At the core of our research is the fusion of several dynamic fields: materials chemistry, molecular genetics, immune engineering, synthetic biology, machine learning, and data science. We harness emerging technologies such as deep learning and next-generation sequencing to push the boundaries of nonviral delivery systems. These systems are meticulously engineered to enhance the performance of engineered RNA cargos, including mRNA, circRNA, and CRISPR-Cas gene editing tools, with a special focus on non-liver tissues and immune cells. The core of our interdisciplinary strategy lies in tackling and surmounting the existing challenges in delivery technologies. Our mission is to pioneer new treatment modalities for complex diseases that currently have insufficient or nonexistent therapeutic options.

High Throughput Design of Biomaterials for RNA Delivery

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 a proprietary automated combinatorial platform to enable high-throughput synthesis, screening, and optimization of new LNPs for target tissue or cell types. 

RNA-based Vaccines and Immunomodulatory Therapy

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 or immunomodulatory therapy against cancer, infectious diseases, and autoimmunity. 

Nonviral Delivery Techniques for Genome Editing Tools

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.