SUMMARY Cells are highly dynamic entities that are pulling and pushing on one another and on their surroundings. Understanding these minuscule forces is the key for unraveling important biological processes. However, a major challenge in cell biology is the lack of molecular probes to visualize and quantify cellular forces. Here, I propose to use state-of-the-art DNA nanotechnology to develop next-generation molecular probes and nanodevices to address important challenges in mechanobiology, an emerging multidisciplinary field that encompasses the study of mechanisms by which cells sense and respond to mechanical signals. As an expert in DNA nanotechnology, my lab's research is built upon three pillars: self-assembly complex DNA structures, DNA-directed assembly of materials and devices, and most importantly, DNA nanodevices for biological and biomedical research and applications. In recent years, I have published high-impact work in single-molecule mRNA detection, DNA-based in vivo delivery of therapeutic small molecules and RNA for cancer treatment, and methods for ultra-sensitive biosensing and bioimaging. In the next five years, I propose to develop novel, state-of-the-art DNA-based molecular devices/probes for study of T cells and B cells, with special focus on the following directions: (1) Multivalent DNA force probe nanoarrays for investigating multivalent binding, (2) Multiplexed DNA tension probes for studying cross-regulation between mechanoreceptors, (3) DNA nanodevices to catch receptor conformation change under force for Cryo-EM study. The proposed research is built upon our exciting progress on developing novel DNA-based system for studying mechanobiology in recent years. Noticeably, we developed a DNA origami- based system for programmable arrangement of TCR and CD4 for studying their cooperative binding, and I also developed a few new methods to improve DNA tension sensors for mechanobiology study, including the first DNA-origami-based multivalent tension sensors, super-resolution tension sensors that uses DNA PAINT, ultra- sensitive tension sensors that employ a DNA-based hairpin chain reaction for signal amplification. My strong expertise in DNA nanodevices, protein assembly on DNA nanostructures, DNA-based tension sensors, and my track record of synergy and collaboration, place our lab at an excellent position for proposed research activities. The tools developed herein are applicable to study of other molecular interactions of T cells and other cells in the immune system or other biological systems, thereby potentially impacting the broader biomedicine field where cell surface molecular interactions are being targeted for treatment of various diseases, including autoimmunity, viral infection, and cancer.