Probing nano/bio interactions to understand and overcome biological barriers limiting nanomedicine

项目总结/文摘

PROJECT SUMMARY/ABSTRACT The Day Lab engineers nanoparticles (NPs) with unique physicochemical properties to transform the treatment of various diseases and elucidates how architecture impacts function by studying nano/bio interactions from the subcellular to whole organism level. The NPs we develop enable high precision therapy by: (1) delivering antagonistic antibodies or nucleic acids to cells to inhibit genes that drive disease progression, (2) supplying heat or other payloads only to diseased cells in response to activation with tissue-penetrating near-infrared light, or (3) facilitating cell-specific cargo delivery by using cell-derived membranes as coatings that minimize immune recognition and enable target cell binding. We are applying our technologies to manage aggressive cancers, blood disorders, and maternal/fetal health conditions. Further, we are proving through rigorous studies that both what is packaged in NPs and how it is packaged dictate therapeutic potency. Much of our work advancing nanomedicine over the last five years was funded by the MIRA program. Moving forward, we will use our acquired tools and knowledge to probe unanswered questions in nanomedicine and advance the ability of NPs to surpass biological barriers. There is currently an undesired disparity between preclinical and clinical performance of nanomedicines that is driven by biological barriers that limit NP delivery efficiency, efficacy, and safety. These include immune barriers (protein corona formation leading to macrophage clearance), vascular barriers (limited extravasation), and tissue barriers (poor penetration through extracellular matrix, mucus, etc. to reach desired cells in heterogeneous populations). Over the next five years we will address these biological barriers through mechanistic studies that incorporate and adapt NPs previously developed in our lab to enhance delivery and efficacy. Specifically, we will investigate questions related to protein corona-mediated immune clearance, the role of inflammation in NP extravasation, and NP interaction with reproductive tissue barriers and the vaginal microbiome. Answering these questions will guide the development of NPs with improved clinical performance. In addition to advancing the broader field of nanomedicine, the information gained will lead into the long-term research of the Day Lab addressing both extracellular and intracellular barriers to nanomedicine. Overall, our work has both basic scientific and translational significance, and our discoveries will transform the application of nanomedicine to diverse healthcare problems by developing technologies with unmatched clinical performance.