The Siegwart Laboratory operates at the interface of materials chemistry, biomedical engineering, and molecular genetics. Our overarching goal is to understand and manipulate the physical and chemical principles governing synthetic macromolecular delivery to enable precision, cell-specific genomic medicines in vivo.
(1) Selective Organ Targeting (SORT) Platform
Overview: Lipid nanoparticles (LNPs) have revolutionized the clinical delivery of RNA therapeutics; however, conventional formulations predominantly accumulate in the liver. To overcome this fundamental bottleneck, our laboratory developed Selective Organ Targeting (SORT)—a modular platform that alters nanoparticle biophysical properties and internal architecture to redirect delivery to specific extrahepatic tissues.
Key Focus Areas:
- Systematic Biophysical Tuning: Incorporating rationally chosen SORT molecules (cationic, anionic, ionizable, zwitterionic, etc.) into standard four-component LNPs to predictably alter surface properties, pKa, internal morphology, and endogenous protein corona recruitment.
- Extrahepatic Tissue & Cell Tropism: Achieving high-efficiency mRNA expression and genome editing across distinct organs, including lungs (endothelial and epithelial cells), spleen (T cells, B cells, and macrophages), liver, and bone marrow.
- Clinical Translation: Refining formulation chemistry for high stability, low immunogenicity, and scalable manufacturing for therapeutic pipelines.
Selected Research Highlights:
“In vivo editing of lung stem cells for durable gene correction in mice.” Science, 384, 1196 (2024).
“Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing.” Nature Nanotechnology, 15, 313–320 (2020)
(2) Genetic Therapeutics & Mechanisms
Overview: The clinical success of genetic medicines relies heavily on safe, synthetic delivery systems capable of transporting large, fragile nucleic acids into target cells in vivo. Our laboratory pioneered the first non-viral systems for in vivo CRISPR/Cas editing and continues to advance next-generation gene correction platforms. We also elucidate the fundamental mechanisms underpinning tissue and cell enriched delivery.
Key Focus Areas:
- Modular Delivery Platforms: Formulating nanoparticles for mRNA, siRNA, miRNA, tRNA, saRNA, circRNA, DNA, mRNA + sgRNA, Cas ribonucleoproteins (RNPs), base editors, and prime editors without viral vector limitations.
- Intracellular Trafficking & Endosomal Escape: Investigating the rate-limiting steps of nanoparticle delivery—including cell-surface receptor engagement, endosomal membrane destabilization, cytosolic cargo release, and nuclear entry.
- Disease Models & Gene Correction: Applying targeted delivery platforms to treat genetic disorders (such as cystic fibrosis, metabolic disorders, and muscular dystrophies) and selectively disrupt oncogenic drivers in solid tumors.
Selected Research Highlights:
“Dual SORT LNPs for multi-organ base editing.” Nature Biotechnology, 44, 578-586 (2026)
“Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy” Nature Nanotechnology, 17, 777–787 (2022).
(3) RNA Chemistry & Cell Engineering
Overview: Beyond organ-level biodistribution, the therapeutic window of genomic medicines depends on the chemical optimization of the nucleic acid cargo and the selective reprogramming of target cell populations. We engineer tailored nucleic acids to enhance cellular specificity, translational efficiency, and immuno-modulatory potency.
Key Focus Areas:
- Polymer & Lipid Synthesis: Synthesizing biodegradable polymers, ionizable dendrimers, and functional lipids designed for rapid systemic clearance, low off-target toxicity, and robust payload protection.
- mRNA & Oligonucleotide Engineering: Optimizing modified mRNA and siRNA architectures for prolonged, cell-specific protein expression and gene knockdown.
- Immunotherapy & Cell Reprogramming: Delivering genetic cargo to immune cell subsets in vivo to engineer CAR-T/NK cells, modulate tumor microenvironments, and develop robust RNA vaccines. We also enable the “body as a biofactory” leveraging signal peptide nucleic acid design (SEND) to produce and localize therapeutic proteins.
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).
“Co-transcriptional modifications of 2′-hydroxyls on synthetic mRNA enhance ribonuclease resistance and lipid nanoparticle thermostability.” Molecular Therapy Nucleic Acids, 36, 4102749 (2025).
