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Structural Profiling of Lipid Nanoparticles at Sub-10 nm Resolution via AF4 Coupled Online to SAXS and SANS

Bittrich, Eva ; Boye, Susanne ; Van Niekerk, Zanelle ; Stanvliet, Zahn ; Porfetye, Arthur ; Herranz-Trillo, Fátima ; Bolinsson, Hans LU orcid ; Gaydarova, Stefaniya ; Tzachev, Christo and Martel, Anne , et al. (2026) In Small Methods
Abstract

Precise mapping of structural heterogeneity at the sub-10 nm scale is pivotal for rational nanoparticle design, yet conventional analytical workflows remain inadequate. Here we integrate dilution-controlled asymmetric flow field-flow fractionation (AF4) with small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) to interrogate ellipsoidal solid–liquid lipid nanoparticles (LNPs). The dilution-controlled AF4 mode amplifies scattering contrast, enabling robust, shape-resolved analysis across entire elution profiles. Coupling AF4 to SANS in D2O further sharpens resolution for the smallest fractions by reducing particle diffusion through increased solvent viscosity. Comparative sizing shows that SAXS/SANS... (More)

Precise mapping of structural heterogeneity at the sub-10 nm scale is pivotal for rational nanoparticle design, yet conventional analytical workflows remain inadequate. Here we integrate dilution-controlled asymmetric flow field-flow fractionation (AF4) with small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) to interrogate ellipsoidal solid–liquid lipid nanoparticles (LNPs). The dilution-controlled AF4 mode amplifies scattering contrast, enabling robust, shape-resolved analysis across entire elution profiles. Coupling AF4 to SANS in D2O further sharpens resolution for the smallest fractions by reducing particle diffusion through increased solvent viscosity. Comparative sizing shows that SAXS/SANS accurately capture primary particles down to ∼5 nm, whereas multi-angle light scattering chiefly detects loosely associated aggregates. Morphology profiling reveals that surfactant identity governs particle shape, polydispersity, and overall architecture. Joint SAXS/SANS modeling uncovers a 2–3 nm polar shell enveloping an internal core–shell morphology. Together, these insights refine our understanding of LNP size, morphology and drug localization and establish dilution-controlled AF4-SAXS/SANS as a high-resolution platform for dissecting complex nanoparticle systems relevant to biomedical applications.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
AF4-SANS, AF4-SAXS, drug delivery system, ellipsoidal nanoparticles, lipid nanoparticles, online/in situ coupling, quinine
in
Small Methods
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105034587552
  • pmid:41906876
ISSN
2366-9608
DOI
10.1002/smtd.70639
language
English
LU publication?
yes
id
46612073-5a57-4bd8-afe2-c6c8599a6ae2
date added to LUP
2026-05-13 10:10:55
date last changed
2026-06-24 13:19:47
@article{46612073-5a57-4bd8-afe2-c6c8599a6ae2,
  abstract     = {{<p>Precise mapping of structural heterogeneity at the sub-10 nm scale is pivotal for rational nanoparticle design, yet conventional analytical workflows remain inadequate. Here we integrate dilution-controlled asymmetric flow field-flow fractionation (AF4) with small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS) to interrogate ellipsoidal solid–liquid lipid nanoparticles (LNPs). The dilution-controlled AF4 mode amplifies scattering contrast, enabling robust, shape-resolved analysis across entire elution profiles. Coupling AF4 to SANS in D<sub>2</sub>O further sharpens resolution for the smallest fractions by reducing particle diffusion through increased solvent viscosity. Comparative sizing shows that SAXS/SANS accurately capture primary particles down to ∼5 nm, whereas multi-angle light scattering chiefly detects loosely associated aggregates. Morphology profiling reveals that surfactant identity governs particle shape, polydispersity, and overall architecture. Joint SAXS/SANS modeling uncovers a 2–3 nm polar shell enveloping an internal core–shell morphology. Together, these insights refine our understanding of LNP size, morphology and drug localization and establish dilution-controlled AF4-SAXS/SANS as a high-resolution platform for dissecting complex nanoparticle systems relevant to biomedical applications.</p>}},
  author       = {{Bittrich, Eva and Boye, Susanne and Van Niekerk, Zanelle and Stanvliet, Zahn and Porfetye, Arthur and Herranz-Trillo, Fátima and Bolinsson, Hans and Gaydarova, Stefaniya and Tzachev, Christo and Martel, Anne and Nilsson, Lars and Schweins, Ralf and Lederer, Albena}},
  issn         = {{2366-9608}},
  keywords     = {{AF4-SANS; AF4-SAXS; drug delivery system; ellipsoidal nanoparticles; lipid nanoparticles; online/in situ coupling; quinine}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Small Methods}},
  title        = {{Structural Profiling of Lipid Nanoparticles at Sub-10 nm Resolution via AF4 Coupled Online to SAXS and SANS}},
  url          = {{http://dx.doi.org/10.1002/smtd.70639}},
  doi          = {{10.1002/smtd.70639}},
  year         = {{2026}},
}