Multiple myeloma (MM) is a complex and aggressive hematologic malignancy characterized by the proliferation of malignant plasma cells within the bone marrow. Despite advancements in MM therapeutics, challenges such as drug resistance, poor drug penetration, and adverse side effects persist. Nanoparticle (NP)-based RNA therapeutics present a promising strategy to overcome these obstacles, offering targeted and efficient delivery of therapeutic agents to MM cells and their microenvironment. In my research, I have focused on developing innovative NP platforms to deliver RNA therapeutics, leveraging the unique properties of lipid-polymer hybrid NPs and ionizable lipid NPs. These delivery systems are designed to enhance the stability, specificity, and bioavailability of RNA molecules, such as siRNA and mRNA, which can silence oncogenes or reprogram immune cells to recognize and attack MM cells. One of the key advancements in my research is using lipid-polymer siRNA NPs for bone marrow delivery. These NPs are engineered to navigate the complex bone marrow environment, ensuring therapeutic siRNA reaches its target precisely. By silencing genes involved in MM progression and drug resistance, these NPs can potentially improve the efficacy of existing treatments and overcome resistance mechanisms. Additionally, I have developed targeted lipid NPs specifically designed for myeloma cell delivery. These NPs can encapsulate mRNA or Cas9 mRNA/sgRNA, protecting them from degradation and facilitating their uptake by myeloma cells. The targeted delivery ensures that the therapeutic RNA is released directly into the cancer cells, minimizing off-target effects and enhancing therapeutic outcomes. Moreover, I have developed a manufacturing protocol using mRNA lipid NPs to glycoengineer BCMA CAR T cells to enforce their trafficking to the bone marrow, representing another innovative strategy in MM treatment. By modifying CAR T cells to augment interactions with E-selectin, which is overexpressed in many cancers, including MM, this approach can enhance the effectiveness of CAR T cell therapy. These engineered CAR T cells could more effectively home to and penetrate tumor sites, leading to sustained anti-tumor responses. By integrating advanced nanoparticle designs and RNA technologies, it is possible to develop more effective, targeted, and personalized therapies against MM.