Research
Our research focuses on nucleic acid-based nanomedicines driven by data science/artificial intelligence (DSAI), with an emphasis on mRNA, circRNA, tRNA, and CRISPR technologies. At the intersection of molecular bioengineering, biochemistry, immunoengineering, and DSAI, we design de novo lipid-based delivery systems to enable precise, tissue-specific targeting of RNA therapeutics. By integrating DSAI to optimize biomaterial discovery and delivery design, we accelerate the development of platforms capable of delivering RNA medicines to extrahepatic tissues, such as the lungs. Our goal is to pioneer DSAI-enhanced RNA therapies for complex diseases, providing innovative solutions for conditions currently lacking effective treatments.
AI-Guided High Throughput Design of RNA Delivery Systems
RNA medicines have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown of pathological genes, expression of therapeutic proteins, and programmed gene editing. Due to the inherent instability and negative charges, these RNA cargos necessitate appropriate delivery systems to overcome biological barriers and release them into the cytosol. The classical formulation of lipid nanoparticles (LNPs) is composed of four compositions, among which ionizable lipids that stabilize RNA molecules and facilitate their endosomal escape play a key role in affecting the RNA transfection efficiency. A one-size-fits-all approach does not work for RNA delivery as the transfection performance of LNPs varies in different tissues and cells. To maximize the performance of RNA-based vaccines and therapeutics, the Li lab develops an AI-guided automated platform to enable high-throughput synthesis, screening, and optimization of new LNPs for target tissue or cell types.
Next-Generation RNA Vaccines
Any protein antigen can be encoded and expressed by mRNA and circRNA, in principle enabling the development of personalized vaccines and immunomodulatory therapy fighting diseases as diverse as cancer, infections, and autoimmune diseases. The Li lab engineers LNPs to deliver and potentiate the action of antigens or therapeutics encoded by RNA. These LNPs offer special features of size and surface chemistry for penetration of interstitial and mucosal barriers to access lymphoid tissues and cellular targets efficiently, proactive immune stimulation/suppression, and appropriate subcellular release of sensitive RNA payload after endocytosis. The Li lab also investigates self-adjuvanted RNA that activates innate immune sensors to further enhance the efficacy of RNA-based vaccines against cancer, infectious diseases, and senescence.
Nonviral Delivery of RNA and Gene Editors
The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) system has revolutionized biomedical research and facilitated the development of new therapies based on genome editing. A major roadblock to achieving the therapeutic potential of the CRISPR/Cas system is the lack of a safe and effective in vivo delivery method. Adeno-associated virus (AAV)-assisted delivery of the CRISPR/Cas9 system has shown gene targeting efficacy in vivo, however, the long persistence and immunogenicity of AAV in the host prevent the wide therapeutic application of AAV-based CRISPR/ Cas9 delivery. Leveraging the design of RNA structures and nanoparticles, Li lab develops fully non-viral Cas9 genome editing systems allowing efficient gene correction in specific tissues with minimized side effects.
Funding support
The Li research group acknowledges the funding support from
