Gene therapy has the potential to treat a wide range of diseases and ailments from cancer to blindness by altering or overcoming disease at its genetic roots. This is accomplished by adding or alternating genetic information of diseased tissue or at a distant site for systemic treatment. Genetically modified viruses are the most efficient tools for delivery of genes, but have significant side effects that have limited the success of clinical trials. Adenovirus (Ad) is a DNA virus that has been tested in over 100 clinical trials and is the focus of this dissertation. Innate and adaptive immune responses, hepatic clearance, and cellular tropism are the primary causes of poor Ad clinical translation. Cloaking technologies using synthetic or biologic materials have the potential to overcome these issues. Chapter 2 & 3 describes a method to address clinical barriers by encapsulating Ad in silica as a nanoparticle formulation. Silica is biodegradeable, biocompatible, and used in variety of nanoparticle formulations to enhance drug delivery. Silica encapsulated Ad (SiAd) enhances transduction and expands tropism in vitro. In immune-compromised mice, SiAd enhanced tumor transduction while reducing liver uptake and in immune-competent mice, SiAd reduced both the innate and adaptive immune response against Ad. As a model for cancer gene therapy, we used Ad expressing TNF-related apoptosis-inducing ligand (TRAIL) and show inhibited tumor growth with SiAd-TRAIL. In chapter 4, we explore applying the concepts of the previous chapters to Adeno-associated virus (AAV), which is another viral vector gaining traction for gene therapy in the clinic and one that is subject to similar barriers to clinical success as Ad. We explore exosome membrane cloaking and silica cloaking as methods to enhance AAV transduction in vitro. Overall, this dissertation covers techniques that seek to merge the efficiency of viral gene expression with the versatility of nanoparticle technology to address clinical challenges in the field of gene therapy.