Daniel J. Siegwart is the W. Ray Wallace Distinguished Chair in Molecular Oncology Research and Professor at the University of Texas Southwestern Medical Center. His research program is focused on developing advanced lipid and polymer based systems with precise control over structure and responsiveness for applications in drug delivery, imaging, genetic diseases, and cancer. 2023 – Present: Professor, University of Texas Southwestern Medical Center, Department of Biomedical Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center 2023: Co-founder, Signify Bio 2023: Co-founder, Jumble Therapeutics 2022 – Present: Director, Program in Genetic Drug Engineering 2022 – Present: Director, Drug Delivery Program in Biomedical Engineering, Department of Biomedical Engineering 2020 – Present: Co-Director, Chemistry and Cancer Program, SCCC 2018 – 2023: Associate Professor, University of Texas Southwestern Medical Center, Department of Biochemistry, Simmons Comprehensive Cancer Center 2015: Co-founder, ReCode Therapeutics 2012 – 2018: Assistant Professor, University of Texas Southwestern Medical Center, Department of Biochemistry, Simmons Comprehensive Cancer Center 2008 – 2012: Postdoctoral Fellow, Massachusetts Institute of Technology (MIT), Department of Chemical Engineering, Koch Institute for Integrative Cancer Research (Advisors: Institute Professor Robert Langer and Professor Daniel Anderson) 2003 – 2008: Ph.D. Chemistry, Carnegie Mellon University (CMU), (Advisor: University Professor Krzysztof Matyjaszewski) 1999 – 2003: B.S. Biochemistry, Lehigh University Awards and Fellowships National Academy of Inventors (NAI) Fellow (2024), National Academy of Medicine (NAM) Emerging Leaders in Health and Medicine (ELHM) Scholar (2024), Controlled Release Society (CRS) College of Fellows (2023), American Institute for Medical and Biological Engineering (AIMBE) College of Fellows (2022), Howard Hughes Medical Institute (HHMI) Gilliam Fellowship for Advanced Study (adviser-student pair) (2021), Biomaterials Science Emerging Investigator (2019), Young Innovator Award in Nanobiotechnology (2018), American Cancer Society (ACS) Research Scholar (2017), Friends of the Comprehensive Cancer Center Award in Cancer Research (2014), Cancer Prevention and Research Institute of Texas (CPRIT) Scholar Award (2012), National Institutes of Health (NIH) Ruth L. Kirschstein National Research Service Award (NRSA) F32 Postdoctoral Fellowship (2010), National Science Foundation (NSF) East Asia and Pacific Summer Institutes (EAPSI) Fellowship at The University of Tokyo (Advisor: Professor Kazunori Kataoka) (2006), The Joseph A. Solomon Memorial Fellowship in Chemistry (CMU) (2005), Chemistry Department Research Honors (Lehigh) (2003)

Delivery is a major barrier to success of genetic medicines to treat cancer, genetic diseases, and infections. The development of new materials that can deliver nucleic acids and genome editors to improve disease outcomes constitutes the paramount challenge in treating diseases using the emerging class of drugs. Genetic drugs cover a diverse biophysical space, from 20 base pair siRNA to 15,000 nucleotide mRNA. Our lab has elucidated the fundamental guidelines for delivery of different cargoes, revealing how changes in chemical structure of the lipids and polymers that comprise nanoparticles, in concert with engineering formulation can be rationally optimized for deployment of various cargoes that enable therapeutic intervention from siRNA-mediated gene silencing to CRISPR/Cas-mediated genome correction. In addition to establishing core chemical structure-activity relationships (SAR) and clear in vivo mechanisms of action (MOA), we have realized therapeutic applications in models of cancer and genetic disease.

