Size | Reduced opsonization and RES uptake at <200 nm |
| Affects transport (transvascular and interstitial) and retention (enhanced in tumors for 50–200 nm NP) |
| Internalization of inorganic NP and liposomes (maximum at 30–50 nm) |
| Intracellular trafficking/processing |
Surface charge | Affects opsonization (rapid RES clearance of cationic liposomes) |
| Affects electrostatic interaction with vessel pore |
| Promotes interactions with ECM components, reduces interstitial transport |
| Increases binding to cell membrane and internalization (positively charged NP shows higher binding and internalization compared with neutral or negatively charged NP) |
Biomaterial and surface modification | Coating with hyaluronic acid reduces immunogenicity |
| Cationic cell-penetrating peptide promotes NP internalization and perinuclear localization |
| Collagenase and hyaluronidase alter ECM, promote interstitial transport |
| Ligands for targeting (e.g., folate, transferrin, CD19, CD20, uPAR, HER2) enhances uptake and accumulation |
| pH-sensitive fusogenic polymers, peptides, or lipids enhance cargo release in endosomes |
Shape and geometry | Higher curvature leads to a larger degree of membrane wrapping |
| Higher uptake of spherical NP vs. rod-shaped NP in murine macrophages and human HeLa cells |
| Higher uptake of nanorods with shorter aspect ratio (length-to-width) in HeLa and human breast MCF7 cells vs. longer ratio, whereas the opposite was found for cationic crosslinked pegylated hydrogel NP in HeLa cells |
| Lower uptake for smaller NP (100 and 300 nm) vs. larger NP with the same aspect ratio |
For mesoporous silica NP, spherical NP uses clathrin-mediated endocytosis, whereas the rod- or worm-shaped analogs prefer macropinocytosis |
Gold nanorods align to cell membrane in a near-parallel manner followed by rotating by ∼90° to enter the cell via a caveolae-mediated pathway |
Molecular dynamic simulations suggest slow membrane wrapping of NP with sharp edges or high curvature (e.g., cubes) |
Shape of NP affects biodistribution; for example, 1) longer circulation for higher aspect ratio NP (e.g., filomicelles, rods) vs. spherical NP; 2) discoidal/plate-like NP accumulate in the heart and lungs, presumably due to the margination under flow leading to the accumulation on vascular walls; and 3) spheres and short rods tend to accumulate more in the liver than longer rods, whereas NP with a higher aspect ratio concentrate more in the spleen and lungs |