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Therapeutic micro/nano-robots

Although it may seem like science fiction, ongoing research by many, including myself, is focused on the design of miniaturized robots that can deliver therapeutics or capture pathogens while circulating in the body, with the potential to revolutionize the future of medicine. For these micro/nano-robots to be effective, they must be capable of moving around within the body, locating disease sites, identifying targets, analyzing signals in the microenvironment, making local decisions, and reporting outcomes. Therefore, the ability to meet these design criteria is critical for the development of therapeutic micro/nano-robots that can effectively execute their intended functions.

My passion for creating these robots led me to pursue a Ph.D. in nanomedicine. Advances in nanotechnology for biomedical applications have significant potential for treating diseases due to their unique properties. However, translating nanomedicine from lab to bedside is limited by the complexity of biological systems and barriers that can interfere with and deactivate foreign nanomaterials. My Ph.D. research addressed this by incorporating stimuli-responsive molecules, such as polymers and oligomeric DNAs, into nanomaterials to alter their properties and improve delivery efficiency and therapeutic efficacy.

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Cell nanoengineering

The idea of using stimuli-responsive nanoparticles for theranostics (also known as smart nanomedicine) to improve delivery efficiency has potential, but its complex design raises concerns about its translatability. On the other hand, cells in our body already have the ability to communicate with each other and migrate to target sites. Some cell types, like immune cells and stem cells, can recognize targets, analyze signals in the microenvironment, and make their own decisions. These capabilities make cells great therapeutic micro-robots, which is why cell-based therapy is already in use.

However, tracking and controlling the functions of therapeutic cells after they have been administered is difficult. This is important for monitoring and predicting the cells' biological activity for efficient therapy. Nanotechnology and endogenous cells can be combined to address this problem. By engineering endogenous cells with nanomaterials, we can give cells new physical and optical properties, allowing us to track and control their functions using various imaging instruments and external stimuli. Additionally, using endogenous cells to deliver nanomaterials can enhance delivery by bypassing intrinsic biological systems and barriers.

To that end, my future lab, the Laboratory for Cell Nanoengineering at UC Davis, aims to develop nanotechnology-enhanced cells that combine the benefits of both cell systems and nanoparticles. Initially, we will focus on engineering endogenous immune cells, specifically T cells, with functional nanomaterials for noninvasive image-guided cancer immunotherapy and for monitoring and controlling immune cell activity over time. Eventually, our approach will be extended to other types of endogenous cells, including NK cells and stem cells, to improve cell-based therapies.

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Non-invasive and longitudinal imaging

As previously mentioned, the nanoengineered cells can be spatially tracked and functionally monitored using various imaging modalities to determine their location and behavior. Especially, real-time, non-invasive, and longitudinal assessment of cell location and function is particularly crucial for effective treatment monitoring. However, current evaluations of cell therapy outcomes rely heavily on invasive endpoint analyses, such as histology and biomarker assays, which can cause tissue damage and do not offer real-time insights into the tissue microenvironment.

Among various imaging modalities, ultrasound-guided and photoacoustic (US/PA) imaging has shown immense potential in providing functional imaging with high spatial resolution and deep tissue anatomical information. US/PA imaging offers non-invasive and non-ionizing imaging, the equipment is familiar to clinical staff, has a small footprint, is portable, and is relatively low cost, making it a valuable tool for clinical applications.

US imaging provides clear anatomical images of tissues with high spatial resolution. PA imaging complements this by conveying functional information with high contrast, resolution, imaging depth, and sensitivity. The PA signals are generated by the optical absorption of endogenous or exogenous contrast agents. By using stimuli-responsive exogenous contrast agents, PA signals can be significantly enhanced, allowing for the monitoring of cellular and molecular events over time. Thus, to gain subcellular and biological insights into cell therapies, US/PA imaging can use stimuli-responsive nanoparticles as contrast agents. This provides a means to monitor and influence highly specific biological and molecular events in niche microenvironments longitudinally.

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Based on the synergistic combination of nanotechnology, cell engineering, and noninvasive bioimaging, the Laboratory for Cell Nanoengineering aims to 1) create nanoengineered cells using functional and stimuli-responsive nanomaterials and 2) track and monitor cell therapies utilizing noninvasive imaging tools, predominantly the US/PA imaging modality. This interdisciplinary approach offers great potential for advancing the understanding and translation of various types of autologous or adoptive cell therapies in the future.

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