Yamuna Krishnan

Next-generation targeting has organelle-level precision

Organelles are relatively autonomous sub-systems within the cell, whose activity and chemical composition reflect the cell’s metabolic state.  Metabolism is altered in diseased or aging cells and this is also reflected at the level of organelles. In fact sometimes, introducing compensatory changes in organelles can restore cells to normalcy given the inherent feedback between cells and their organelles. Nature already targets the delivery of exogenous cargo with organelle-level precision in living organisms as evidenced by invading pathogens as well as endogenous signaling molecules. DNA can be self-assembled into molecularly precise, well-defined, synthetic assemblies on the nanoscale, commonly referred to as designer DNA nanodevices. Over the last decade, my lab developed a way to target DNA nanodevices to specific cells in vivo, but with organelle-level precision. Our first discovery in 2011 revealed that DNA nanodevices could reach organelles called lysosomes specific cells of live nematodes, where it functioned as a reporter of pH (1-2). Until this innovation, it was not at all obvious whether such DNA nanodevices could function inside a living cell without being interfered with, or interfering with, the cells own networks of DNA control. We spent 10 years studying the environment within lysosomes. Today I will discuss how we use the lysosome as a portal to control cell state, flip cell function and turn cold tumors hot, but in mice (3-4). 

References: 
1.    Modi, S., et al. A DNA nanomachine that maps spatial and temporal pH changes in living cells. Nat. Nanotechnol., 2009, 4, 325-330.
2.     Surana, S., et al. An autonomous DNA nanomachine maps spatiotemporal pH changes in a multicellular living organism. Nat. Commun., 2011, 2, 340.
3.    Suresh, B., et. al. Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis. Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2113174118.
4.     C. Cui et al A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumors. Nat. Nanotechnol. 2021 16, 1394-1402.