Sandia Labs FY22 Laboratory Directed Research & Development Annual Report

FY22 ANNUAL REPORT

NANOPARTICLE-MEDIATED DELIVERY OF THERAPEUTIC mRNA FOR PROTECTION AGAINST LUNG DAMAGE. Researchers developed a generalized approach to nanoparticle (NP) mediated delivery of messenger RNA (mRNA) to the lung, for use in transient

mRNA-based lung therapies, including three that appear exceptionally promising. (PI: Steve Branda)

programming of host cells to produce proteins that counter lung damage. In initial studies, reporter mRNA (fLuc, encoding luciferase) was delivered using lipid coated mesoporous silica NPs (LC-MSN) and lipid NPs (LNP), the latter proving more reliable. Then,

mRNA encoding known protein therapies were

delivered using LNPs. The control formulation (LNP/ fLuc) showed some toxicity in mice with lung damage. Despite this intrinsic toxicity, several test formulations were modestly therapeutic; these included mRNA encoding modified ACE2 (sACE2 Ig), a cytokine receptor antagonist (IL-1RA), and a glycoprotein that promotes vascular development (ANGPT1). This work advances the state of the art for mRNA delivery to the lung and provides a foundation for evaluating and characterizing The development of equations-of-state and transport models in areas such as shock compression and fusion energy science is critical to DOE programs. Notable shortcomings in these activities are phase transitions in highly compressed metals. Fully characterizing high energy density phenomena using pulsed power facilities is possible only with complementary numerical modeling for design, diagnostics, and data interpretation. This team constructed a multiscale simulation framework based on a

combination of high-fidelity electronic structure data, ML, and molecular dynamics enabling quantum-accurate, computationally efficient predictions. This provides kinetics of magneto structural phase transitions along shock Hugoniots and ramp compression paths in the equations of state, and transport properties such as viscosity, electrical and thermal conductivities. Findings from this project were published in the Journal of Material Science and npj computational materials . (PI: Mitchell Wood) A. NPs (100 ug) loaded with fLuc MRNA (5 µg) were administered to C57BI/6J mice via OPA (3 mice per treatment condition); PBS served as a negative control. At 6 h post-treatment, d-luciferin (3 mg) was administered via IP injection, and 5 min later tissues were collected for measurement of luminescence (indicative of luciferase expression) via IVIS analysis (565 nm emission). Representative ivis images (tissues from one mouse per treatment condition) are shown. B. aGalCer (5 µg) and LPS (150 µg) were sequentially (2 d interval) administered to C57BI/6J mice via OPA to induce lung damage. At 1 d post-LPS administration, an LNP/mRNA formulation (2 µg mRNA) was administered via OPA (8 mice per treatment condition). Mortalilty was monitored for 10 d following treatment.

QUANTUM-ACCURATE MULTISCALE MODELING IN HIGHLY COMPRESSED METALS.

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