Exploring the functions of polymers in adenovirus-mediated gene delivery: Evading immune response and redirecting...

Adenovirus (Ad) is a promising viral carrier in gene therapy because of its unique attribution. However, clinical applications of Ad vectors are currently restricted by their immunogenicity and broad native tropism. To address these obstacles, a variety of nonimmunogenic polymers are utilized to modify Ad vectors chemically or physically. In this review, we systemically discuss the functions of polymers in Ad-mediated gene delivery from two aspects: evading the host immune responses to Ads and redirecting Ad tropism. With polyethylene glycol (PEG) first in order, a variety of polymers have been developed to shield the surface of Ad vectors and well accomplished to evade the host immune response, block CAR-dependant cellular uptake, and reduce accumulation in the liver. In addition, shielding Ad vectors with targeted polymers (including targeting ligand-conjugated polymers and bio-responsive polymers) can also efficiently retarget Ad vectors to tumor tissues and reduce their distribution in nontargeted tissues. With its potential to evade the immune response and retarget Ad vectors, modification with polymers has been generally regarded as a promising strategy to facilitate the clinical applications of Ad vectors for virotherapy. STATEMENT OF SIGNIFICANCE: There is no doubt that Adenovirus (Ads) are attractive vectors for gene therapy, with high sophistication and effectiveness in overcoming both extra- and intracellular barriers, which cannot be exceeded by any other nonviral gene vectors. Unfortunately, their clinical applications are still restricted by some critical hurdles, including immunogenicity and native broad tropism. Therefore, a variety of elegant strategies have been developed from various angles to address these hurdles. Among these various strategies, coating Ads with nonimmunogenic polymers has attracted much attention. In this review, we systemically discuss the functions of polymers in Ad-mediated gene delivery from two aspects: evading the host immune responses to Ads and redirecting Ad tropism. In addition, the key factors in Ad modification with polymers have been highlighted and summarized to provide guiding theory for the design of more effective and safer polymer-Ad hybrid gene vectors.