Targeting aims to put more of the dose where disease is and less everywhere else. Passive targeting uses the body's own anatomy, such as leaky tumour vessels; active targeting adds ligands that recognise receptors on the cells you want to reach.
- Passive mechanism
- EPR effect, organ filtration
- Active ligands
- Antibodies, peptides, aptamers, sugars
- Median tumour delivery
- ~0.7% of injected dose
Most systemically injected drugs spread throughout the body, and only a small fraction reaches the diseased tissue. Targeting strategies raise that fraction, increasing efficacy while sparing healthy organs.
Passive targeting relies on size and anatomy. Nanoparticles of roughly 20–200 nm escape the normal, tight vasculature but can leak through gaps in tumour or inflamed vessels and stay because lymphatic drainage is poor — the enhanced permeability and retention (EPR) effect. Size and charge also naturally direct particles to the liver, spleen or lymph nodes.
Active targeting decorates the carrier surface with ligands — antibodies, antibody fragments, peptides, aptamers, folate, transferrin or GalNAc sugars — that bind receptors overexpressed on target cells. Active targeting mostly improves cell uptake and selectivity once the carrier has arrived; it works on top of, not instead of, good circulation and tissue access.
Targeting at three levels
Organ level
Particle size, surface charge and lipid composition steer carriers to liver, spleen, lungs or lymph nodes.
Tissue level
EPR, inflammation and local delivery concentrate carriers in tumours or diseased tissue.
Cell level
Ligand–receptor binding triggers receptor-mediated endocytosis in specific cell types.
Subcellular level
pH-responsive or signal-peptide designs release cargo in the cytosol, nucleus or mitochondria.
How it works
- 1
Circulate
A stealth coating such as PEG lets carriers avoid immediate clearance and stay in blood long enough to accumulate.
- 2
Extravasate
Particles leave the bloodstream through leaky vessels or via active transport across the endothelium.
- 3
Bind and internalise
Surface ligands engage receptors and trigger endocytosis into target cells.
- 4
Release
The carrier escapes the endosome or responds to local signals to free its payload.
Passive versus active targeting
| Feature | Passive targeting | Active targeting |
|---|---|---|
| Mechanism | Size, charge and leaky vasculature (EPR) | Ligand–receptor recognition |
| Main benefit | Accumulation in tissue | Selective cell uptake |
| Design complexity | Lower | Higher (conjugation, ligand density) |
| Dependence on patient | High — EPR varies widely | Depends on receptor expression |
| Example | Liposomal doxorubicin | GalNAc–siRNA conjugates, antibody–drug conjugates |
Common targeting ligands
| Ligand | Receptor | Target cells |
|---|---|---|
| GalNAc | Asialoglycoprotein receptor | Hepatocytes |
| Folate | Folate receptor-α | Many epithelial cancers |
| Transferrin | Transferrin receptor | Brain endothelium, tumours |
| RGD peptide | αvβ3 integrin | Tumour vasculature |
| Anti-HER2 antibody | HER2 | Breast and gastric cancer |
| Mannose | Mannose receptor | Macrophages, dendritic cells |
Strengths
- Higher local dose. More drug at the disease site improves efficacy.
- Fewer side effects. Reduced exposure of healthy organs widens the therapeutic window.
- Cell-specific uptake. Ligands improve internalisation into hard-to-reach cells.
- Clinical precedent. GalNAc conjugates and ADCs show targeting works in patients.
Challenges
- Variable EPR. Human tumours show far less, and more heterogeneous, leakiness than mouse models.
- Protein corona. Plasma proteins can cover ligands and mask targeting.
- Liver and spleen capture. The mononuclear phagocyte system removes most nanoparticles regardless of ligand.
- Manufacturing complexity. Ligand density, orientation and stability add quality-control burden.
Where it is used
Oncology
Liposomal and albumin nanoparticles and antibody–drug conjugates for solid tumours.
Liver disease
GalNAc–siRNA medicines silence liver-made disease proteins with infrequent dosing.
Immunotherapy
Targeting dendritic cells and lymph nodes for vaccines and immune modulation.
Brain delivery
Receptor-mediated transcytosis to cross the blood–brain barrier.
What comes next
Targeting is moving from simple accumulation towards precise control of which organs and cells take up the dose.
Organ-selective LNPs
Lipid compositions that reach lung, spleen or bone marrow without ligands.
In vivo cell engineering
Targeted nanoparticles that reprogramme T cells inside the body.
Corona engineering
Designing surfaces that recruit helpful plasma proteins for targeting.
Patient selection
Imaging and biomarkers to identify patients with high EPR or receptor expression.
Passive targeting gets carriers to the right tissue, active targeting gets them into the right cells — the best systems combine long circulation, tissue access and precise recognition.