Engineering lipid nanoparticle platform for selective and enhanced delivery in vivo - Project Summary The long-term goal of my independent research program is to develop robust LNP platforms for treating genetic diseases and protein replacement therapies. Lipid nanoparticles (LNP) have emerged as a promising technology for mRNA delivery without the drawbacks associated with viral delivery. Despite this progress, a major hurdle remains the lack of efficient and selective delivery vehicles, as most mRNA targets are difficult to reach and primarily accumulate in the liver. Despite progress in this field, these fundamental questions remain unanswered - 1) How do LNPs interact with endogenous systems and get trafficked, and can we leverage these interactions to redesign and improve delivery systems? 2) How does the incorporation of endogenous ligands change key LNP properties such as encapsulation efficiency, endosomal escape, protein expression, and immunomodulation responses? Addressing these critical questions is essential for developing more effective next generation LNP systems that can function as advanced therapeutics and create a streamlined approach to move these innovations from lab to clinical application. Over the next five years, my research program will seek to bridge the knowledge gap regarding how surface decoration with endogenous ligands interacts with plasma proteins and influences the physicochemical and biochemical properties of LNPs. To accomplish this, we will explore three distinct avenues that will work together synergistically to improve the performance of LNPs in vivo. First, we will develop LNP platforms with enhanced targeting properties by incorporating endogenous small molecules and neutral lipids as a fifth component to modify LNP surface properties. We will assess how these modifications impact biodistribution in vivo, with a primary focus on targeting the pancreas and immune system. Next, we will gain a mechanistic understanding of the interaction between targeting LNPs and protein corona. We will investigate how the physicochemical characteristics of nanoparticles influence protein corona formation and interact with endogenous receptors that regulate trafficking to the target site. Identified proteins will be further validated using their agonists as the fifth component. Finally, we aim to optimize LNP formulations by incorporating endogenous small molecules as the fifth component that can stabilize ribosomal assembly, and boost ribosome production, thereby increasing protein expression. We will examine how the physicochemical properties of nanoparticles affect endosomal trafficking and contribute to enhanced protein expression.
