Research

The overall goal of this research is to develop innovative approaches for overcoming drug resistance and immunosuppression in cancer therapy. Despite the progress in molecular therapy and immunotherapy, multiple underlying cellular mechanisms cause resistance to cancer therapy. There are urgent needs to develop innovative approaches to meet these challenges. The current research is to develop subcellular enzyme-instructed self-assembly (sEISA) at the tumor sites, which includes mitochondrial EISA (mitoEISA) and cytoplasmic EISA (cytoEISA), for generating molecular nanofibers to overcome drug resistance and immunosuppression in cancer therapy. Our preliminary studies have shown that sEISA selectively targets the mitochondria of cancer cells and minimizes drug resistance. Most importantly, our preliminary study shows that sEISA inhibits the growth of immunosuppressive tumors in vivo. Thus, we will further develop sEISA against drug resistant cancer cells and tumors. The central hypothesis is that sEISA spatiotemporally generates molecular nanofibers, which interact with multiple cellular proteins and interrupt multiple cellular processes inside cancer cells to minimize drug resistance. The long-term goal of the proposed work is to develop sEISA to generate molecular nanofibers at tumor sites for overcoming resistance and immunosupression in cancer therapy. This research will provide innovative anticancer approaches to address the problems of drug resistance and immunosuppression in cancer therapy, thus ultimately will improve the survivorship of cancer patients

Human induced pluripotent stem cells (iPSCs) have enormous potential to generate a variety of cell types for cell therapy. The tumorigenic risk of undifferentiated iPSC cells, however, remains a major obstacle for clinical application of iPSC-derivatives. Developing novel molecules for selectively eliminating undifferentiated iPSCs is urgently needed. We recently succeeded using enzyme-instructed self-assembly (EISA) to selectively kill iPSCs without harming iPSC-derived cells. Because alkaline phosphatase (ALP) is overexpressed in iPSCs, but not in iPSC-derived cell, ALP-catalyzed dephosphorylation of phospho-L-peptides (pLPs) only form intranuclear peptide nanoribbons in iPSCs. This EISA process selectively kill iPSCs. Current study is to explore ALP-instructed EISA of pLPs for eliminating undifferentiated iPSCs from the cell mixtures of differentiated cells. The aim of this research is to develop and to evaluate the pLPs for eliminating undifferentiated iPSCs using molecular engineering, cell assays, and a murine model. The success of the research will lead to new molecular targeting agents for rapidly and selectively eliminating unwanted iPSCs for cell therapy.

Enzymatic noncovalent synthesis (ENS) exploits enzymatic reactions to produce spatially organized higher-order supramolecular assemblies that modulate cellular processes. While ENS is emerging as a general mechanism to create protein assemblies for diverse cellular functions, the exploration of ENS of other bioactive molecules, such as peptides, is rather limited. We invented ENS of peptide assemblies. We found that ENS, generating non-diffusive peptide assemblies, provides a unique approach for controlling cell behavior and acquiring basic biomedical knowledge. We are further developing ENS of peptide assemblies in specific cellular spaces to address the remaining technical challenges and unresolved issues, such as the structure-function relationship of the substrates of ENS, the mechanisms of cell functions modulated by ENS of peptide assemblies, and the in vivo applications of ENS of peptide assemblies. This research aims to establish ENS of peptide assemblies as an innovative technology that uses localized molecular processes (i.e., enzymatic reaction and self-assembly), for controlling cell fates, understanding diseases, and developing therapeutics.

We have pioneered the design and biomedical application of multifunctional magnetic nanoparticles. After their conjugation with proper ligands, antibodies, or proteins, the biofunctional magnetic nanoparticles exhibit highly selective binding. These results indicate that such nanoparticles could be applied to biological problems such as bacterial detection, protein purification, and toxin decorporation. The hybrid nanostructures, which combine magnetic nanoparticles with other nanocomponents, exhibit paramagnetism alongside features such as fluorescence or enhanced optical contrast. Such structures could provide a platform for enhanced medical imaging and controlled drug delivery. We have shown that the combination of unique structural characteristics and integrated functions of multicomponent magnetic nanoparticles has lead to new opportunities in nanomedicine.