Enhancing LNP characterization with multi-angle dynamic light-scattering (MADLS)

3D render of a lipid nanoparticle (LNP)

The use of lipid nanoparticle (LNP) technology shows no signs of slowing down, with a surge in applications supported by reproducible and scalable manufacturing. However, obtaining regulatory approval for products utilizing LNPs can be a significant hurdle.

Meeting the requirements of global regulatory organizations can be a challenge for LNP developers, as it often involves extensive studies and documentation of the product’s features and manufacturing processes. This can be a significant drain on time and resources for developers, who must balance the need for thorough validation to ensure product safety, stability and efficacy, with the need to bring their products to market as quickly as possible.

Developers therefore require methods that enable them to characterize their LNP delivery vectors efficiently and effectively.

What role does MADLS play?

Accurate determination of the biophysical characteristics of a product is key to successful development and approval.

Dynamic light scattering (DLS) is an accepted method for biophysical characterization of LNPs. It is a powerful tool for determining particle size and aggregate formation. Conventional DLS uses a light source to illuminate the scatter of light from a particle, which is detected at a single, specified angle. Scattering intensity fluctuations are then analyzed to calculate the particle size.

Multi-angle dynamic light scattering (MADLS) goes a step further. By measuring samples at multiple angles, MADLS offers improved resolution and accuracy over conventional DLS, providing a more accurate representation of different sized particles in a sample, giving developers greater confidence in their results.

Read more about MADLS here

DLS and MADLS: Same question, slightly different answers

While DLS and MADLS are both routinely used to evaluate consistency between batches and can cover a wide range of particle sizes, MADLS is particularly useful for LNP developers who need more detailed information about the populations within a sample. This is because MADLS not only provides a higher resolution particle size distribution (PSD) with a more accurate representation of different sized particles in a sample, but it also gives particle concentration for every individual population, helping developers elucidate insights that allows them to develop more effective LNP-based mRNA delivery.

Size distribution obtained by Single Angle DLS (red) and MADLS (red), showing higher resolution and actual two particle populations.

For a more detailed and direct comparison of DLS and MADLS features read the application note, read the application note What can MADLS tell you about LNP samples and when should you use it?

The benefits of using MADLS

  • There are several key advantages of using MADLS in your LNP development and manufacturing process, including:
  • Representative measurement of particle size with reduced smoothing
  • Angular independent PSD
  • Multicomponent nanoparticle dispersion characterization with improved resolution
  • Size-resolved concentration measurement of particles unresolvable by orthogonal techniques

How can MADLS support product development?

  • MADLS can support product development in several ways:
  • Assessing batch consistency over time
  • Providing insight into the potential instability of a sample
  • Detecting small populations of larger aggregates in a sample
  • Serving as orthogonal verification for other particle concentration measurement techniques, such as nanoparticle tracking analysis (NTA) or enzyme-linked immunosorbent assay (ELISA)

A powerful combination for mRNA-LNP analysis

In a recent study, our researchers used both DLS and MADLS to analyze two mRNA-LNP formulations using the Zetasizer Ultra. The analyses were automatically optimized by the integrated software (ZS XPLORER) and replicated five times.

This enlightening experiment illustrates the practical capabilities and cross-validation offered by supplementing DLS with MADLS, as well as the versatility of the Zetasizer Ultra. The results revealed the composition of the two samples, with DLS and MADLS each offering unique insights into the particles.

Read the application note What can MADLS tell you about LNP samples and when should you use it? to access the full details of the method and results, and discover how MADLS can support your LNP development.