At the Li lab, we are interested in engineering cellular and molecular systems to address a range of diseases, including gastrointestinal disorders, cancer, and infectious diseases. Examples are shown below:
1. Microbial-based cancer therapy armored with membrane-bound biologics for targeted therapeutic delivery
Two recent studies from our groups address (1) cancer immunotherapy in solid tumors (A) and (2) neutralization of a bacterial genotoxin in colorectal cancer (CRC) (B-D). In the solid tumor setting, our teams recently armored nonpathogenic tumor-tropic E. coli with membrane-bound immune cytokines as an innovative strategy to (1) overcome limitations of conventional microbial-based cancer therapy, (2) reduce toxicities associated with systemic delivery of cytokines, and (3) enhance the efficacy of aPD1 in syngeneic mouse cancer models. Our second case study focuses on colibactin, a genotoxic metabolite encoded by the pks gene cluster, which is one of the most prevalent pathogenicity islands among enteric bacteria colonizing CRC patients. Since its initial description in 2006, colibactin-positive (pks⁺) bacteria have attracted increasing attention. Nature Microbiology, 2025; Nature Biotechnology, 2025
2. Developing a new class of chemically modified small RNA inhibitors to modulate the oral microbiome
The oral microbiome represents an exciting frontier in medicine, and early successes in the field have demonstrated the dynamic interactions among individual microbial species, highlighting the crosstalk between oral microbiota and their hosts at the mucosal interface. Recent studies have uncovered the roles of host-derived small RNAs (sRNAs) in inhibiting the growth of pathogenic bacteria. However, the spectra and mechanistic functions of host sRNAs as defense molecules in the context of host-microbiome interactions remain unclear. Moreover, considering the success of RNA medicines in recent years, this presents an exciting opportunity to utilize the host’s sRNAs to target pathogenic bacteria. Building on the profiling of sRNAs in human saliva, we will engineer host-derived sRNAs to target specific bacteria in a complex environment comprising bacterial pathogens, commensal bacteria, and the host. ISME J, 2023; IJOS, 2025.
3. Engineering commensal bacteria to sense and respond to the intracellular redox imbalance toward mitochondrial dysfunction
Mitochondrial dysfunction is associated with many diseases, including, but not limited to, aging, cancer, neurodegeneration, and diabetes. The dysfunction of the mitochondrial electron transport chain (ETC) is a hallmark of mitochondrial diseases, and emerging studies indicate that the elevated NADH/NAD+ ratio resulting from ETC dysfunction can lead to reductive stress. The second project will enable a smart bio-robot to ameliorate mitochondrial dysfunction by coupling a common mitochondrial disease marker, lactate, to redox levels within host cells. ACS Synthetic Biology, 2025.
4. Engineering Bacillus subtilis spores as a versatile and stable platform for the production of therapeutics
The ability to manufacture biologics from engineered cells has revolutionized biotechnology research and therapeutic biologic production. In most cases, the designed protein product is freeze-dried to reduce cold-chain requirements. However, lyophilization has traditionally been plagued by complications. A better approach would be a viable cell that can remain dormant for prolonged periods until activated by a specific biological cue to produce the desired proteins. In this project, we will develop a highly stable and integrated platform based on Bacillus subtilis spores to streamline the production and storage of temperature-sensitive biomolecules for various applications. ACS Synthetic Biology, 2025; AEM, 2020
