This is organized by Natural Serotypes (found in nature) and Engineered Capsids (specifically designed to overcome the challenging pulmonary mucus barrier).

Quick Legend: Administration Routes

• IN (Intranasal): Non-invasive delivery to upper airways (nasal cavity/sinuses) and conducting airways.
• IT (Intratracheal) / Aerosol: Delivery directly into the trachea or via nebulization; essential for reaching the lower lungs (bronchioles/alveoli).
• IV (Intravenous): Systemic delivery. Requires capsids that can traverse the alveolar-capillary barrier or reach the lung endothelium.

---

1. Natural AAV Serotypes

Serotype	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV5	Airway Epithelium (Conducting), Alveolar Type II Cells	IN / IT	The Airway Specialist. • Enters cells via sialic acid receptors on the apical (air-facing) surface. • Highly efficient at transducing ciliated airway cells and alveolar type II cells (the cells that produce surfactant).
AAV6	Airway Epithelium (Ciliated), Alveolar Cells	IN / IT	High Efficiency. • Often considered the most efficient natural serotype for airway epithelium in mice and dogs. • Can transduce both conducting airways and alveoli effectively. • Close homology to AAV1 but generally superior in lung tissue.
AAV9	Alveolar Epithelium (Type I & II), Septal Cells	IT / IV	Deep Lung / Systemic. • IV: Can transduce lung tissue when injected systemically (unlike AAV2/5). • IT: Highly effective for deep lung parenchyma (alveoli) but less efficient than AAV5/6 for the upper conducting airways.
AAV1	Airway Epithelium, Alveoli	IN / IT	Similar to AAV6 but generally shows lower transduction efficiency in direct head-to-head comparisons for lung epithelium.
AAV2	Inefficient in Lung	N/A	Historical Reference. • Generally poor transduction in lungs due to inability to bypass the mucus barrier and lack of apical receptors on airway cells.

---

2. Engineered & Synthetic Capsids

The lung presents unique barriers, primarily the thick mucus layer in diseases like Cystic Fibrosis (CF) and the tight junctions of the epithelium.

Variant	Primary Target Cells	Preferred Route	Key Characteristics & Notes
AAV6.2	Ciliated Airway Epithelium	IN / IT	The Mucus Bypass. • A single point mutation (F129L) in the AAV6 capsid. • Drastically improves transduction of airway epithelium by evading proteasomal degradation and traversing mucus better than wild-type AAV6.
AAV204	Bronchial & Nasal Epithelium	IT / Aerosol	CF-Specific Design. • A novel capsid engineered specifically to target the pulmonary regions of Cystic Fibrosis patients. • Shown to restore CFTR function more effectively than AAV6 in preclinical models.
AAV-DJ	Alveolar & Airway Epithelium	IT	Hybrid Power. • A chimera of AAV2, 8, and 9. • Shows robust transduction in lung tissue in vitro and in vivo, often outperforming wild-type serotypes in general expression levels.
AAV2/9 (Formulated)	Alveolar Epithelium	IT	Lipid-Enhanced. • While AAV9 is natural, formulating it with specific cationic lipids (like Dexamethasone-spermine) can alter its tropism to target conducting airways more effectively.

---

3. Tropism by Target Tissue

If you are targeting a specific cell type or disease model:

• Conducting Airways (Trachea/Bronchi): AAV6, AAV5, or engineered AAV6.2.
• Deep Lung (Alveoli / Surfactant Production): AAV9 (especially for systemic reach) or AAV5 (direct delivery).
• Cystic Fibrosis (CFTR delivery): AAV6.2 is a leading capsid candidate due to its ability to handle mucus; AAV5 is a strong natural alternative.
• Lung Endothelium: AAV1 or AAV9 (via Intravenous injection).

Critical Factor: The Mucus Barrier

In lung gene therapy, the serotype is often secondary to the barrier problem, especially in Cystic Fibrosis.

• The Trap: Natural AAVs often get trapped in the thick, sticky mucus layer before they even touch the cell surface.
• The Solution:
  • Engineered Capsids: Variants like AAV6.2 are chemically distinct enough to slip through mucus better.
  • Mucolytics: You often must co-administer mucolytic agents (like NAC or mannitol) to “clear the path” for the vector, regardless of the serotype used.