Xu Lab publishes two papers in PNAS

In the Department of Biomedical Engineering at Tufts University, Professor Qiaobing Xu studies biomedical applications of material science engineering, with a focus on developing new materials for delivering therapeutic biomacromolecules. His recent research spans topics like novel nanomachines, lipid nanoparticle design, and cancer vaccines.

In December 2023, Xu’s team published two new papers in the journal Proceedings of the National Academy of Sciences. In one paper, the group demonstrated the usage of non-Watson-Crick base pairing for various nucleic acid-based applications. Z-base was first discovered in the genomic DNA of S-2L cyanophage, forming the genetic alphabet ZTGC. This naturally occurring modified nucleobase allows formation of three hydrogen bonds with thymine, violating Watson-Crick pairing rules.  The team demonstrated that Z-bases can be compatible with endogenous gene expression machinery in many living systems – including yeast, bacteria, and mammalian cells – with results that demonstrated that “genetic information written in Z-DNA or Z-RNA can be read in multiple living systems,” according to the researchers. 

The paper, titled “Harnessing non-Watson-Crick’s base pairing to enhance CRISPR effectors cleavage 1 activities and enable gene editing in mammalian cells,” is among the first studies to demonstrate gene editing and gene expression experiments with ZTGC RNA or DNA in prokaryotes and eukaryotes. The team’s findings have implications for the improvement of gene editing tools and gene therapy drugs, genome evolution, and building artificially-designed ZTGC genomes. The paper was highlighted in the PNAS edition in which it was published, appearing in the “In This Issue” section that features articles of particular interest.

Authors included first author Shuliang Gao, postdoctoral scholar in the Xu Lab, and Xu as corresponding author, with MD/PhD student Hanan Bloomer (Tufts Graduate School of Biomedical Sciences), postdoctoral scholars Donghui Song, Zhongfeng Ye, and Yu Zhao; biomedical engineering PhD students Douglas Wich, Jennifer Khirallah, and Mengting Chen; and undergraduate students Chutian Xu, E24, and Lihan Liu, A24. 

In its second PNAS paper published in December 2023, the team from the Xu Lab worked with colleagues from the University of Texas, Boston University, State University of New York, and MIT to study mRNA COVID-19 vaccines. With COVID-19 variants continuing to spread, researchers across the globe are continually developing and updating booster vaccines. However, the ongoing mutation of spike proteins in both the original COVID-19 virus and variants like Omicron, and the inadequacy of relying on only antigen-specific antibody responses to address these constantly-evolving viruses, make it difficult to design and deploy new vaccines quickly enough for them to be effective.

The multi-institutional team incorporated optimized UTRs [untranslated regions] combinations and advanced lipid nanoparticle (LNP) formulations in its development of new mRNA-LNP vaccines that effectively activate higher CD4⁺ and CD8⁺ T cell response and humoral immune response when compared to regular spike mRNA construct. The team found that the new vaccines provided “complete protection against WA1/2020, Omicron variants, BA.1 and BQ.1, in hamsters.” Their two vaccines controlled Omicron variant BQ.1 in the lungs and also provided enhanced protection in the upper respiratory airways. In the future, the researchers wrote, “Our mRNA vaccine platform with optimized UTRs and spleen-targeting LNPs can induce broader protection against current SARS-CoV-2 VOCs [variants of concern] and further adapt to future VOCs.”

First authors of the paper were Tufts postdoctoral scholar Zhongfeng Ye and Srinivasa Reddy Bonam of the University of Texas Medical Branch (UTMB). Xu and UTMB Associate Professor Haitao Hu served as corresponding authors. Fellow authors included Lindsay G. A. McKay and Anthony Griffiths from Boston University; Jessica A. Plante, Jordan Walker, and Kenneth S. Plante from UTMB; Yamin Li from State University of New York (formerly a postdoctoral scholar in the Xu Lab); Jianzhu Chen from MIT; and, from the Xu Lab at Tufts, postdoctoral scholars Yu Zhao, Shuliang Gao, and Donghui Song; former postdoctoral scholars Jinjin Chen and Changfeng Huang; undergraduates Chutian Xu, E24, Lihan Liu, A24, and Joseph Harmon, E22;  and MS student Zhibo Zhang, EG21.

PNAS is a prestigious multidisciplinary peer-reviewed journal, highly cited across the physical, biological, and social sciences. It is a journal of the US National Academy of Sciences and publishes research from across the globe.