Decoding and engineering the protein interactions of cell membrane-derived nanoparticles: ligand spacing, biophysical characterisation, and translational therapeutic testing in human brain tissue

About the project

About the Project Cell membrane-derived nanoparticles (CMNPs) are biomimetic therapeutics that inherit the surface proteins of their source cells, giving them intrinsic targeting and barrier-crossing properties. In a biological environment their surface is remodelled by protein–protein interactions — involving both retained membrane ligands and an acquired protein corona — and it is these interactions, together with the spatial arrangement, density and spacing of the displayed ligands, that govern targeting, uptake, biodistribution and therapeutic efficacy. Yet the protein interactions of CMNPs, and how ligand spacing tunes them, remain poorly characterised, with no framework linking a nanoparticle's protein-interaction 'fingerprint' to therapeutic performance. This project combines Dr Pluen's expertise in the biophysics of protein–protein interactions with Dr Tapeinos' expertise in cell membrane-derived nanoparticles and microfluidic barrier models. Using a library of CMNPs produced in the Tapeinos laboratory, the student will: (i) physicochemically characterise the library (size, charge, morphology, stability); (ii) engineer ligand presentation by introducing lipid spacers (e.g., PEG-lipids) of defined length to vary inter-ligand spacing and surface density; (iii) quantitatively map the protein–protein interactions and protein corona of each formulation and determine how ligand spacing modulates binding avidity, multivalency and corona composition, using biophysical and proteomic methods; (iv) relate these interaction and spacing profiles to nanoparticle behaviour in microfluidic barrier-on-chip models under flow; and (v) rank the library to identify the lead candidate for translation. In the translational phase, the therapeutic effect of the best-performing nanoparticle will be assessed directly in human brain tissue using ex vivo organotypic brain-slice cultures and patient-derived tissue, with readouts of penetration, cellular uptake, viability and anti-inflammatory response. Registered at the University of Manchester, the candidate will gain interdisciplinary expertise across biophysics, nanomedicine, pharmaceutical sciences and translational neuroscience, delivering a spacing- and protein-interaction-driven framework for the rational design of biomimetic nanotherapeutics with clear clinical relevance. Eligibility Candidates are expected to hold (or be about to obtain) a minimum upper second class (2.1) honours degree (or international equivalent) in Pharmacy, Pharmaceutical Sciences, Biophysics, Biochemistry, Nanotechnology, Chemistry, Biology, Biomedical Sciences or a closely related discipline. A Master's degree in a relevant area is desirable. Candidates with prior hands-on experience in biophysical / molecular-interaction techniques, fluorescence microscopy, proteomics, nanoparticle synthesis/characterisation, cell culture or microfluidics, or with a demonstrable interest in protein–protein interactions, nanomedicine, drug delivery or the blood–brain barrier, are particularly encouraged to apply. Strong written and spoken English is required. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Pharmacy Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

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