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.
At UT Southwestern, we have pioneered the controlled delivery of genetic drugs to specific tissues including the liver, lungs, spleen, muscle, bone marrow, brain, lymph nodes, and tumors. We discovered and developed the first system to mediate tissue-specific gene delivery and gene editing called Selective Organ Targeting (SORT) initially reported in Nature Nanotechnology. SORT LNPs were recently highlighted in “Seven technologies to watch in 2022” (Nature 601, 658-661 (2022)), signifying its recognized importance to address future delivery challenges. We were also the first to report successful in vivo CRISPR/Cas genome editing using a synthetic nanoparticle (Angewandte Chemie, publication in December 2016).
We have systematically developed, through novel chemical synthesis and engineering, a series of platform technologies to deliver siRNA, miRNA, mRNA, tRNA, sgRNA, DNA, CRISPR/Cas, base editors, prime editors, and proteins for applications including genetic disease treatment, cancer treatment, and vaccines. These technologies, along with explanation of fundamental mechanisms of action, and therapeutic application to treat diseases and cancer, have been published in Nature Nanotechnology, Nature Materials, Nature Communications, Proceedings of the National Academy of Sciences, Journal of the American Chemical Society, Angewandte Chemie, Advanced Materials, Nature Protocols, and other leading journals of biomedical science.
In addition to gene and drug delivery, we have also developed tumor imaging probes based on fundamental physical chemistry properties including charge transfer, photon upconversion, and pH-responsive fluorescence activation (HOMO/LUMO). These imaging modalities have been combined with RNA therapies to create theranostic LNPs for tumor detection and therapy.
Our research is grounded in chemical design and takes advantage of unique collaborative opportunities at UTSW.
Selected Research Highlights:
“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).
“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).
“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).
“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).
- Highlighted in a UT Southwestern press release entitled “Lipid nanoparticles carry gene-editing cancer drugs past tumor defenses.” (June 23, 2022).
- Highlighted in The Scientist, “Researchers Develop a CRISPR-Based Therapy That Penetrates Solid Tumors.”
“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).
“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).
“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).
- Highlighted in News & Views “Overcoming delivery barriers with LNPs” Nature Materials, 20, 575-577 (2021).
“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).
- Highlighted in a UT Southwestern press release entitled “SORTing gene editing tools to where they’re needed.” (April 6, 2020)
- Highlighted in News & Views “Nanotechnology for organ-tunable gene editing” Nature Nanotechnology, 15, 253-255 (2020).
- Highlighted in “Seven technologies to watch in 2022” Nature, 601, 658-661 (2022).
“High-contrast fluorescence detection of metastatic breast cancer including bone and liver micrometastases via size-controlled pH-activatable water-soluble probes.” Hu Xiong, Hao Zuo, Yunfeng Yan, Gino Occhialini, Kejin Zhou, Yihong Wan, and Daniel J. Siegwart* Advanced Materials, 29, 1700131 (2017).
“Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA.” Jason B. Miller, Shuyuan Zhang, Petra Kos, Hu Xiong, Kejin Zhou, Sofya S. Perelman, Hao Zhu, and Daniel J. Siegwart* Angewandte Chemie International Edition, 56, 1059-1063 (2017). (Published online December 16, 2016.)
- Highlighted in C&EN’s cover story on CRISPR/Cas delivery entitled “CRISPR’s breakthrough problem: If the CRISPR gene editing system is to live up to its disease-curing potential, researchers must devise a plan to deliver it into the body” (February 13, 2017)
- Received the Very Important Paper (VIP) designation by Angew. Chem.
- Highlighted in a Timeline of key advances for mRNA therapeutics and delivery in “Tools for translation: Non-viral materials for therapeutic mRNA delivery.”
“Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.” Yunfeng Yan, Li Liu, Hu Xiong, Jason B. Miller, Kejin Zhou, Petra Kos, Kenneth E. Huffman, Sussana Elkassih, John W. Norman, Ryan Carstens, James Kim, John D. Minna, and Daniel J. Siegwart.* Proceedings of the National Academy of Sciences, U.S.A., 113, E5702–E5710 (2016)
- Highlighted in a UT Southwestern press release entitled “Drug-loaded synthetic nanoparticles can distinguish lung cancer cells from healthy cells.” (September 14, 2016)
- Highlighted in Carnegie Mellon Today, as a part of an alumni profile story entitled “Cancer Breakthrough” (December 6, 2016)
“Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model.” Kejin Zhou, Liem H. Nguyen, Jason B. Miller, Yunfeng Yan, Petra Kos, Hu Xiong, Lin Li, Jing Hao, Jonathan T. Minnig, Hao Zhu, and Daniel J. Siegwart.* Proceedings of the National Academy of Sciences, U.S.A., 113, 520-525 (2016).
- Highlighted in a UT Southwestern press release entitled “Scientists synthesize nanoparticles that can deliver tumor suppressors to damaged livers.” (January 25, 2016)
- Highlighted in the UT Southwestern Annual Review 2016: “Breaking new ground in research and treatment.” (February 7, 2017)
“Rapid synthesis of a lipocationic polyester library via ring-opening polymerization of functional valerolactones for efficacious siRNA delivery.” Jing Hao, Petra Kos, Kejin Zhou, Jason B. Miller, Lian Xue, Yunfeng Yan, Hu Xiong, Sussana Elkassih, and Daniel J. Siegwart.* Journal of the American Chemical Society, 137, 9206-9209 (2015).