“Isosteric 3D bicyclo[1.1.1]pentane (BCP) core-based lipids for mRNA delivery and CRISPR/Cas gene editing.” Shiying Wu, Yangyang Yang, Xizhen Lian, Fangyu Zhang, Chao Hu, Jet Tsien, Zexiang Chen, Yehui Sun, Amogh Vaidya, Minjeong Kim, Yun-Chieh Sung, Yufen Xiao, Xiaoyan Bian, Xu Wang, Zeru Tian, Erick Guerrero, Joshua Robinson, Pratima Basak, Tian Qin,* and Daniel J. Siegwart.* Journal of the American Chemical Society, 146, 34733-34742 (2024). “Expanding RNAi to kidneys, lungs, and spleen via Selective ORgan Targeting (SORT) siRNA lipid nanoparticles.” Amogh Vaidya, Stephen Moore, Sumanta Chatterjee, Erick Guerrero, Minjeong Kim, Lukas Farbiak, Sean A. Dilliard, and Daniel J. Siegwart.* Advanced Materials, 36, 2313791 (2024). “In vivo editing of lung stem cells for durable gene correction in mice.” Yehui Sun,# Sumanta Chatterjee,# Xizhen Lian, Zachary Traylor, Sandhya R. Sattiraju, Yufen Xiao, Sean A. Dilliard, Yun-Chieh Sung, Minjeong Kim, Sang M. Lee, Stephen Moore, Xu Wang, Di Zhang, Shiying Wu, Pratima Basak, Jialu Wang, Jing Liu, Rachel J. Mann, David F. LePage, Weihong Jiang, Shadaan Abid, Mirko Hennig, Anna Martinez, Brandon A. Wustman, David J. Lockhart, Raksha Jain, Ronald A. Conlon, Mitchell L. Drumm, Craig A. Hodges, and Daniel J. Siegwart.* Science, 384, 1196 (2024). “Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.” Xizhen Lian, Sumanta Chatterjee, Yehui Sun, Sean A. Dilliard, Stephen Moore, Yufen Xiao, Xiaoyan Bian, Kohki Yamada, Yun-Chieh Sung, Rachel M. Levine, Kalin Mayberry, Samuel John, Xiaoye Liu, Caroline Smith, Lindsay T. Johnson, Xu Wang, Cheng Cheng Zhang, David R. Liu, Gregory A. Newby, Mitchell J. Weiss, Jonathan S. Yen, and Daniel J. Siegwart.* Nature Nanotechnology 19, 1409-1417 (2024). “In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma.” Qiang Cheng, Lukas Farbiak, Amogh Vaidya, Erick Guerrero, Eunice E. Lee, Elysha K. Rose, Xu Wang, Joshua Robinson, Sang M. Lee, Tuo Wei, William E. Miller, Ester Alvarez Benedicto, Xizhen Lian, Richard C. Wang, and Daniel J. Siegwart.* Proceedings of the National Academy of Sciences, U.S.A., 120, e2313009120 (2023). “Modular design of biodegradable ionizable lipids for improved mRNA delivery and precise cancer metastasis delineation in vivo.” Zhaoming Chen, Yang Tian, Jieyu Yang, Fapu Wu, Senyao Liu, Wenwen Cao, Weijia Xu, Tao Hu, Daniel J. Siegwart, and Hu Xiong* Journal of the American Chemical Society, 145, 24302–24314 (2023). “Spleen SORT LNP generated in situ CAR T cells extend survival in a mouse model of lymphoreplete B cell lymphoma.” Ester Álvarez-Benedicto, Zeru Tian, Sumanta Chatterjee, Domenico Orlando, Minjeong Kim, Erick D. Guerrero, Xu Wang, Daniel J. Siegwart.* Angewandte Chemie International Edition, 62, e202310395 (2023). “Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.” Tuo Wei, Yehui Sun, Qiang Cheng, Sumanta Chatterjee, Zachary Traylor, Lindsay T. Johnson, Melissa L. Coquelin, Jialu Wang, Michael J. Torres, Xizhen Lian, Xu Wang, Yufen Xiao, Craig A. Hodges, Daniel J. Siegwart.* Nature Communications, 14, 7322 (2023). “Nanotechnology-based mRNA vaccines.” Shuying Chen, Xiangang Huang, Yonger Xue, Ester Álvarez-Benedicto, Yesi Shi, Wei Chen, Seyoung Koo, Daniel J. Siegwart,* Yizhou Dong,* Wei Tao.