New nucleic-acid delivery technologies, such as DNA delivery, have recently come to the forefront of scientific advances. As this field is relatively new, the parameters and mechanisms that guide successful and potent DNA immunotherapies still require further elucidation. DNA delivery of monoclonal antibodies (DMAbs) remains challenging because there is no way to directly control in vivo DMAb expression; this presents a barrier to clinical translational of lead DMAb candidates. On the vaccine side, DNA delivery of nanoparticle vaccines induce potent immune responses, but are challenged by the difficulty in engineering stabilized, full-length antigens to present to the immune system to avoid MHC class restriction. To address both important challenges, we utilized sequence and structure engineering approaches to optimize DMAb and nanoparticle vaccine design. For DMAbs, we developed a novel chain-swapping method that involved deliberate mismatch of antibody heavy and light chains. Using information from this mispairing, as well as large antibody repertoire sequencing data from the OAS, we devised new antibody scoring metrics to indicate positions to mutate to improve in vivo expression. Applying such metrics to a SARS-CoV-2 targeting DMAb resulted in significant expression improvements; this showed proof of concept application to address a key roadblock to DMAb clinical translation. For DNA-delivered nanoparticle vaccines, we made use of new machine learning structural prediction algorithms and their associated confidence metrics, as well as additional computational design to engineer stabilized nanoparticle vaccines in a proof-of-concept study for HPV16 E6 and E7 antigens. We demonstrated successful formation of nanoparticle designs and in vivo studies demonstrated that they were able to elicit strong T-cell responses. We further showed expanded epitope targeting in an outbred mouse model. These results serve as a proof-of-concept study on how to engineer potent vaccines that can elicit immunity against multiple epitopes. In summary, this dissertation makes use of sequence and structure engineering toolsets through several proof-of-concept studies to aid in the advancement of both DMAbs and DNA-delivered nanoparticle vaccines and ensure creation of more successful, next generation, DNA-delivered therapies.