Why LNPs find the liver — and how we tune that selectivity
ApoE-mediated endocytosis is the dominant mechanism of LNP hepatocyte uptake after IV injection. Here's what drives it — and how formulation parameters shift organ distribution.
Passive targeting via serum protein adsorption
LNPs don't carry a hepatocyte-targeting ligand. Instead, they exploit endogenous serum biology: Apolipoprotein E (ApoE) spontaneously adsorbs to the LNP surface in circulation, generating a protein corona.
ApoE is a natural ligand for the Low-Density Lipoprotein Receptor (LDLR) expressed at high density on hepatocytes. LDLR-mediated clathrin endocytosis internalizes ApoE-opsonized LNPs — efficiently and selectively.
This mechanism is robust, reproduced across dozens of clinical LNP programs, and does not require modification of the LNP surface chemistry — just the right formulation to allow ApoE adsorption.
LNP circulates in blood; serum ApoE binds to PEG-lipid corona gaps
LNPs (80–120 nm) pass through liver sinusoidal endothelium fenestrae (100–180 nm) to reach hepatocyte surface
ApoE-coated LNP binds hepatocyte LDLR → clathrin-coated pit → early endosome
pH drops to 5.0; ionizable lipid protonates; mRNA released to cytoplasm for translation
How formulation affects hepatic selectivity
Three formulation parameters dominate organ distribution. Gendelivr's screen optimizes all three simultaneously.
PEG Density
Higher PEG density reduces ApoE adsorption and LDLR engagement → lower hepatic uptake but longer circulation time. 1.5–2.0 mol% is typical for hepatic programs. Gendelivr screens 0.5–3.5 mol% to find the selectivity-stability trade-off specific to your payload.
Particle Size
Particles 80–150 nm pass through hepatic fenestrae. Below 60 nm: renal clearance. Above 200 nm: splenic uptake by marginal zone macrophages. Our hit ranking pre-filters for predicted size 80–130 nm by default.
Surface Charge
Near-neutral surface charge at pH 7.4 (zeta potential –5 to +5 mV) minimizes non-specific interactions. Ionizable lipids with pKa >7.0 carry residual positive charge in circulation → macrophage uptake and cytokine release. Our pKa filter directly controls this.
Tuning hepatic selectivity for your gene editing program
Our Formulation Engine optimizes for ApoE adsorption surface, size range for fenestral passage, and pKa-controlled endosomal escape — simultaneously.