@article{1fd3288a44b34986a9f312d5e69d8150,
title = "Coupling Lipid Nanoparticle Structure and Automated Single-Particle Composition Analysis to Design Phospholipase-Responsive Nanocarriers",
abstract = "Lipid nanoparticles (LNPs) are versatile structures with tunable physicochemical properties that are ideally suited as a platform for vaccine delivery and RNA therapeutics. A key barrier to LNP rational design is the inability to relate composition and structure to intracellular processing and function. Here Single Particle Automated Raman Trapping Analysis (SPARTA) is combined with small-angle X-ray and neutron scattering (SAXS/SANS) techniques to link LNP composition with internal structure and morphology and to monitor dynamic LNP–phospholipase D (PLD) interactions. This analysis demonstrates that PLD, a key intracellular trafficking mediator, can access the entire LNP lipid membrane to generate stable, anionic LNPs. PLD activity on vesicles with matched amounts of enzyme substrate is an order of magnitude lower, indicating that the LNP lipid membrane structure can be used to control enzyme interactions. This represents an opportunity to design enzyme-responsive LNP solutions for stimuli-responsive delivery and diseases where PLD is dysregulated.",
keywords = "enzyme-responsive systems, label-free dynamic monitoring, lipid nanoparticles, phospholipase D",
author = "Barriga, {Hanna M.G.} and Pence, {Isaac J.} and Holme, {Margaret N.} and Doutch, {James J.} and Jelle Penders and Valeria Nele and Thomas, {Michael R.} and Marta Carroni and Stevens, {Molly M.}",
note = "Funding Information: H.M.G.B. acknowledges support from the H2020 through the Individual Marie Sk{\l}odowska‐Curie Fellowship “SmartCubes” (703666). I.J.P. acknowledges support from the Whitaker International Program, Institute of International Education, USA. M.N.H. acknowledges support from the FP7 Marie Curie Intra‐European Fellowship “SMase LIPOSOME” (626766). This research is published with the support of the Swiss National Science Foundation (P300PA 171540). J.P. acknowledges funding from the NanoMed Marie Sk{\l}odowska‐Curie ITN from the H2020 programme under grant number 676137. V.N. acknowledges support from the Ermenegildo Zegna Founder's Scholarship program. J.P, V.N., and M.M.S. acknowledge support from the Rosetrees Trust. M.R.T. and M.M.S. acknowledge support from the Engineering and Physical Sciences Research Council (EPSRC) toward the i‐sense: EPSRC IRC in “Agile Early Warning Sensing Systems for Infectious Diseases and Antimicrobial Resistance” (EP/R00529X/1) and IRC in “Early Warning Sensing Systems for Infectious Diseases” (EP/K031953/1; www.i-sense.org.uk ). M.M.S. also acknowledges the EPSRC grant “Bio‐functionalized nanomaterials for ultrasensitive biosensing” (EP/K020641/1), the Royal Academy of Engineering Chair in Emerging Technologies award (CiET2021\94) and ERC Seventh Framework Programme Consolidator grant “Naturale CG” (616417). H.M.G.B., M.N.H., and M.M.S. are grateful for support from the Swedish Foundation of Strategic Research through the Industrial Research Centre “FoRmulaEx” (IRC15–0065). The authors acknowledge Diamond Light Source (beamline I22, beamtime awards SM23642, SM18658) for the award of synchrotron beamtime and would like to thank Dr. Andy Smith and Dr. Tim Snow for their support and assistance using the beamlines, as well as Dr. Nayoung Kim, Dr. Miina Ojansivu, Dr. Michael Potter, and Dr. Derrick Roberts for experimental assistance at the beamlines. Experiments at the ISIS Neutron and Muon Source were supported by a beamtime allocation from the Science and Technology Facilities Council (RB1810329). This work benefited from the use of the SasView application, originally developed under NSF award DMR‐0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement 654000. The Cryo‐EM Swedish National Facility was funded by the Knut and Alice Wallenberg, Family Erling Persson, and Kempe Foundations, SciLifeLab, Stockholm University and Ume{\aa} University. Publisher Copyright: {\textcopyright} 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.",
year = "2022",
month = jul,
day = "1",
doi = "10.1002/adma.202200839",
language = "English (US)",
volume = "34",
journal = "Advanced Materials",
issn = "0935-9648",
publisher = "Wiley-VCH Verlag",
number = "26",
}