During my PhD, I worked on an ambitious collaboration between the Hammond and Bhatia Labs at MIT that brought together the lessons learned from my prior work on layer-by-layer nanoparticles to produce a novel nanotheranostic – a nanoparticle capable of carrying out both a therapeutic and diagnostic function (Boehnke, Correa, and Hao et al. Angewandte Chemie, 2020). This work developed a novel surface chemistry I had previously discovered (Correa et al. ACS Nano 2020) that mediated prolonged retention on cancer cell membranes followed by eventual caveolar uptake. This capability was attractive for this new technology because our nanoparticle needed to carry out distinct functions in the extracellular space and intracellular space. We used click chemistry techniques to incorporate the Bhatia Lab’s protease-sensitive synthetic biomarker technology onto our LbL nanoparticle in order to mediate urinary-based detection of tumors. These biomarker molecules are cleaved by proteases over-expressed in tumors, freeing a reporter molecule that can then be detected in the urine. However, in order for this function to be carried out, the biomarker must be cleaved extracellularly, before the nanoparticle entered the cell. My poly aspartate coatings provided an extended residence time on cell membranes that permitted this functionality, before ultimately internalizing via caveolar pathways to deliver an siRNA gene therapy. For the gene delivery aspect of this work, we took leveraged of our work that optimized the incorporation of siRNA into LbL nanoparticles (Correa and Boehnke, ACS Nano 2019). Ultimately, this project combined multiple aspects of my PhD to yield a highly multifunctional nanomedicine that could silence specific genes and noninvasively detect tumors in vivo across several models of cancer.

This work highlights how important multifunctionality is for the future of nanomedicine. Even the ‘simplest’ nanoparticles must be inherently multi-functional in order to be effective drug delivery vehicles, and must be able to i) protect their therapeutic cargo; ii) navigate the body without prematurely degrading; iii) avoid premature clearance from filtration organs and the immune system; iv) selectively release their payloads in target tissues; and v) safely degrade after carrying out their mission. On top of these capabilities, certain drug delivery applications require even more complex functionality, such as the ability to both enter cells and navigate to a specific sub-cellular compartment – as is the case for gene therapies. On top of these necessary capabilities, additional functionality can further enhance the clinical value of nanotechnology. Additional functionalities include diagnostic capabilities, exogenously triggered functions, and staged release of multiple drug payloads. Overall, my future research endeavors look seriously at ways to introduce novel functionality into nanoparticles to address a host of outstanding biomedical challenges.

Read more about these innovations here:

  1. Boehnke N, Correa S, Hao L, Wang W, Straehla JP, Bhatia SN, Hammond PT. Theranostic Layer-by-Layer Nanoparticles for Simultaneous Tumor Detection and Gene Silencing. Angewandte Chemie International Edition. 2020;59(7):2776-83.

  2. Correa S, Boehnke N, Barberio AE, Deiss-Yehiely E, Shi A, Oberlton B, Smith SG, Zervantonakis I, Dreaden EC, Hammond PT. Tuning Nanoparticle Interactions with Ovarian Cancer through Layer-by-Layer Modification of Surface Chemistry. ACS Nano. 2020;14(2):2224-37.

Correa S, Boehnke N, Deiss-Yehiely E, Hammond PT. Solution Conditions Tune and Optimize Loading of Therapeutic Polyelectrolytes into Layer-by-Layer Functionalized Liposomes. ACS Nano. 2019;13(5):5623-34.