2026-10-13T08:01:00Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34046886 2026-10-01T16:06:08Z category_1 category_4 category_146 category_915 category_7 category_12 category_13 category_14 category_19 category_873 category_64 category_135 portal_63 item_type_6 month_year_10_2026

RNA-Lipid Interactions Control Structure and Dynamics of Lipid Nanoparticles Xiaobing Chen (572034) Cong Xu (203537) Carlos R. Baiz (2261029) Biophysics Biochemistry Space Science Physical Sciences not elsewhere classified Medicine Cell Biology Genetics Molecular Biology Pharmacology Chemical Sciences not elsewhere classified Cancer Computational Biology ∼ 10 cm strong electrostatic interactions nucleic acid encapsulation local environment surrounding important factor influencing ester carbonyl band enabling applications ranging lipid ester linkage lipid electrostatic interactions increased interfacial heterogeneity influence delivery performance mc3 ), play results highlight rna loaded lnps relative lipid packing intracellular delivery rational design providing molecular mrna vaccines lnp cores level insights leading platform lamellar phases ionizable lipids inverse hexagonal internal organization interfacial hydration highly sensitive empty lnps dimensional infrared dependent structure dependent changes dependent behavior crispr therapeutics central role 8 narrows 2d ir Lipid nanoparticles (LNPs) are the leading platform for RNA delivery, enabling applications ranging from mRNA vaccines to CRISPR therapeutics. Ionizable lipids, such as DLin-MC3-DMA (MC3), play a central role in nucleic acid encapsulation and intracellular delivery, yet the molecular mechanisms governing LNP structure and function remain incompletely understood. The internal organization of LNP cores is highly sensitive to pH and has been described by inverse hexagonal, cubic, and lamellar phases that influence delivery performance. Here, we investigate the pH-dependent structure and dynamics of MC3-containing LNPs using two-dimensional infrared (2D IR) spectroscopy and molecular dynamics (MD) simulations. Both experiments and simulations reveal pronounced pH-dependent changes in the local environment surrounding the lipid ester linkage. At pH 4, strong electrostatic interactions between RNA and protonated MC3 produce broader spectral features consistent with increased interfacial heterogeneity and hydration. In addition, the frequency fluctuation dynamics exhibit a 46% slowdown in RNA-loaded LNPs relative to empty LNPs. In contrast, increasing the pH from 4 to 8 narrows the ester carbonyl band by ∼10 cm^–1 and yields nearly identical dynamics for loaded and empty LNPs, indicating a more homogeneous and less hydrated lipid interface. MD simulations further demonstrate that MC3 protonation modulates RNA binding, interfacial hydration, and lipid packing. Together, these results highlight RNA-lipid electrostatic interactions as an important factor influencing the local environment within LNPs and potentially their pH-dependent behavior, providing molecular-level insights into the rational design of next-generation RNA delivery systems. 2026-10-01T00:00:00Z Text Journal contribution 10.1021/acs.jpcb.6c04413.s001 https://figshare.com/articles/journal_contribution/RNA-Lipid_Interactions_Control_Structure_and_Dynamics_of_Lipid_Nanoparticles/34046886 CC BY-NC 4.0