Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization.
ACS Nano
; 18(33): 22181-22193, 2024 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-39105751
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
ARN Mensajero
/
Peptoides
/
Nanopartículas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Nano
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos