Reconstructing Cellular Architecture in 3D: Integrated Nanoscale Imaging of Organelles, Molecules and Tissue Structure

About the project

About the Project The objective of this project is to develop and apply novel high-resolution quantitative imaging approaches capable of mapping the organelles and structures that constitute cells in three dimensions and within their physiological tissue context. The project will establish an advanced correlative imaging pipeline with broad applications across cell biology and biomedical research. By combining expansion microscopy (ExM) ( Vo et al., Nat Rev Met, 2026 ) and imaging hardware under development at 3i, quantitative PAINT (qPAINT) pioneered by Dr Sabrina Simoncelli at UCL ( Zaza et al., Nat Com., 2025 ), and volume electron microscopy (EM) available through the LMCB EM Platform, we will create a correlative 3D imaging workflow capable of resolving subcellular architecture with nanometre-scale precision whilst simultaneously quantifying the molecular composition of selected structures in situ within intact tissues. Aims: Develop and optimise a novel ExM – qPAINT workflow for quantitative 3D imaging of intracellular structures; organelles, cytoskeletal networks, and membrane trafficking machinery, within intact tissues. Integrate ExM with volume EM to achieve comprehensive structural and compositional mapping of cells at subcellular resolution in their native tissue environment. Apply these methods to diverse tissues, including the genetically tractable Drosophila intestinal epithelium, under conditions of ageing and dietary regimes. Determine how the spatial organisation of intracellular components supports cellular function and how these relationships scale to tissue-level physiology. Rationale and Importance: Cellular function depends on the precise spatial organisation of intracellular components. Disruption of this organisation underlies ageing, metabolic dysfunction, and disease. Yet current imaging technologies face major limitations: they rarely combine nanoscale three-dimensional resolution with quantitative molecular measurements, and most high-resolution methods are restricted to isolated cells, making it difficult to connect subcellular organisation with tissue physiology. Understanding how intracellular architecture supports organ function requires imaging cells in their native tissue context. Expansion microscopy physically enlarges specimens, enabling super-resolution imaging while preserving tissue architecture. Recent work showed that DNA-PAINT can be performed in polyacrylamide hydrogels while maintaining nanoscale docking strand localisation ( Stein et al., ASC Sen, 2025 ), providing proof-of-concept for ExM–DNA-PAINT integration. Building on this, the project will develop ExM–qPAINT into a quantitative 3D imaging pipeline. Combined with volume EM for ultrastructural context, these approaches will provide unprecedented insight into organelle positioning, cytoskeletal organisation and the molecular machinery underpinning cellular function. The project will use the genetically tractable Drosophila intestine, a tissue composed of multiple cell types that cooperate to absorb nutrients and maintain homeostasis, to investigate how ageing and dietary regimes, affect intracellular organisation and tissue function. The resulting methodologies and biological insights will have broad relevance across cell biology and translational significance for understanding mammalian tissue function, ageing, and age-related decline. Research environment: The student will be based within the LMCB at UCL, an internationally recognised centre of excellence in cell biology, advanced microscopy, and quantitative imaging. The LMCB provides a highly collaborative and interdisciplinary research environment, with access to world-class imaging, electron microscopy, computational, and biological research facilities, as well as a vibrant programme of seminars, workshops, and scientific meetings. 3i (Intelligent Imaging Innovations), is an internationally recognised leader in the development of advanced microscopy instrumentation and imaging solutions for life science research. Through this iCASE partnership, the student will gain direct access to an industrial research and development environment focused on the design, optimisation, and implementation of cutting-edge imaging technologies used by researchers worldwide. During their PhD, they will receive comprehensive training in advanced imaging technologies, quantitative image analysis, electron microscopy, experimental design, data management, scientific communication, and research integrity. Through the iCASE partnership, they will also gain direct exposure to industrial research and development, technology innovation, product development, and collaborative working practices within 3i. We are committed to fostering an inclusive, respectful, and supportive research culture that promotes wellbeing, equality, diversity, and professional development. The student will be encouraged to take advantage of UCL’s extensive doctoral skills training programme, present their work at conferences, engage in networking activities, and develop the scientific, professional, and leadership skills necessary for a successful research career. Project timeline: Year 1: The student will be based at the LMCB (UCL) where they will establish expansion microscopy and qPAINT workflows with 3i. A dedicated 3i imaging centre is being set up at the LMCB, supported by the Division and Faculty, creating an academia–industry interface, which we anticipate will benefit the student by opening career opportunities. A 3i application -engineering specialist will be embedded at the LMCB at least one day per week to support optimisation, troubleshooting, and training. The student will also undertake placements at 3i London to gain experience in instrument development, hardware integration, and commercial R&D. Year 2: The project will integrate expansion microscopy with volume electron microscopy to develop quantitative 3D correlative imaging pipelines. The student will continue work with 3i through London placements, contributing to testing and refinement of imaging hardware and software. If needed, a visit to 3i headquarters in Denver will provide specialist expertise. Biological applications will begin in Drosophila tissues under ageing and dietary stress conditions. Year 3: The student will apply imaging pipeline to biological questions linking intracellular organisation to tissue function. Work will include data acquisition, quantitative analysis, and dissemination of outputs. Continued interaction with 3i will ensure translation into robust, widely applicable workflows. The project will operate within an integrated academic–industrial environment with sustained co-development, supervision, and exposure to translational research and innovation pathways.

Research areas