Challenges and Opportunities in Gene Delivery - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 61

Polycation

DNA

A

C

D C Neutralization by

extracellular
components

B

Extracellular
compartment

Complex

HSPG

F

E

Cell cytoplasm

G

Early endosome

Late endosome

Lysosome

H

I

Nucleases

K

J

DNA
degradation

Protein

L

Cellular
factors

N

R

M

Translation

Entry during
mitosis

Q

Nuclear pore complex

Nucleus

O

mRNA
transcription

P

DNA

Figure 2.3 Schematic representation of the intracellular barriers to nonviral gene delivery
vectors. The polycation (cationic lipid or polymer) and DNA are electrostatically complexed
to form DNA-polycation complex (A), which in the extracellular compartment may be
neutralized and deactivated by opsonization and phagocytosis, with reduced cellular
dissociation (B). The DNA-polycation complex interacts electrostatically with the cell surface
proteoglycans (C) (HSPG) and evokes the endocytosis of the DNA-polycation complex (D).
The endocytosized complex is trafficked to early endosomes (E), which may be recycled back
to the cell surface (F); or they may be further trafficked to late endosomes (G), which results
in either trafficking of the complex to lysosome (H) for degradation of the DNA (J) or escape
of the DNA, with or without carrier system, into cytoplasm (I). The dissociation of DNA from
the carrier system (K) may occur in endosome or cytoplasm to release free DNA, which may
be degraded by cytoplasmic nuclease (L); may be linked with the nuclear pore, with the help
of cellular factors (M); or may enter the nucleus during mitosis (N). The DNA is transported to
the nucleus through nuclear pore transport by active or passive transport (O) and is transcripted
to mRNA (P) by cellular machinery. The mRNA crosses the nuclear membrane (Q) to enter
cytoplasm for translation in ribozymes (R) to form therapeutic proteins for the desired action.