Bionanotechnology is a branch of nanotechnology that applies nanometer-sized tools to biological and medical problems. It has created exciting new opportunities to advance the biotech industry and medicine. For example, inorganic nanoparticles such as metallic and magnetic are widely used in in vitro diagnostics, imaging, cell separation, and cell engineering. In parallel, nanoparticles made from organic compounds such as polymers, lipids, and proteins have found major applications in vivo ranging from drug delivery to vaccine development.

Since the late 1990s when bionanotechnology research entered the fast lane, the scientific community has learned a great deal about how nanoparticles interact with the biological system. The effects of particle size, shape, chemical composition, surface charge, coating material, and targeting ligand on colloidal stability, plasma circulation, biodistribution, clearance, degradation, and toxicity have been determined quantitatively, although how to intelligently combine these key parameters to target nanoparticles specifically to the desired organ or type of cells, promote deep tissue penetration, and clear them out of the body after the job is finished remain to be challenging.  

In 2004 as a graduate student working with Professors Shuming Nie, a bioengineer, and Leland Chung, a cancer biologist, I published one of the first papers reporting the development of quantum dots (Qdots) for simultaneous targeting and imaging of tumors in vivo (https://www.nature.com/articles/nbt994). On the imaging probe side, Qdots were encapsulated and dispersed in aqueous solutions via a spontaneous self-assembly process, which solved the problems of particle aggregation and fluorescence loss previously encountered for in vivo applications. To minimize non-specific binding while increasing specific uptake by tumor cells, the Qdots were pegylated and linked to an antibody against the prostate-specific membrane antigen (PSMA). On the instrumentation side, we explored the use of hyperspectral imaging (HSI) for the removal of autofluorescence background through collaborations with Dr. Richard Levenson. The combination of Qdots and HSI allows cancer cells as few as 100 to be detected in live animals, which opens new opportunities for cancer early detection. Last week, this paper was selected by Nature Biotech as one of the 25 landmark papers in the 25^th Anniversary Collection, and I was invited by the editor to write an ‘after the paper’ blog post on its impact on my career development beyond its scientific contribution to the fields of molecular imaging and bioengineering. It definitely gave me a jump-start when starting as a faculty member at the University of Washington (UW) in 2005.

As a multidisciplinary multifaceted study, the paper covered many aspects of the design principles for nanoparticle probes and laid the groundwork for further development and use of nanoparticles in molecular imaging. For example, following the same discovery process, my colleague at UW Bioengineering, Professor Matt O’Donnell, and I reported a magnetic and plasmonic-coupled nanoparticle that offers contrasts for electron microscopy, MRI, optical imaging, and photoacoustic imaging (https://www.nature.com/articles/ncomms1042). This was the first report showing the combination of multiple nanocomponents leads to the creation of a new imaging mode (magnetomotive photoacoustic imaging, or mmPA) that is unavailable from either of the individual components. During real-time PA data acquisition, an oscillating magnetic field is applied. The magnetic and plasmonic-coupled nanoparticles move as a result of their strong magnetization, creating a moving source within a PA image. Non-magnetic PA sources do not move coherently with the applied field during this entire interval. Consequently, coherent motion processing of a PA image sequence can identify sources related to the coupled nanoparticles and reject all background signals. Similar to my 2004 Nature Biotech paper where Qdots and HSI were combined, the combination of magnetic and plasmonic dual-functional nanoparticles with the motion filtering technique can enhance imaging contrast by 2-3 orders of magnitude.

In parallel to research, I also found that the Qdot synthesis, functionalization, bioconjugation, in vitro and in vivo behaviors discussed in the paper are the best model system to introduce nanotechnology to bioengineering students. In the first 2-3 years of undergraduate studies in STEM-majors, most students have accumulated an extensive background in physics, chemistry, biology, and physiology. In the Bionanotechnology course I teach, many students suddenly realize that they can apply what they have learned to dissect problems in nanotechnology. For example, they could use the particle-in-a-box model and the molecular orbital theory from physics to explain why the color of Qdot fluorescence is tunable; use organic chemistry and analytical chemistry to make and purify Qdot bioconjugates; and use mass transport models from physiology to predict the fate of Qdots in vivo. It was personally satisfying to see the many Aha moments that could inspire the next generation of scientists.