Therapeutic TAC-nology & targeted drug delivery for precision medicines
Embargo Date
2027-09-03
OA Version
Citation
Abstract
Therapeutics that harness induced proximity between biomolecules are emerging as transformative tools in biological engineering and precision medicine. By spatially controlling molecular interactions, these approaches enable selective degradation, stabilization, relocalization, or functional modulation of disease-associated proteins. This dissertation introduces three novel strategies and platforms that expand the capabilities of proximity-based therapeutics and drug delivery systems, with applications ranging from oncology and viral infections to fundamental tool development. First, a modular protein degradation system is developed using midnolin, a recently identified proteasomal adaptor that operates via a unique ubiquitin-independent mechanism. By fusing proteasomal binding motifs of midnolin to synthetic binding domains, we create synthetic midnolin (Syn-MIDN) constructs that enable ubiquitin-independent, proteasome-mediated degradation of non-native intracellular target proteins. This system demonstrates programmable activity against diverse model targets and oncogenic transcription factors spanning various subcellular localizations and reveals mechanistic flexibility in how proximity-induced degradation can be achieved beyond canonical pathways.
Extending this concept to therapeutic selectivity, a new therapeutic modality termed antibody-RIPTAC conjugates (ARCs) is engineered to induce dual-logic cytotoxicity for oncology applications. These bioconjugates require the co-expression of both an intracellular and extracellular protein to trigger cell death, offering unprecedented selectivity in targeting cancer cells while sparing healthy tissue. We validate this approach in proof-of-concept cell models and large -omics datasets identify actionable therapeutic axes priming this modality for therapeutic development.
In a separate effort targeting infectious disease, a nanoparticle-based delivery system is designed to direct antiviral agents to pulmonary tissue and endolysosomal compartments—key sites for viral entry and replication. Biodegradable polymeric nanoparticles loaded with mefloquine achieve lysosomal localization and inhibit infection and spread of multiple coronaviruses, including multiple murine and human coronavirus strains such as the SARS-CoV-2 Omicron variant. This platform demonstrates efficacy in both prophylactic and post-exposure settings, offering a versatile approach for broad-spectrum antiviral therapy and rapid pandemic response.
Together, these efforts represent significant advances in therapeutic engineering, spanning synthetic biology, chemical biology, and nanomedicine. By expanding the toolkit for induced proximity and improving site-specific drug delivery, this work lays the foundation for novel therapeutics capable of targeting previously undruggable proteins, implementing complex logic-gated cytotoxicity, and combating viral diseases through precision pulmonary delivery.
Description
2025
License
Attribution 4.0 International