Project Summary/Abstract Research: Despite the recent groundbreaking discoveries in the field of nanomedicine, tumor-specific delivery of therapeutics still poses a big hurdle for translation of nanoparticle-based approaches. Engineered bacteria have recently emerged as a novel delivery vehicle against cancer by producing therapeutics such as bacterial toxins and checkpoint blockade to take advantage of their capability to produce therapeutics in situ. However, their therapeutic efficacy has been limited against tumors and unable to accommodate non-biological therapies. This project aims to understand interaction between bacteria and nanoparticles in tumor microenvironment to enable coordination of these two platforms for cancer therapy through synergy between synthetic biology and nanomedicine. Aim 1 will engineer bacteria to reprogram tumor microenvironment to enhance penetration of nanoparticles. Bacteria will be programmed to reorganize aberrant extracellular matrix of tumor by producing proteases and inhibitor of the upstream pathway. Aim 2 will program in situ interaction between nanoparticles and bacteria for enhanced delivery of nanoparticles in tumor. Bacteria will be engineered to display peptide tag that nanoparticle can target, and this programmable interaction will allow spatial coordination between bacteria and nanoparticles for drug delivery. The data generated here will reflect potential opportunities and challenges of combining two platforms to create biohybrid systems for cancer therapy. The completion of these aims will generate strategies to program bacteria and nanoparticles that can spatially and temporally coordinate with each other to develop biohybrid cancer therapy. Candidate: Jaeseung Hahn, PhD, is a postdoctoral research scientist at Columbia University. Dr. Hahn obtained his PhD in Medical Engineering and Medical Physics through the Harvard-MIT joint program. The proposed career development plan will augment his previous training to prepare his independent career: (1) experiential learning in synthesis of therapeutic nanoparticles, (2) technical experience in design and construction of bacterial gene circuits, (3) scientific knowledge and technical skills in cancer and immunology, and (4) leadership and professional skills for transition to independence. Mentors/Environment: Dr. Hahn has assembled a strong team of mentor (Kam Leong), co-mentor (Tal Danino), and collaborators (Nicholas Arpaia, Simone Schürle, Kenneth Olive, Minah Kim) to guide him through the proposed research and training activities. The proposed career development plan utilizes expertise of the mentorship team and intellectual and technical resources available through Columbia University. In addition, Dr. Hahn will attend national seminars and workshops when the resource is not available locally to obtain necessary training. Columbia University is committed to supporting postdoctoral research scientists through various courses, workshop, and professional development seminars organized by Office of Postdoctoral Affairs. All mentors have agreed to meet biannually to ensure Dr. Hahn’s progress toward training goals.

Project Narrative Advances in nanomedine and synthetic biology have brought us ever so close to attain the “magic bullet” against cancer. However, targeted delivery of drugs to tumors is still challenging for the most advanced technologies we have. This proposal aims to combine approaches from nanomedicine and synthetic biology to create highly cooperative system that can be useful for cancer therapy.