Non-viral delivery: LNPs and beyond

Challenging the GalNAc dogma: intrinsic LNP chemistry enables LDLR-independent hepatic delivery

Nucleic Acid Insights 2026; 3(3), 161–165

DOI: 10.18609/nuc.2026.021

Published: 22 April
Commentary
Arnab Rudra

Current dogma mandates GalNAc conjugation for LDLR-independent hepatocyte mRNA delivery. However, groundbreaking research from the Anderson and Dahlman labs, alongside Sanofi’s preclinical data, reveals that optimizing internal LNP architecture robustly bypasses the LDLR without complex surface ligands, streamlining future hepatic genetic medicines.

The problem

Standard LNPs rely on the LDLR pathway to enter hepatocytes – a route unavailable to patients with homozygous familial hypercholesterolemia (HoFH).

GalNAc conjugation became the industry workaround, redirecting particles via ASGPR – but adds significant manufacturing complexity.

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The discovery: intrinsic LNP chemistry bypasses LDLR
1
Anderson lab & Alnylam cKK-E12 maintains hepatic delivery in LDLR-deficient models
2
Dahlman lab LDLR dependency is driven by ionizable lipid structure
3
Sanofi GA-16 ionizable lipid achieves fully LDLR-independent hepatocyte delivery
Sanofi's GA-16 LNP showed equivalent hepatocyte delivery in wild-type and LDLR knockout models – with zero effect from LDLR blockade – proving GalNAc is not a prerequisite.
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Key implications
✓
No GalNAc requiredOptimized lipid core bypasses LDLR without surface ligands
⛭
Simpler manufacturingEliminates GalNAc-PEG lipid conjugation
⇧
Broader patient reachEnables treatment of HoFH and other LDLR-deficient conditions
Key interests
LNP delivery Hepatic gene therapy mRNA medicines HoFH

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