* Nature Reviews Methods Primers, 3, 63 (2023). “The interplay of quaternary ammonium lipid structure and protein corona on lung-specific mRNA delivery by selective organ targeting (SORT) nanoparticles.”Sean A. Dilliard, Yehui Sun, Madeline O. Brown, Yun-Chieh Sung, Sumanta Chatterjee, Lukas Farbiak, Amogh Vaidya, Xizhen Lian, Xu Wang, Andrew Lemoff, Daniel J. Siegwart.* Journal of Controlled Release, 361, 361-372 (2023). “In vivo screening identifies SPP2, a secreted factor that negatively regulates liver regeneration.” Yu-Hsuan Lin, Qiyu Zeng, Yuemeng Jia, Zixi Wang, Lin Li, Meng-Hsiung Hsieh, Qiang Cheng, Chase A Pagani, Nicholas Livingston, Jeon Lee, Yu Zhang, Tripti Sharma, Daniel J Siegwart, Dean Yimlamai, Benjamin Levi, and Hao Zhu.* Hepatology, 78, 1133-1148 (2023). “Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs.” Sean A. Dilliard and Daniel J. Siegwart* Nature Reviews Materials, 8, 282–300 (2023). “Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery.” Xu Wang, Shuai Liu, Yehui Sun, Xueliang Yu, Sang M. Lee, Qiang Cheng, Tuo Wei, Junyu Gong, Joshua Robinson, Di Zhang, Xizhen Lian, Pratima Basak, and Daniel J. Siegwart* Nature Protocols, 18, 265–291 (2023). “Lipid nanoparticle (LNP) chemistry can endow unique in vivo RNA delivery fates within the liver that alter therapeutic outcomes in a cancer model.” Lindsay T. Johnson, Di Zhang, Kejin Zhou, Sang M. Lee, Shuai Liu, Sean A. Dilliard, Lukas Farbiak, Sumanta Chatterjee, Yu-Hsuan Lin, and Daniel J. Siegwart* Molecular Pharmaceutics, 19, 3973–3986 (2022). “Next-generation Diprovocims with potent human and murine TLR1/TLR2 agonist activity that activate the innate and adaptive immune response.” Ming-Hsiu Yang, Jamie L. Russell, Yuto Mifune, Ying Wang, Hexin Shi, Eva Marie Y. Moresco, Daniel J. Siegwart, Bruce Beutler,* and Dale L. Boger.* Journal of Medicinal Chemistry, 65, 9230-9252 (2022). “Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy” Di Zhang, Guoxun Wang, Xueliang Yu, Tuo Wei, Lukas Farbiak, Lindsay T. Johnson, Alan Mark Taylor, Jiazhu Xu, Yi Hong, Hao Zhu, Daniel J. Siegwart.* Nature Nanotechnology, 17, 777–787 (2022). “News & Views: Disrupting off-target Cas9 activity in the liver.” Sean A. Dilliard, Daniel J. Siegwart.* Nature Biomedical Engineering, 6, 106–107 (2022). “In vivo CRISPR screening identifies BAZ2 chromatin remodelers as druggable regulators of mammalian liver regeneration.” Yuemeng Jia, Lin Li, Yu-Hsuan Lin, Purva Gopal, Shunli Shen, Kejin Zhou, Xueliang Yu, Tripti Sharma, Yu Zhang, Daniel J. Siegwart, Joseph M. Ready, Hao Zhu.* Cell Stem Cell, 29, 1–14, (2022). “On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles.” Sean A. Dilliard, Qiang Cheng,* Daniel J. Siegwart.* Proceedings of the National Academy of Sciences, U.S.A., 118, e2109256118 (2021). “Zwitterionic phospholipidation of cationic polymers facilitates systemic mRNA delivery to spleen and lymph nodes.” Shuai Liu, Xu Wang, Xueliang Yu, Qiang Cheng, Lindsay T. Johnson, Sumanta Chatterjee, Di Zhang, Sang M. Lee, Yehui Sun, Ting-Chih Lin, John L. Liu, and Daniel J. Siegwart.* Journal of the American Chemical Society, 143, 21321-21330 (2021). “Optimization of phospholipid chemistry for improved lipid nanoparticle (LNP) delivery of messenger RNA (mRNA).” Ester Álvarez-Benedicto, Lukas Farbiak, Martha Márquez Ramírez, Xu Wang, Lindsay T. Johnson, Osamah Mian, Erick D. Guerrero, and Daniel J. Siegwart..