Reprogramming mRNA Delivery Tropism via Nitrogen-To-Sulfur Substitution in Ionizable Lipids

Area of Science:

• Biochemistry
• Drug Delivery
• Nanotechnology

Background:

• Ionizable lipids are crucial for mRNA therapeutics, with current lipids like ALC-0315 showing strong liver targeting.
• This liver-specific tropism limits applications for extrahepatic (outside the liver) delivery.
• Developing new lipid formulations faces significant safety validation hurdles.

Purpose of the Study:

• To explore a nitrogen-to-sulfur (N-to-S) switching strategy in lipid head groups to modulate tissue distribution of lipid nanoparticle (LNP)-mRNA.
• To assess the potential of this modification for extrahepatic delivery and therapeutic applications.

Main Methods:

• A nitrogen-to-sulfur (N-to-S) atomic-level modification was applied to the marketed ALC-0315 lipid to create S-ALC-0315.
• Formulation optimization involved combining S-ALC-0315 with its parent lipid at a 1:2 molar ratio.
• The resulting LNPs were evaluated for tissue targeting, immune response induction, and anti-tumor efficacy in preclinical models.

Main Results:

• The N-to-S modification successfully redirected LNP-mRNA delivery tropism from the liver to pulmonary tissues.
• Optimized formulations containing S-ALC-0315 demonstrated spleen targeting.
• These spleen-targeted LNPs promoted antigen-specific cytotoxic T lymphocyte (CTL) generation and showed significant anti-tumor effects in two models.
• The N-to-S modification strategy maintained a favorable safety profile.

Conclusions:

• The N-to-S lipid modification is a versatile platform for engineering LNP-mRNA tropism for targeted delivery.
• This strategy effectively enables extrahepatic delivery, particularly to the lungs and spleen.
• The approach holds promise for accelerating the clinical translation of mRNA therapeutics by overcoming delivery limitations and enhancing efficacy, especially in cancer treatment.