1378–1412.
2. Zhao, Z., Ukidve, A., Kim, J. and Mitragotri, S. (2020) Targeting strategies for tissue-specific drug delivery. Cell 181: 151–167.
3. Dong, J. and Davis, A.P. (2021) Molecular Recognition Mediated by Hydrogen Bonding in Aqueous Media. Angewandte Chemie International Edition 60: 8035–8048.
4. Kon, E., Ad-El, N., Hazan-Halevy, I., Stotsky-Oterin, L. and Peer, D. (2023) Targeting cancer with mRNA-lipid nanoparticles: key considerations and future prospects. Nature Reviews Clinical Oncology 20: 739–754.
5. Cheng, Q., Wei, T., Farbiak, L., Johnson, L.T., Dilliard, S.A. and Siegwart, D.J. (2020) Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nature Nanotechnology 15: 313–320.