Collaborative: Precision Modulation of Macrophages using Chemokine-RNA Therapeutics to Regress Fibrosis and Address Treatment Inequalities in Chronic Liver Diseases

MRC’s Collaborative awards provide students with experience of collaborative research with a non academic partner, enabling the student to spend a period of time with the non-academic partner (usually no less than three months over the lifetime of the PhD).

Background

Fibrotic diseases are a major cause of global mortality, yet there are few effective therapies that actively promote scar resolution. Liver fibrosis is a leading example: chronic injury drives excessive extracellular matrix deposition, tissue stiffening and ultimately liver failure, often before patients have access to treatment. Chronic liver disease (CLD) is a major contributor to premature morbidity and mortality in Scotland and the UK.[1] Importantly, CLD has a disproportionate burden in socioeconomically deprived communities where risk factors, delayed diagnosis, multimorbidity and barriers to specialist care inhibit access to clinical interventions and resut in poor patient outcomes.[1] Developing precise, mechanism-based therapies that can halt or reverse fibrosis therefore has direct relevance to health equality, because even modest improvements in treatment effectiveness, safety and deployability could deliver substantial benefit to deprived populations currently experiencing the worst outcomes. 

Monocyte-derived macrophages (MDMs) are key regulators of fibrosis progression. In particular, recruited CCR2+ monocytes and macrophages can contribute to inflammatory damage, but can also be reprogrammed towards tissue regeneration. These cells therefore represent an attractive target for precision therapeutics.[2] However, a major therapeutic challenge is how to selectively target pathogenic MDMs without disrupting macrophages or other cells responsible for homeostatic functions. The central hypothesis is that CCR2 can be exploited as a drug-delivery target, rather than a signalling target, to reprogram MDMs towards a scar-degrading phenotype, establishing chemokine-RNA conjugates as a new precision medicine toolkit for fibrotic diseases. The project will build on established expertise in the Vendrell laboratory in designing chemokine-drug conjugates (REF1) and adapt these workflows to the delivery of therapeutic RNA payloads. As a proof of concept, CCL2 will be used as a targeting chemokine to direct RNA therapeutics to CCR2+ monocytes and CCR2+ macrophages. This will address a central challenge in cell-selective RNA therapeutics: determining how much RNA actually reaches the cytosol of target cells and how much is required to change their phenotype. To tackle this, the student will develop chemical linker strategies that support efficient chemokine-RNA conjugation and optimised intracellular release with the help of fluorescence quantitative imaging tools developed by the supervisory team, which report conjugate integrity and payload release rather than total fluorescence.[3] 

The project will use a data-driven approach to RNA target selection. Candidate macrophage targets will be identified from single-cell RNA sequencing and spatial transcriptomic datasets from fibrotic human liver, focusing on disease-associated genes including OLR1, CLEC5A, TREM2, CTSD and MMP9.[4]. Using linked clinical metadata, target prioritisation will also consider indicators linked to socioeconomic deprivation, disease aetiology and other demongraphics, to ensure that candidate targets are relevant across clinically diverse patient groups rather than being optimised only for narrowly selected cohorts. 

RNA payloads will be siRNA and antisense oligonucleotides, whose size and chemistry make site specific conjugation to a small chemokine likely to succeed for tartget knockdown, with mRNA retained as a longer-term option for target overexpression. These will first be screened in primary human MDMs from liver disease patients to confirm target modulation and functional activity, with sample selection designed, where feasible, to capture clinically relevant heterogeneity in disease aetiology, fibrosis severity, age, sex and comorbidity. Then, selected RNAs will then be conjugated to CCL2 and assessed for selective delivery and effect on macrophage phenotype. 

