(7az) Platform Technologies for Nucleic Acid-based Therapeutics

Research Interests:

RNA-based therapeutics, such as small-interfering (siRNAs), antisense oligonucleotides (ASOs), aptamers and synthetic mRNAs, have great potential to target a large part of the currently undruggable genes and gene products and to generate entirely new therapeutic paradigms in disease, ranging from cancer to pandemic influenza to Alzheimer's disease. However, there is still unmet need to improve their efficacy in cell, tissue and organ levels. My research interests aim to reconceptualize the way we have been delivering nucleic acids in the past decades and hence to innovate solutions to enhancing the potency of existing RNA-based therapeutics. To achieve this goal, I plan to leverage macromolecular assembly and non-natural polypeptide synthesis to transform the delivery of siRNAs, ASOs and synthetic mRNAs. By combining multidisciplinary approaches, including state-of-the-art protein and nucleic acid engineering (graduate work), animal models (graduate work), and polymer chemistry (postdoctoral training), our studies could potentially find utility in cancer immunotherapy, infection diseases, genetic disorders and wound healing.

Successful Proposals: My studies have led to a few successful proposals with my PhD and postdoctoral mentors including Cornell Nanobiotechnology Center Grant, DARPA, NSF and NIH.

Postdoctoral Project: Synthetic Polypeptide-Assisted Assembly of Ribonucleoproteins for Enhanced Delivery of siRNAs and mRNAs.

Under supervision of Prof. Paula Hammond, Department of Chemical Engineering, Massachusetts Institute of Technology

PhD Dissertation: Blood-Borne Cancer Metastasis: from Mechanisms to Therapeutics.

Under supervision of Prof. Michael King, Department of Biomedical Engineering, Vanderbilt University.

Research Experience:

My academic career path has been a blend of many fields of science and engineering. I pursued my PhD work with a focus on engineering novel platelet functions to neutralize circulating tumor cells through both genetic modification and biomimetic functionalization. In 2016, along with two other laboratories in the world, we demonstrated for the first time a prototype of Trojan Horse platelets for cancer prevention. In addition, my PhD work has prepared me with a variety of skillsets including genetic engineering of bone marrow stem cells (BMSCs), BMSC transplantation, and cancer mouse models. Following my graduation, I chose to conduct my postdoctoral research in Prof. Paula Hammond's lab at the Department of Chemical Engineering, MIT to learn engineering disciplines including polymer chemistry and nanotechnology.

Soon after I joined the Hammond lab, I pioneered a new strategy of co-delivering ribonucleic acids with their complementary proteins in a format of ribonucleoproteins (RNPs) by harnessing macromolecular assembly and synthetic polypeptide. Such approach has demonstrated superior efficacy in improving the delivery efficacy of siRNAs and mRNAs in vitro and in vivo. Additionally, our researches have led to collaborations with pharmaceutical companies including Moderna Therapeutics (a leading mRNA-based company) and Alnylam (a leading RNAi company).

In my future faculty position, as a follow-up study from my postdoctoral work, I am very interested in gaining a deep understanding of how synthetic polypeptides enable the assembly between RNAs and complementary proteins at an atomic level. With this knowledge in mind, I plan to further address additional challenges for each type of RNA-based therapeutics. Furthermore, I intend to apply a similar preassembly strategy spearheaded in my postdoctoral training to assemble and deliver other forms of biologics including lipids, carbohydrates and proteins. The proposed researches could potentially find utility in cancer immunotherapy, infection diseases, genetic disorders and wound healing.

Teaching Interests: One of the greatest opportunities as a mentor is to train the next generation of scientists and engineers to serve our society. Throughout my academic, I have been committed to teaching future scientists and engineers in various roles including: teaching assistant, guest lecturer, and research mentor. I have also had the privilege of mentoring five undergraduates, three master students and six PhD students in the laboratories from Cornell and MIT. Majority of them have had first-author or co-author publications under my mentorship, which is one of the most rewarding aspects of my academic career to date. I am interested and qualified in teaching both Chemical Engineering and Bioengineering courses (undergraduate and graduate level) in the areas of biomaterials, reaction kinetics, and thermodynamics. Additionally, I am excited to create a graduate course in the emerging fields of Molecular Engineering, Drug Delivery, and Synthetic Biology.

Publications:

1. Li J, King MR. Adhesion receptors as therapeutic targets for circulating tumor cells. Front Oncol. 2012;2:79.

2. Li J, Bu, P., Chen, K. and Shen, X. Spatial perturbation with synthetic protein scaffold reveals robustness of asymmetric cell division. Journal of Biomedical Science and Engineering, 2013, 6, 134-143.

3. Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N, Li J, Yang H, Milsom J, Lee S, Zipfel W, Jin MM, GŸmŸş ZH, Lipkin SM, Shen X. A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell. 2013;12:602-15.

4. Li J, Guillebon AD, Hsu JW, Barthel SR, Dimitroff CJ, Lee YF, King MR. Human fucosyltransferase 6 enables prostate cancer metastasis to bone. British Journal of Cancer. 2013;109:3014-22.

5. Geng Y, Chandrasekaran S, Agastin S, Li J, King MR. Dynamic Switch Between Two Adhesion Phenotypes in Colorectal Cancer Cells. Cellular and Molecular Bioengineering. 2014;7:35-44.

6. Li J, Sharkey CC, Huang D, King MR. Nanobiotechnology for the Therapeutic Targeting of Cancer Cells in Blood. Cellular and Molecular Bioengineering. 2015:1-14.

7. Li J, Sharkey C, King MR. Piperlongumine and immune cytokine TRAIL synergize to promote tumor death. Scientific Reports. 2015;5:9987.

8. Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, Wun B, Roy S, Shen X, King MR. Platelet membrane-functionalized particles to target tumor cell-associated micro-thrombi. Biomaterials. 2016 Jan;76:52-65.

9. Sharkey CC, Li J, Roy S, Wu Q, King MR. Two-stage nanoparticle delivery of piperlongumine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) anti-cancer therapy. Technology. 2016 Feb.

10. Li J, Sharkey CC, Liesveld J, King MR. Genetic engineering of platelets to neutralize circulating tumor cells. J Control Release. 2016 Apr 28;228:38-47.

11. Chandrasekaran S, Chan MF, Li J, King MR. Super natural killer cells that target metastases in the tumor draining lymph nodes. Biomaterials. 2016 Jan;77:66-76.

12. Li J, Wang W, He Y, Li Y, Yan E, Irvine DJ, Hammond PT. Structurally programmed assembly of translation initiation nanoplex for superior mRNA delivery. ACS Nano, 2017 Mar 28;11(3):2531-2544.

13. He YP^*, Li J*, He HK, Irvine DJ, Hammond PT. Synthesis of a novel star-shaped release polymer for layer-by-layer drug films. (In review). * Equal contribution.