Research

(1) Nanotechnology: We aim to develop nanotechnology tools for manipulating signaling activity, gene expression, and function of specific cells at the nanoscale using various physical stimulations. Nanomaterials are capable of transducing physical modalities (e.g., light, magnetic field, ultrasound) into a range of biologically relevant signals. These tools will allow on-demand, targeted, and wireless delivery of signaling inputs, such as biochemical, mechanical, and spatiotemporal cues, to specific receptors at a single-cell level both in vitro and in vivo. 

(2) Synthetic biology: We aim to design and build custom-made signaling pathways to interrogate and control cell signaling. Synthetic signaling circuits employ artificial receptors and signaling molecules, rewired signaling pathways, or gene expression programs to selectively activate or inhibit specific signaling and modulate cellular responses. Combined with nanotechnology, our synthetic biology tools will offer effective and powerful approaches to control the signaling activity with spatiotemporal precision. 

2. Illuminating the physical basis of receptor activation and cell signaling 

(1) Membrane protein organization: Protein localization plays a critical role in the regulation of cell signaling through the formation of signaling platforms to facilitate protein-protein interactions and create a local environment favorable to signal activation. Various mechanisms (i.e., phase separation, membrane compartmentalization, and physical segregation) have been proposed as the molecular principles governing protein-protein interactions and spatial reorganization in the plasma membrane. We develop novel nanotechnology tools enabling spatiotemporal control of the membrane re-organization of receptors and signaling proteins while simultaneously visualizing cellular responses in real-time at single-cell resolution. Using these new tools, we will dissect how spatiotemporal control of membrane proteins modulate receptor activation and signaling responses. 

(2) Cell mechanics and mechanotransduction: Many receptors (i.e., Notch, T cell receptor) and ion channels (i.e., Piezo1/2, TREK-1) are mechanosensitive, meaning their activities are regulated by force. Using nanomaterial-enabled perturbation techniques and synthetic biology strategies such as receptor engineering or rewiring of signaling pathways, we seek to elucidate the fundamental mechanisms of mechanosensory activation and cellular mechanotransduction.   

Membrane protein segregation for controlling membrane proteolysis

Membrane biophysics video.mp4

Time-lapse imaging of mechanical activation of Notch receptor signaling

3. Remote, spatiotemporal, and non-invasive control of nervous and immune systems 

Through the integration of nanotechnology, mechanobiology, and synthetic biology, we are developing powerful technologies for remote and non-invasive manipulation of cellular functions within deep tissues of living animals.

(1) Neuroscience: Here, we focus on the development of magnetogenetic (MG) technologies for remote and long-distance modulation of deep brain neurons in freely moving animals. We seek to expand MG platforms as effective and reliable neuroscientific research tools for studying neural systems underlying animal behaviors, physiology, and pathology, and as novel treatments for neurological disorders.

(2) Immunology: Despite the recent clinical successes of engineered T cell-based immunotherapies, cellular immunotherapies are not effective for everyone and show only limited efficacy against many cancer types. With the advantages of magnetism and nanomaterial, we are developing novel strategies for remote, on-demand, and spatiotemporal control of immune cell responses to enhance efficacy and safety of therapies. With synthetic biology, we are developing T cell engineering strategies to modify and reprogram T cell signaling and transcription, which can enhance T cell functions and overcome challenges such as immunosuppressive tumor microenvironment and T cell exhaustion.

Remote and on-demand magnetic control of engineered T cells for next-generation cellular immunotherapies