Physics-Guided Quantitative Liquid-EM of Lipid Nanoparticles

 Physics-Guided Quantitative Liquid-EM of Lipid Nanoparticles

Aim

This PhD will develop a time- and dose-dependent framework for quantitative liquid-phase electron microscopy, liquid-EM, of lipid nanoparticles, LNPs, around 100 nm. Building on an existing EM simulation model, the project will investigate how electron scattering, radiation damage, and Brownian motion jointly determine image formation and measurement reliability. Purpose-designed nanofluidic cells will be used to control these effects, test model predictions, and define reliable imaging conditions for LNPs.

Motivation

Liquid-EM is promising for studying soft nanoparticles in liquid, but reliably extracting particle size, morphology, aggregation, dynamics, and beam-induced changes from the images remains challenging because of

• Electron scattering from the liquid and cell windows, which reduces contrast and resolution.

• Radiation damage due to beam-induced processes that can alter the particle and liquid environment.

• Brownian motion and confinement effects, which influence particle dynamics and cause image blur.

• Limited predictive understanding of how these effects combine in images and movies.

The project will combine physical modelling with controlled liquid-EM experiments using purpose-designed nanofluidic cells. An existing EM simulation framework will support the interpretation of image contrast and scattering, while the candidate will investigate how cell geometry, Brownian motion, and radiation damage jointly affect quantitative measurements of LNPs.

Central Hypothesis

A time- and dose-dependent extension of the existing EM model can predict how liquid and window scattering, Brownian motion, and beam-induced changes jointly affect quantitative liquid-EM measurements. Experiments using purpose-designed nanofluidic cells will test the model predictions and identify reliable imaging conditions for LNPs.

Work Packages

WP1: Quantitative Image Formation in Liquid-EM

The student will investigate how scattering from the liquid and cell windows determines the contrast and information obtainable from LNP images. Controlled liquid-EM experiments will be combined with physical modelling and existing EM simulation tools.

Main focus:

• establish how liquid and window thickness affect LNP contrast, noise, and resolution;
• determine which particle properties can be recovered under different scattering conditions;
• test image-formation predictions using controlled nanofluidic geometries;
• quantify the accuracy and uncertainty of image-derived LNP properties.

Deliverable: a quantitative understanding of how liquid and window scattering determine LNP observability in liquid-EM.

WP2: Brownian Motion and Radiation Damage

The student will investigate how confined particle dynamics and electron exposure change the information recorded in liquid-EM images and movies.

Main focus:

• determine how nanofluidic confinement affects LNP motion and surface interactions;
• quantify how particle motion during exposure influences measured size, shape, and contrast;
• identify the onset and evolution of dose-dependent changes in particle morphology, aggregation, contrast, or dynamics;
• distinguish intrinsic particle behaviour from beam-induced and imaging effects.

Deliverable: physical insight into how Brownian motion and radiation damage affect quantitative liquid-EM measurements.

WP3: Nanofluidic Control and Quantitative LNP Imaging

The student will translate the insights from WP1 and WP2 into nanofluidic cells that provide controlled liquid thickness and confinement. A limited number of hypothesis-driven cell geometries will be fabricated and used to test the coupled effects of scattering, motion, and radiation damage.

Main focus:

• design controlled geometries that isolate specific scattering and confinement effects;
• experimentally test predicted relationships between cell geometry, particle dynamics, and image formation;
• identify imaging conditions under which selected LNP properties can be measured reliably;
• compare selected liquid-EM measurements with orthogonal characterization methods.

Deliverable: experimentally validated principles connecting nanofluidic geometry to quantitative liquid-EM measurements of LNPs.

Scope

The project will focus on one primary LNP system and a small number of hypothesis-driven cell geometries. Radiation damage will focus on measurable beam-induced changes rather than a complete radiolysis-reaction network. Brownian motion will focus on confined dynamics relevant to image formation. Image analysis will be developed or adapted as needed to quantify LNP properties, particle dynamics, and beam-induced changes.

Optional Extensions

If the core LNP work is successful, the project may explore:

• protein-containing nanoparticles,

• surface-based radical scavenging,

• electrode-assisted particle positioning or trapping,

• ML-based particle classification.

These remain optional and are not required for PhD success.

One-Sentence Summary

This PhD will use controlled liquid-EM experiments and purpose-designed nanofluidic cells to investigate how electron scattering, radiation damage, and Brownian motion affect quantitative imaging of LNPs, supported by physical modelling.