Therapeutic nanoscale matrimeres

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PROJECT SUMMARY The extracellular matrix in tissue is significantly disrupted in many disease conditions, but it is essential for cells to function. Endothelial cells become leaky when they no longer receive functional matrix signals upon tissue injury. Failure to restore endothelial barrier function can result in persistent edema, long-term tissue damage, and irreversible tissue fibrosis. Since many organs are highly vascularized, there is a need to find a general solution to treat tissue injury by restoring matrix-mediated signaling. There is currently no effective strategy to achieve this goal, since the activation of matrix signaling pathways requires the delivery of matrix molecules with proper molecular conformation and physiochemical properties. Here, we define a novel class of cell-secreted, non-vesicular nanoparticles that bear matrix molecules, which we call matrimeres. Our preliminary data show that mesenchymal stromal cells naturally secrete matrimeres consisting of fibronectin and DNA, which can directly activate endothelial cells to restore junctions disrupted by endotoxemia-induced injury. Importantly, we show that functional matrimeres can be reconstituted from purified fibronectin protein and genomic DNA fragments in a chemical environment similar to secretory compartments in cells. We will build on these results to test the hypothesis that fibronectin matrimeres treat tissue injury by restoring endothelial barrier function. In Aim 1, we will determine how fibronectin matrimeres restore endothelial barrier function after inflammatory injury in the lungs. In Aim 2, we will investigate biogenesis mechanisms of fibronectin matrimeres in mesenchymal stromal cells. In Aim 3, we will engineer synthetic matrimeres that restore endothelial barrier function. We predict that highly functional nanomedicine can be developed based on the fundamental insight that cells are able to recycle and repackage matrix molecules into nanoparticles by complexing with DNA fragments, which circulate in the body and play a homeostatic role in limiting vascular permeability. The project is highly multidisciplinary in that it will employ a combination of expertise in nanoscale biology, nanotechnology, chemical, biomaterials, computational, advanced imaging, cellular and molecular biology, and in vivo approaches to address the specific aims. The results will help develop a number of fundamental concepts of matrimeres in terms of their mechanisms of action, biogenesis, and reverse engineering. Success of the project will also enable the generalization of matrimeres as natural nanomedicine to deliver macromolecules for improved regenerative outcomes.