Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization

Webster, Elizabeth R.; Peck, Nicole E.; Echeverri, Juan Diego; Gholizadeh, Shima; Tang, Wei-Lun; Woo, Rinette; Sharma, Anushtha; Liu, Weiqun; Rae, Chris S.; Sallets, Adrienne; Adusumilli, Gowrisudha; Gunasekaran, Kannan; Haabeth, Ole A. W.; Leong, Meredith; Zuckermann, Ronald N.; Deutsch, Samuel; McKinlay, Colin J.

doi:10.1021/acsnano.4c05513

Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization

Journal Article · Tue Aug 06 00:00:00 EDT 2024 · ACS Nano

DOI:https://doi.org/10.1021/acsnano.4c05513· OSTI ID:2440664

^[1]; Peck, Nicole E. ^[1]; ^[1]; Gholizadeh, Shima ^[1]; Tang, Wei-Lun ^[1]; Woo, Rinette ^[1]; Sharma, Anushtha ^[1]; Liu, Weiqun ^[1]; Rae, Chris S. ^[1]; Sallets, Adrienne ^[1]; Adusumilli, Gowrisudha ^[1]; Gunasekaran, Kannan ^[1]; Haabeth, Ole A. W. ^[1]; Leong, Meredith ^[1]; ^[2]; Deutsch, Samuel ^[1]; ^[1]

Nutcracker Therapeutics, Inc., Emeryville, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Molecular Foundry

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2440664

Journal Information:: ACS Nano, Journal Name: ACS Nano Journal Issue: 33 Vol. 18; ISSN 1936-0851

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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