Gene therapy holds tremendous promise in prevention and treatment of diseases as the approach is based on regulating the expression of genes that are responsible for pathological conditions. The biggest bottleneck for gene delivery has been the development of safe and efficacious delivery systems. Although non-viral vectors are considered as much safer options than their viral counterparts, they suffer from low transfection efficiency. In this review, we highlight the role of non-condensing polymeric delivery systems for oral and systemic gene delivery. Using evidence from contemporary literature, non-condensing polymeric microparticle and nanoparticle systems afford physical encapsulation of the nucleic acid construct and can be engineered for targeted delivery to tissues and cells. Additionally, these systems have shown less toxicity and afford sustained cytoplasmic DNA delivery for efficient nuclear uptake and transfection for both DNA vaccines and therapeutic genes.