Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery.
J Am Chem Soc
; 146(22): 15085-15095, 2024 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-38776232
ABSTRACT
The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure-activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Baço
/
RNA Mensageiro
/
Imidazóis
/
Lipídeos
Limite:
Animals
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China