Developing Technological Platforms for Targeted Cancer Therapies, Protein Drug Delivery, and Pathogen Detection

 Biomedical engineering has made remarkable progress in enhancing human healthcare, contributing significantly to the fight against human diseases. However, we still confront grand challenges in accurate disease diagnosis, efficient therapeutic delivery, and the development of targeted therapies. For example, the diagnosis of coronavirus disease (COVID-19) remains challenging in low-resource settings where access to specialized medical equipment and trained personnel is severely limited. Cystic fibrosis patients carrying cystic fibrosis transmembrane conductance regulator (CFTR) mutations that lead to non-functional CFTR protein production remain ineligible for CFTR modulator treatments. Traditional cancer chemotherapies, though effective, frequently encounter "on-target, off-tissue" cytotoxicity associated with target molecule prevalence on healthy tissue. 

To tackle the critical challenges in disease diagnosis, therapeutic delivery, and targeted therapies in various human disease, in this thesis, we engineered disease diagnostic device for COVID-19 detection in low-resource settings, efficient therapeutic delivery system for cystic fibrosis patients carrying CFTR mutations, and targeted therapy for cancer treatment. In chapter 1, we developed TASE (TArgeted Split Enzyme), an innovative cancer treatment strategy featuring an AND-gated dual-targeting mechanism. TASE effectively reduces off-tissue cytotoxicity by utilizing a tunable payload, leveraging a pair of split human simplex virus (HSV) thymidine kinase (TK). This enzyme converts the prodrug ganciclovir (GCV) into a cytotoxic form exclusively within cancer cells, thus enhancing targeted therapy efficacy. Chapter 2 developed an innovative extracellular vesicle-based protein drug delivery system for the direct transport of CFTR protein to the plasma membrane of human bronchial epithelial cells. It holds significant promise for treating cystic fibrosis patients with non-functional CFTR protein production. Chapter 3 developed a Surfactant-Infused Space-Domain RT-qPCR (SiSd-RT-qPCR) device for ultrafast, one-step SARS-CoV-2 virus detection in low-resource settings.