This summary table outlines AAV tropism for the liver, a primary target for gene therapy due to its role in metabolic diseases and protein secretion (e.g., clotting factors for Hemophilia).

Quick Legend: Administration Routes

• IV (Intravenous): Systemic delivery via peripheral vein. Most common clinical route but prone to high liver sequestration (the “liver sponge” effect).
• PV (Portal Vein): Direct injection into the portal circulation. Bypasses some systemic hurdles but is more invasive.
• I.H. (Intrahepatic): Direct injection into the liver parenchyma.

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1. Natural AAV Serotypes

Serotype	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV8	Hepatocytes	IV	The Preclinical King. • The most efficient natural serotype in murine (mouse) models. • Successfully used in Hemophilia B trials (Nathwani et al.). • Species Difference: Remarkably potent in mice, but significantly less efficient in humans/primates.
AAV3B	Human Hepatocytes	IV	The Human Specialist. • Uses the human hepatocyte growth factor receptor (HGFR) for entry. • Shows superior transduction of human liver cells compared to AAV8, which is often mediocre in humans.
AAV5	Hepatocytes	IV	Low Immunogenicity. • Lower prevalence of pre-existing neutralizing antibodies (NAbs) in the human population compared to AAV2 or AAV8. • Currently used in approved therapies for Hemophilia A (Roctavian).
AAV9	Hepatocytes, Alveoli, Neurons	IV	Broad & Robust. • Highly efficient liver transduction but lacks specificity; it will also hit the heart, skeletal muscle, and CNS.
AAV2	Hepatocytes	PV / IV	The Prototype. • The first serotype used for liver gene therapy. Often requires portal vein injection for high efficiency; loses significant potency via peripheral IV.

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2. Engineered & Synthetic Capsids

Designed to solve the “Mouse-to-Human” translation gap and evade pre-existing immunity.

Variant	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV-LK03	Human Hepatocytes	IV	The Clinical Frontrunner. • A “shuffled” capsid (derived from 7 serotypes) selected specifically for its ability to infect human liver cells. • Shares ~98% homology with AAV3B. • Outperforms AAV8 in humanized mouse models and is used in Spark Therapeutics’ Hemophilia trials.
AAV-DJ	Hepatocytes	IV	Superior In Vitro. • A chimera of 8 different serotypes. • Displays incredibly high infectivity in lab settings (cell culture). • In vivo, it remains highly hepatotropic but is sensitive to neutralizing antibodies.
AAV-NP59	Human Hepatocytes	IV	NHP & Human Focused. • Engineered via directed evolution in humanized mice. • Shows high efficiency in Non-Human Primates (NHP) and primary human hepatocytes.
AAVzk2	Liver-Specific	IV	Detargeted Specialist. • A mutant of AAV5 designed to hit the liver specifically while minimizing off-target delivery to the heart, lungs, and kidneys. • Lower NAb prevalence similar to AAV5.

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3. Tropism by Target Tissue

If you are designing a liver-directed study, consider these priorities:

• Human Clinical Application: AAV3B or AAV-LK03 (due to HGFR binding).
• Mouse Research (Proof of Concept): AAV8 (highest efficiency in rodents).
• Maximum Safety (Liver-Specific): AAVzk2 or pair a capsid with the AAT (Alpha-1 Antitrypsin) or TBG (Thyroxine-Binding Globulin) promoter.
• Bypassing Antibodies: AAV5 or AAV-Spark200 (modified AAV8).

Critical Factor: The “Liver Sponge” & Species Gap

The liver is the body’s natural filter for AAV.

1. The Sponge: Because the liver is so efficient at capturing AAV, it acts as a “sink.” If you want to target the heart or brain systemically, you often have to use engineered capsids (like AAV-PHP.eB) specifically designed to avoid the liver.
2. The Species Gap: Never assume a serotype that works in mice will work in humans. AAV8 is 10–100x more potent in mice than in humans, whereas AAV3B and AAV-LK03 are specifically tuned for the human liver.