AI-Guided Design of Nucleic Acid Delivery Systems

The delivery of nucleic acids remains the central barrier to realizing their therapeutic potential, particularly for applications outside the liver. Traditional approaches rely on empirical screening, which is slow, resource-intensive, and rarely generalizes across tissues or disease contexts. Our lab develops autonomous AI-guided platforms that integrate generative modeling, molecular graph learning, combinatorial chemistry, and high-throughput testing to accelerate the discovery of nonviral delivery materials. These platforms generate predictive frameworks that map how molecular structure (e.g., ionizable lipid) and formulation composition determine cellular uptake, endosomal escape, and organ-specific biodistribution. Through this approach, we aim to unlock access to diverse tissues, including the lung, brain, heart, muscle, spleen, and kidney, and expand the therapeutic reach of nucleic acid medicines.

Computational and Molecular Engineering of Nucleic Acids

Nucleic acids such as mRNA represent a fundamentally programmable class of medicines, enabling therapies to be designed at the level of genetic information. Our lab integrates computational and molecular approaches to expand the scope of RNA programmability. We develop computational platforms that use language models, structure-aware neural networks, and evolutionary data to optimize sequence features, including codon usage, untranslated regions, chemical modifications, and structural motifs that govern stability, translation, immunogenicity, and therapeutic performance. In parallel, we engineer nucleic acids with embedded regulatory elements such as microRNA-responsive switches and ADAR-based RNA editing modules to confer precise spatiotemporal control in vivo. These strategies allow therapeutic molecules to remain inactive in healthy tissues and become functional only in diseased cells, thereby enhancing selectivity and safety. By integrating computational and molecular programmability, we aim to maximize the therapeutic potential of emerging nucleic acids.

Nonviral Genetic Medicines

Genome and epigenome editors hold transformative potential for treating genetic diseases, yet their clinical translation remains limited by low editing efficiency, off-target effects, and the absence of safe and precise delivery systems. These challenges are particularly urgent for rare diseases, which affect hundreds of millions of people worldwide, many of them children, and for which the vast majority lack approved therapies. Our lab addresses this unmet need by delivering CRISPR nucleases, base and prime editors, and epigenetic regulators that are optimized through machine learning and directed evolution, using bespoke nonviral nanocarriers. This strategy aims to achieve programmable in vivo gene correction and regulation in specific tissues and cell types. By advancing precision genome and epigenome editing, we seek to accelerate the development of personalized and accessible cures capable of slowing, reversing, or preventing chronic genetic diseases at their root.

Immunomodulatory Therapy and Immune Engineering

Our lab develops RNA-based immunomodulatory therapies that precisely reprogram immune responses to treat cancer, autoimmune, and inflammatory diseases. By integrating AI-guided molecular design with nanotechnology, we engineer nanoparticles that deliver mRNA encoding immune regulators or antigenic cues to specific subsets of immune cells. These programmable systems enable spatially and temporally controlled immune activation or suppression, tailored to the pathological context. In cancer, our tumor-customized mRNA nanomedicines induce immunogenic cell death, remodel the tumor microenvironment, and synergize with checkpoint inhibitors to overcome resistance. In autoimmune disease, we design RNA constructs that restore immune tolerance by promoting regulatory pathways and attenuating aberrant inflammation. Through this convergence of RNA engineering, immune modulation, and data-driven discovery, we aim to establish a new generation of precise, adaptable immunotherapies capable of both activating and restraining the immune system as needed for durable disease control.

Funding support

The Li research group acknowledges the funding support from