Intracellular Action of DNA-based Nano-materials

ongoing

Self-organization of matter into structured architectures with emerging functionality is arguably the most important phenomenon to enable life. Unfortunately, human efforts to successfully engineer materials that control hierarchical order and achieve precise action in cells, have suffered from structural heterogeneity and limitations in functional precision. Immune pathways are prime examples of cascades where a finely balanced sequence of interactions decides between life-changing outcomes, varying from tolerance to active fight. Immune-modulating materials, therefore, would uniquely benefit from precision control over functionality. DNA-based nanomaterials have the potential to change our current bioengineering standards due to their inherent architectural uniformity and nanometer control of functionalization, allowing for a quantitative analysis of material parameters on cell activation. The goal of this ERC proposal is to use structural geometry of DNA-based materials to provoke controlled intracellular manipulation of immune signaling via the hierarchical and spatial organization of constitutive DNA binding proteins. We create a circular paradox where DNA defines protein synthesis, yet protein function is controlled by self-organization following interaction with designer DNA. Our approach stands out in its controlled-by-nature strategy: 1) we exclusively use materials derived from cellular building blocks; that 2) respond to stimuli generated without artificial intervention, 3) that we quantify using pathway specific activation markers and 4) image via label-free microscopy to track inherent structural changes in physical material properties. We apply our approach on two important signaling pathways involved in immunology: TLR9 as Th1 trigger for vaccine adjuvants and innate cGAS inhibition to fight autoimmunity. Using spatial organization as foundation for geometry-based immune-engineering will revolutionize the design of novel immune-modulating materials.