Delivery is a key challenge in novel protein therapeutic development. Even though numerous proteins are potential therapeutic candidates, a lack of delivery method limits the development of protein therapeutics. I have studied protein delivery and designed three novel delivery systems: gold nanoparticle based polymer particle system, multifunctional oligonucleotide, and nanostructured microparticles. Each of delivery system was designed to deliver CRISPR/Cas9 ribonucleoprotein, transcription factors, and oral protein drugs. First of all, CRISPR/Cas9 is a great tool in genome editing field. Moreover, CRISPR/Cas9-mediated genome editing has the potential to revolutionize the treatment of genetic diseases and the development of cell-based therapies. However, precise gene editing with Cas9 is still challenging in vivo because it requires simultaneous and efficient delivery of Cas9, guide RNA, and donor DNA into cells. We designed a gold nanoparticle-based delivery vehicle, CRISPR-Gold, which can directly deliver Cas9 protein, guide RNA (gRNA), and donor DNA in vitro and in vivo and efficiently induce homology directed repair (HDR). CRISPR-Gold is composed of gold nanoparticles assembled with the Cas9-gRNA ribonucleoprotein (RNP) complex, donor DNA, and an endosomal disruptive polymer. We demonstrate that CRISPR-Gold can induce HDR in human stem cells and mouse primary cells with an efficiency that is significantly higher than conventional transfection methods. Notably, we show that CRISPR-Gold can correct a nonsense mutation in the dystrophin gene that causes Duchenne muscular dystrophy in mdx mice, and restore dystrophin protein expression in mouse muscle after a single injection. Another potential protein therapeutic group is the transcription factor, which can have broad effects in gene regulation. We designed a novel multifunctional oligonucleotide, termed DARTs, which can deliver transcription factors with high efficiency in vivo. DARTs are composed of an oligonucleotide that contain a transcription factor binding sequence and hydrophobic membrane disruptive chains that are masked by acid cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to bind transcription factors, trigger endocytosis in hepatocytes, and stimulate endosomal escape. The DARTs target hepatocytes as a result of the galactose residues and can disrupt endosomes efficiently with minimal toxicity because the unmasking of their hydrophobic domains selectively occurs in the acidic environment of the endosome. DARTs showed efficient delivery of the transcription factor Nrf2 to the liver, catalyzed the transcription of Nrf2 downstream genes, and rescued mice from acetaminophen induced liver injury. Another method of delivery that continues to be in the process of improvement is the oral drug delivery system for protein therapeutics. Oral drug delivery faces challenges including harsh acidic environment, rapid clearance of drug, and limited paracellular transport of therapeutic molecules. We studied a nanostructured microparticle system to overcome the challenges with an engineering approach. We showed that planar silica particles coated with silicon nanowires loaded proteins efficiently. The planar particles increased the transepithelial permeation of the protein drug as a result of a larger surface area in contact with the cell layer.