(387t) Insights into Lipid Nanoparticle Morphology and Blebs

Research Interests: crystallization and particle engineering, lipid nanoparticle formulation, automation, pharmaceutical development

Poster abstract:

Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicles for nucleic acid therapeutics (1). Comprising four distinct lipid components, LNPs self-assemble into complex internal architectures that influence delivery efficacy and therapeutic potency. Among these morphological features, blebs—aqueous-filled liposomal protrusions—have garnered increasing attention due to their frequent appearance across diverse LNP formulations and their potential link to structural heterogeneity (1, 2).

In this study, we leverage automated LNP formulation with a multi-modal analytical workflow—combining small-angle X-ray scattering (SAXS), spatially resolved dynamic light scattering (SR-DLS), and extensive cryo-transmission electron microscopy (cryo-TEM)—to systematically investigate the occurrence, formation, and structural role of blebs. We present new insights into the physicochemical drivers of bleb formation and discuss their implications for LNP design and performance.

Acknowledgements: This research was supported by the U.S. Food and Drug Administration under the FDA BAA-22-00123 program, Award Number 75F40122C00200.

References:

1. A. Udepurkar, C. Devos, P. Sagmeister, F. Destro, P. Inguva, S. Ahmadi, E. Boulais, Y. Quan, R. D. Braatz, A. S. Myerson, Structure and Morphology of Lipid Nanoparticles for Nucleic Acid Drug Delivery: A Review. ACS Nano 19, 21206–21242 (2025).
2. M. L. Brader, S. J. Williams, J. M. Banks, W. H. Hui, Z. H. Zhou, L. Jin, Encapsulation state of messenger RNA inside lipid nanoparticles. Biophysical Journal 120, 2766–2770 (2021).