Two-pronged pulmonary gene delivery strategy: a surface-modified fullerene nanoparticle and a hypotonic vehicle.

Abstract

Inhaled gene therapy poses a unique potential of curing chronic lung diseases which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically-relevant gene transfer efficacy in the lung thus far due to the presence of numerous biological delivery barriers. Here, we introduce a simple combinatorial approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung in vivo . We have endowed tetra(piperazino)fullerene epoxide (TPFE)-based nanoparticles with non-adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to percolate the airway mucus gel layer and obviate phagocytic uptake by alveolar macrophages. In parallel, we have utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically-driven regulatory volume decrease (RVD) mechanism. We demonstrate here that this two-pronged delivery strategy provides safe, wide-spread and high-level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.