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. 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 and highlighted the crosstalk between oral microbiota and their hosts at the mucosal interface. Recent studies uncovered the roles of host-derived small RNAs (sRNAs) in the growth inhibition of pathogenic bacteria. However, it remains unclear about the spectra and mechanistic functions of host sRNAs as defense molecules in the context of host-microbiome interaction. Moreover, considering the success of RNA medicines in recent years, it presents an exciting opportunity to make use of the host 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 consisting of bacterial pathogens, the commensal bacteria, and the host. 

2. 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 one of the hallmarks of mitochondrial diseases and emerging studies show 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 dysfunctions by coupling a common mitochondrial disease marker, lactate, to the redox levels inside host cells.

3. 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 mitigate 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 of time until activated with a specific biological cue to produce 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.