Area of Research
Nucleic acid medicines, including mRNA, circular RNA (circRNA), tRNA, and CRISPR-based gene editors, offer a programmable approach to treating disease by enabling therapeutic intervention at the level of genetic information. However, their broader clinical translation remains constrained by challenges in molecular stability, tissue- and cell-specific delivery, intracellular trafficking, immunogenicity, and therapeutic selectivity.
Working at the interface of molecular bioengineering, biomaterials, pharmaceutics, immunology, and artificial intelligence, the Li Lab develops next-generation nucleic acid medicines and nonviral delivery technologies. The laboratory integrates AI and data science with molecular engineering, combinatorial chemistry, high-throughput experimentation, and in vivo biology to design both therapeutic nucleic acids and the nanoparticles that deliver them. A major focus is overcoming extrahepatic delivery barriers and enabling genetic medicines to reach therapeutically relevant cells in tissues such as the lung, brain, muscle, spleen, kidney, and tumors.
The long-term goal of the Li Lab is to establish programmable and precisely targeted genetic medicines for applications including rare genetic diseases, genome editing, cancer immunotherapy, immune modulation, regenerative medicine, and vaccination.
Research Challenge
The success of mRNA vaccines demonstrated the transformative potential of nucleic acid medicines, but most genetic medicines remain difficult to deliver safely and efficiently to the cells where they are needed. Existing lipid nanoparticle technologies predominantly accumulate in the liver, while delivery to extrahepatic tissues and specific cell populations remains considerably more challenging. Different therapeutic cargos, including large mRNAs, circRNAs, tRNAs, and genome editors, impose distinct requirements for formulation, intracellular trafficking, expression, and safety.
A second challenge is the enormous design space associated with both nucleic acid molecules and their delivery materials. Conventional trial-and-error screening examines only a small fraction of possible chemical structures, formulations, and RNA sequences and often provides limited ability to predict performance in new tissues or disease settings.
Addressing these challenges requires moving beyond empirical formulation toward integrated, data-driven approaches that can simultaneously optimize the therapeutic molecule, delivery vehicle, biological target, and disease context.
Proposed Solution
The Li Lab develops integrated computational and experimental platforms for the design of nucleic acid medicines and their delivery systems. Major research directions include:
- AI-guided discovery of nucleic acid delivery systems: Developing machine-learning, generative-modeling, and autonomous-experimentation platforms that connect lipid chemical structure and nanoparticle composition with biological performance, enabling rapid discovery of tissue- and cell-selective delivery materials.
- High-throughput biomaterial and nanoparticle engineering: Using combinatorial chemistry and scalable biological screening to generate and evaluate large libraries of ionizable lipids and lipid nanoparticles for delivery to extrahepatic tissues.
- Computational and molecular engineering of nucleic acids: Optimizing mRNA, circRNA, tRNA, and other RNA molecules through sequence design, chemical modification, structural engineering, and programmable regulatory elements to improve stability, translation, specificity, and therapeutic activity.
- Nonviral genome and epigenome editing: Developing delivery technologies for CRISPR nucleases, base editors, prime editors, and other genetic regulators, with an emphasis on efficient in vivo editing in therapeutically relevant tissues.
- RNA immunotherapy and immune engineering: Designing programmable RNA nanomedicines that activate or suppress specific immune pathways for cancer immunotherapy, autoimmune disease, vaccination, and regenerative medicine.
Impact to Date
The Li Lab has established an integrated research program spanning artificial intelligence, biomaterial discovery, RNA engineering, and genetic medicine. The laboratory has developed computational and autonomous platforms that move lipid nanoparticle development from conventional empirical screening toward predictive and generative design.
Among these advances, the LUMI-lab platform integrates an LNP foundation model with automated experimentation to accelerate the discovery of new ionizable lipids for mRNA delivery, while complementary multi-objective AI approaches enable simultaneous optimization of delivery potency and tissue selectivity. These studies build on earlier machine-learning and combinatorial-chemistry platforms for accelerating ionizable lipid discovery.
The laboratory has also developed nonviral delivery systems capable of transporting genetic medicines beyond the liver. These technologies include nanoparticles for pulmonary mRNA delivery and genome editing, biodegradable materials for delivery to the brain, muscle-selective nanoparticles, and engineered LNPs designed to accommodate the unusually large RNA cargos required for advanced genome editors.
In parallel, the Li Lab is expanding the types of nucleic acids that can be used therapeutically. Recent work demonstrated nonviral delivery of chemically modified suppressor tRNA to overcome nonsense mutations in cystic fibrosis, establishing a strategy for directly restoring protein production without permanently altering genomic DNA. The laboratory has also developed inhaled lipid nanoparticles for therapeutic base editing in the lung and RNA nanomedicines that induce immunogenic cell death and remodel the tumor immune microenvironment.
Notable Awards
- Breakthrough T1D Innovative Award, 2026
- Connaught Innovation Award, 2026
- Terry Fox New Investigator Award, 2026
- Leslie Dan Faculty of Pharmacy Innovator of the Year, University of Toronto, 2025
- Ontario Early Researcher Award, 2025
- Oxford-Harrington Rare Disease Scholar Award, 2024
- AAPS Emerging Leader Award, American Association of Pharmaceutical Scientists, 2024
- CSPS Early Career Award, Canadian Society for Pharmaceutical Sciences, 2024
- Marsha Morton Early Career Investigator Award, Cystic Fibrosis Canada, 2024
- Gairdner Early Career Investigator Award, 2022
- Connaught New Investigator Award, 2026
- Baxter Young Investigator Award, 2019
Publications
Keywords: mRNA vaccines, cancer immunotherapy, gene editing, Type 1 diabetes, nucleic acid delivery, drug delivery systems, biomaterials, genetic medicines, nanomedicines, immunoengineering, regenerative medicine