* Biomaterials Science, 10, 549-559 (2022). “Lipid nanoparticle chemistry determines how nucleoside base modifications alter mRNA delivery.” Jilian R. Melamed, Khalid A. Hajj, Namit Chaudhary, Daria Strelkova, Mariah L. Arral, Norbert Pardi, Mohamad-Gabriel Alameh, Jason B. Miller, Lukas Farbiak, Daniel J. Siegwart, Drew Weissman, and Kathryn A. Whitehead.* Journal of Controlled Release, 341, 206-214 (2022). “Hydrophobic optimization of functional poly(TPAE-co-suberoyl chloride) for extrahepatic mRNA delivery following intravenous administration.” Xueliang Yu, Shuai Liu, Qiang Cheng, Sang M. Lee, Tuo Wei, Di Zhang, Lukas Farbiak, Lindsay T. Johnson, Xu Wang, and Daniel J. Siegwart.* Pharmaceutics, 13, 1914 (2021). “Recent advances in the targeted fluorescent probes for the detection of metastatic bone cancer.” Peng Wu, Daniel J. Siegwart, and Hu Xiong.* Science China Chemistry, 64, 1283–1296 (2021). “All-in-one dendrimer-based lipid nanoparticles enable precise HDR-mediated gene editing in vivo.” Lukas Farbiak, Qiang Cheng, Tuo Wei, Ester Álvarez-Benedicto, Lindsay T. Johnson, Sang Lee, and Daniel J. Siegwart.* Advanced Materials, 33, 2006619 (2021). “TRIM7 inhibits enterovirus replication and promotes emergence of a viral variant with increased pathogenicity.” Wenchun Fan, Katrina B. Mar, Levent Sari, Ilona K. Gaszek, Qiang Cheng, Bret M. Evers, John M. Shelton, Mary Wight-Carter, Daniel J. Siegwart, Milo M.Lin, John W. Schoggins.* Cell, 184, 3410-3425 (2021). “Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing.” Shuai Liu , Qiang Cheng , Tuo Wei , Xueliang Yu, Lindsay T. Johnson , Lukas Farbiak, and Daniel J. Siegwart.* Nature Materials, 20, 701-710 (2021). “A systematic study of unsaturation in lipid nanoparticles leads to improved mRNA transfection in vivo.” Sang M. Lee, Qiang Cheng, Xueliang Yu, Shuai Liu, Lindsay T. Johnson, and Daniel J. Siegwart.* Angewandte Chemie International Edition, 60, 5848-5853 (2021). “Delivery of tissue-targeted scalpels: Opportunities and challenges for in vivo CRISPR/Cas-based genome editing.” Tuo Wei, Qiang Cheng, Lukas Farbiak, Daniel G. Anderson,* Robert Langer,* and Daniel J. Siegwart.* ACS Nano, 14, 9243–9262 (2020). “Theranostic dendrimer-based lipid nanoparticles containing PEGylated BODIPY dyes for tumor imaging and systemic mRNA delivery in vivo.” Hu Xiong,* Shuai Liu, Tuo Wei, Qiang Cheng, and Daniel J. Siegwart.* Journal of Controlled Release, 325, 198-205 (2020). “Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing.” Tuo Wei, Qiang Cheng, Yi-Li Min, Eric N. Olson, and Daniel J. Siegwart.* Nature Communications, 11, 3232 (2020). “Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing.” Qiang Cheng, Tuo Wei, Lukas Farbiak, Lindsay T. Johnson, Sean A. Dilliard, and Daniel J. Siegwart.* Nature Nanotechnology, 15, 313–320 (2020). “The hydrophobic domain structure of linear-dendritic poly(ethylene glycol) lipids affects RNA delivery of lipid nanoparticles.” Kejin Zhou, Lindsay T. Johnson, Hu Xiong, Sergio Barrios, Jonathan T. Minnig, Yunfeng Yan, Bethanie Abram, Xueliang Yu, and Daniel J. Siegwart.*Molecular Pharmaceutics, 17, 1575-1585 (2020). “PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery.” Lian Xue, Yunfeng Yan, Petra Kos, Xiaoping Chen, and Daniel J. Siegwart.* Drug Delivery and Translational Research, 11, 255-260 (2021). “Lipid-modified aminoglycosides for mRNA delivery to the liver.” Xueliang Yu, Shuai Liu, Qiang Cheng, Tuo Wei, Sang Lee, Di Zhang, and Daniel J. Siegwart.* Advanced Healthcare Materials, 9, 1901487 (2020).