Translational Design of Lipid Nanoparticles (LNPs) to Deliver mRNA Therapies to Solid Tumors and to the Lungs
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Huayamares, Sebastian Gonzalo
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Abstract
Lipid nanoparticles (LNPs) are a clinically relevant way to deliver therapeutic mRNA in patients. In this work, improved mRNA delivery to solid tumors was achieved through systemic and localized administration. For systemic delivery, high-throughput LNP screening assays were used to identify an LNP that can functionally deliver mRNA to human head and neck squamous cell carcinoma (HNSCC) solid tumors in vivo while minimizing off-target delivery to the liver. For localized delivery, stereo-pure and scalable ionizable lipids were used to formulate and screen LNPs administered intratumorally. The best-performing LNP was then used to deliver purine nucleoside phosphorylase (PNP)-encoding mRNA intratumorally. In combination with fludarabine phosphate as a prodrug, this elicited cytoreductive anti-tumor effects that resulted in regression of patient-derived xenograft (PDX) HNSCC solid tumors in vivo. Additionally, mRNA delivery to solid tumors was studied on a multi-omic level using single-cell RNA sequencing (scRNA-seq), which identified pathways and upregulated genes related to this therapeutic modality. Finally, translational and clinically relevant LNPs were engineered to deliver therapeutic mRNA to the respiratory airway via nebulization. These improved LNPs were then used to deliver a therapeutically relevant mRNA cargo to develop an LNP-mRNA therapy for the treatment of pulmonary alveolar proteinosis.
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2023-12-19
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Dissertation