At the core of our research lies the fusion of several dynamic fields: chemistry, pharmaceutical sciences, molecular genetics, immune engineering, synthetic biology, and deep learning. We harness emerging technologies, such as AI, to push the boundaries of nonviral delivery of genetic medicines, including mRNA, circRNA, tRNA, and CRISPR-based gene editing tools. Our interdisciplinary strategy focuses on overcoming the existing challenges in RNA delivery to non-liver tissues, such as the lung, brain, and immune organs. Our mission is to pioneer new RNA-based medicines for complex diseases that currently lack effective treatment options.

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