High-Throughput In Vivo Screening Identifies Differential Influences on mRNA Lipid Nanoparticle Immune Cell Delivery by Administration Route

体内 纳米颗粒 细胞内 免疫系统 核苷 信使核糖核酸 纳米技术 细胞 细胞生物学 免疫调节 化学 材料科学 生物 免疫学 生物化学 基因 遗传学
作者
Alex G. Hamilton,Kelsey L. Swingle,Ajay S. Thatte,Alvin J. Mukalel,Hannah C. Safford,Margaret M. Billingsley,Rakan El‐Mayta,Xuexiang Han,Benjamin E. Nachod,Ryann A. Joseph,Ann E. Metzloff,Michael J. Mitchell
出处
期刊:ACS Nano [American Chemical Society]
卷期号:18 (25): 16151-16165 被引量:3
标识
DOI:10.1021/acsnano.4c01171
摘要

Immune modulation through the intracellular delivery of nucleoside-modified mRNA to immune cells is an attractive approach for in vivo immunoengineering, with applications in infectious disease, cancer immunotherapy, and beyond. Lipid nanoparticles (LNPs) have come to the fore as a promising nucleic acid delivery platform, but LNP design criteria remain poorly defined, making the rate-limiting step for LNP discovery the screening process. In this study, we employed high-throughput in vivo LNP screening based on molecular barcoding to investigate the influence of LNP composition on immune tropism with applications in vaccines and systemic immunotherapies. Screening a large LNP library under both intramuscular (i.m.) and intravenous (i.v.) injection, we observed differential influences on LNP uptake by immune populations across the two administration routes, gleaning insight into LNP design criteria for in vivo immunoengineering. In validation studies, the lead LNP formulation for i.m. administration demonstrated substantial mRNA translation in the spleen and draining lymph nodes with a more favorable biodistribution profile than LNPs formulated with the clinical standard ionizable lipid DLin-MC3-DMA (MC3). The lead LNP formulations for i.v. administration displayed potent immune transfection in the spleen and peripheral blood, with one lead LNP demonstrating substantial transfection of splenic dendritic cells and another inducing substantial transfection of circulating monocytes. Altogether, the immunotropic LNPs identified by high-throughput in vivo screening demonstrated significant promise for both locally- and systemically-delivered mRNA and confirmed the value of the LNP design criteria gleaned from our screening process, which could potentially inform future endeavors in mRNA vaccine and immunotherapy applications.
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