Small molecule and nucleic acid-based therapies have a wide variety of powerful clinical applications, but in the case of certain identified targets, protein biologics may be a preferable alternative. Protein therapeutics represent a large clinical market and can modulate targets that have been unsuccessfully managed with existing drugs. However, proteins are very difficult to deliver intracellularly, the required site of action in many of these new applications. Therefore, the goal of this thesis is to develop ionizable lipid nanoparticle (LNP) platforms for the intracellular delivery of multiple protein cargos. Small proteins—for oncology applications—as well as gene editing proteins were used to evaluate multiple methods of LNP optimization and resulting therapeutic efficacy. In Chapter 2, we show that LNPs can be formulated which allow for the encapsulation and delivery of K27—a RAS inhibitor—at a level which reduces tumor burden in an in vivo model of hepatocellular carcinoma. In Chapter 3, this identified LNP was adapted for the delivery of a RAS protease, which reduced tumor growth in an in vivo xenograft model of colorectal cancer. Finally, in Chapter 4, new LNP formulations were tested for ribonucleoprotein delivery, and an extrahepatic particle was identified which can edit clinical targets in the lung with no off-target editing in the liver. In ongoing and future work, this lung-editing LNP will be further improved for use in corrective editing for cystic fibrosis treatment. By identifying LNP formulations that can effectively deliver multiple protein types in vitro and in vivo, this work proves the feasibility of intracellular protein delivery using LNPs. To summarize, this thesis aims: (i) to allow for the modulation of traditionally difficult therapeutic targets in a way which allows for future clinical translation, and (ii) to expand the current breadth of LNP applications to include proteins, creating a foundation of work for others in the field.