Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen

Jan 1, 2025Journal of the American Chemical Society

Specially designed degradable lipids help deliver mRNA throughout the body to the spleen

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Abstract

A library of 270 dendron-like degradable ionizable lipids was constructed to enhance mRNA delivery.

Dendron-like ionizable lipids improved mRNA delivery to the spleen in vivo compared to traditional lipid analogs.
Proteomic analysis indicated that these lipids may enhance the targeting of key protein clusters in the spleen.
The lead formulation, 18-2-9b2, successfully encapsulated Cre mRNA and achieved significant genome modification in splenic macrophages.
18-2-9b2 also enabled effective expression of BACH1 mRNA, leading to reduced Spic levels in splenic red pulp macrophages.
These findings suggest that dendron-like LNPs could facilitate targeted mRNA delivery for various therapeutic applications.

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Lipid nanoparticles (LNPs) have emerged as pivotal vehicles for messenger RNA (mRNA) delivery to hepatocytes upon systemic administration and to antigen-presenting cells following intramuscular injection. However, achieving systemic mRNA delivery to non-hepatocytes remains challenging without the incorporation of targeting ligands such as antibodies, peptides, or small molecules. Inspired by comb-like polymeric architecture, here we utilized a multiarm-assisted design to construct a library of 270 dendron-like degradable ionizable lipids by altering the structures of amine heads and multiarmed tails for optimal mRNA delivery. Following in vitro high-throughput screening, a series of top-dendron-like LNPs with high transfection efficacy were identified. These dendron-like ionizable lipids facilitated greater mRNA delivery to the spleen in vivo compared to ionizable lipid analogs lacking dendron-like structure. Proteomic analysis of corona-LNP pellets showed enhancement of key protein clusters, suggesting potential endogenous targeting to the spleen. A lead dendron-like LNP formulation, 18-2-9b2, was further used to encapsulate Cre mRNA and demonstrated excellent genome modification in splenic macrophages, outperforming a spleen-tropic MC3/18PA LNP in the Ai14 mice model. Moreover, 18-2-9b2 LNP encapsulating therapeutic BTB domain and CNC homologue 1 (BACH1) mRNA exhibited proficient BACH1 expression and subsequent Spic downregulation in splenic red pulp macrophages (RPM) in a Spic-GFP transgene model upon intravenous administration. These results underscore the potential of dendron-like LNPs to facilitate mRNA delivery to splenic macrophages, potentially opening avenues for a range of mRNA-LNP therapeutic applications, including regenerative medicine, protein replacement, and gene editing therapies.

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Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen

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