A central aim will be to determine whether CCL2-RNA conjugates can enhance macrophage mediated scar degradation. The student will test candidate conjugates in primary human MDM cultures and assess ECM remodelling, degradative enzyme expression, inflammatory phenotypes and macrophage function. Delivered intracellular dose will be measured in single cells alongside these readouts, so that response can be related to how much payload a cell actually received and a failure of delivery distinguished from a failure of the target. Lead conjugates that demonstrate pro Page 7 of 13 resolution activity will be taken forward into increasingly complex models of liver fibrosis, including spheroids, precision-cut liver slices and in vivo mouse models. This staged workflow will allow the project to identify RNA payloads with translational potential while establishing robust models for testing macrophage-targeted therapies. 

The project will also explicitly consider future implementation and equity of access. In collaboration with translational colleagues and AbbVie, the student will consider how target product profile features — including dosing frequency, route of administration, manufacturability, safety monitoring requirements and compatibility with existing liver disease care pathways — could influence equitable deployment. This is important because advanced therapies can widen health inequalities if they are difficult to deliver outside specialist centres. By incorporating feasibility and implementation considerations early, the project will train the student to evaluate not only whether a therapy works, but whether it could realistically benefit the high-burden populations most affected by chronic liver diseases. 

The training provided will be highly interdisciplinary and aligned with precision medicine. The student will gain experience in computational transcriptomic data analysis, chemical biology, conjugation chemistry, drug delivery, RNA therapeutic design, macrophage biology and human disease model systems. Practical training will include bioinformatics, synthesis and characterisation of chemokine RNA conjugates, primary human monocyte and macrophage culture, RNA delivery and target knockdown/overexpression assays, flow cytometry, quantitative microscopy, qPCR, immunostaining, functional assays, and analysis of complex multicellular fibrosis models. The student will also develop transferable skills in experimental design, biostatistics, research ethics, data management, scientific communication and collaborative working. 

By the end of the project, the student will have helped establish a modular chemokine-RNA therapeutic platform for macrophage reprogramming, together with a quantitative measure of intracellular delivery that applies equally to other targeted modalities . Although the initial focus is liver fibrosis, this approach could be adapted to other inflammatory and fibrotic diseases where macrophages play a central role.

Training Outcomes

Generic and transferable skills provided by the supervisory team: 

* Development of an in vitro platform for the selection and optimisation of therapeutic agents. 

* Data analysis and management, mining skills and bioinformatics. 

* Design and characterisation of chemokine-RNA agents. Site-specific bioconjugation, oligonucleotide handling, purification and analytical characterisation. 

* Cell culture, microscopy, flow cytometry, functional assays and immunohistochemistry. 

* Assessment of optimal agents in ex vivo human tissues. Page 8 of 13 * Image analysis (qualitative and quantitative). * Research ethics and health and safety skills. 

* Target Product Profile based on current standard of care, health economics data, technical feasibility and equity of access, including consideration of affordability, route of administration, monitoring burden and suitability for deployment across different healthcare settings. 

* Participation in the development of marketing strategy through competitive landscape and future emerging technologies (with EI and AbbVie). 

* Understanding how socioeconomic deprivation, multimorbidity and differential access to specialist care shape outcomes in chronic liver disease. 

* Incorporation of health equality considerations into therapeutic design, including patient stratification, sample diversity, implementation feasibility and equitable access. 

* Evaluation of how precision medicine approaches can either reduce or inadvertently widen health inequalities, and how this risk can be mitigated during early translational development. 

* Study IP landscape and freedom to operate. Secure emerging IP, including paper and patent writing. 

* Communication skills.

References: 

[1] https://liveruk.org/about-liver-disease/liver-disease-in-numbers/#affected 

[2] Bhattacharya M, Ramachandran P. Immunology of human fibrosis. Nat Immunol. 2023, 24, 1423 1433. 

[3] Nadal-Bufi F et al. Fluorogenic Platform for Real-Time Imaging of Subcellular Payload Release in Antibody–Drug Conjugates. J. Am. Chem. Soc. 2025, 147, 9, 7578–7587. 

[4] Papachristoforou E at al. A Human Single-cell Atlas Identifies OLR1+ Scar-associated Macrophages as a Therapeutic Target for Chronic Liver Disease. bioRxiv, 2026, https://doi.org/10.1101/2025.08.27.671899