Intracellular Barriers To Gene Delivery

DNA vectors that deposit in the appropriate lung region and successfully transverse the mucosal barrier encounter a new set of barriers at the cellular level (Fig. 6). Vectors must first gain access to the interior of target cells either nonspecifically, as in adsorptive endocytosis [49,85], or specifically, as in

Figure 6 Intracellular barriers to gene delivery include cellular uptake, intracellular transport, endosome escape, vector unpacking, and nuclear uptake. The gene carrier illustrated here has targeting moieties on the vector surface that are specific for cell surface receptors. The dotted arrow represents the prerequisite step of bypassing physiological barriers of the lung, such as the mucosal layer, and reaching the target cell surface.

Figure 6 Intracellular barriers to gene delivery include cellular uptake, intracellular transport, endosome escape, vector unpacking, and nuclear uptake. The gene carrier illustrated here has targeting moieties on the vector surface that are specific for cell surface receptors. The dotted arrow represents the prerequisite step of bypassing physiological barriers of the lung, such as the mucosal layer, and reaching the target cell surface.

receptor-mediated endocytosis [86].They must subsequently break free of their endosomal compartments by physically disrupting the lipid bilayer that separates the DNA vectors from the cytoplasm [10,17,169]. Alternatively, vectors may induce a phenomenon termed the "proton-sponge effect," which indirectly disrupts endosomes due to osmotic forces [74]. A step in the intracellular DNA trafficking process that may precede or follow endosomal escape is transport to the perinuclear region [118]. DNA vectors must ultimately deliver their cargo into the nucleus, either by physically transporting DNA through the nuclear pore complex (NPC) or by releasing DNA at the door of the NPC, allowing free DNA to gain access. Finally, DNA must be available to the transcription machinery of the cell in order to synthesize the desired protein.

The need to overcome intracellular barriers may require improved methods of determining rate-limiting steps for specific gene carriers, which will lead to the rational design of new carriers. To this end, our lab uses multiple-particle tracking (MPT) to investigate quantitatively the motion of nanometer-sized DNA delivery vehicles [170].

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