A System for Engineering Nanocarriers Able to Transport Cargo Across the Blood-Brain Barrier

This project aims to develop a rapid design and evaluation system for Trojan horse origami receptor-mediated (THOR) nanocarriers (TNCs) for brain science applications, focusing on crossing the blood-brain barrier (BBB). Phase I demonstrated the synthetic and analytical efficiency of TNCs, utilizing the modularity of DNA nanocarriers (DNs) and a Design-Build-Test-Learn (DBTL) system for iterative engineering. Phase II will enhance this system, advancing in silico, in vitro, and in vivo methodologies. Using Parabon’s inS?quio™ Design Studio, we’ll design new TNCs, optimizing them through in vitro tests to select the most effective for in vivo BBB transport studies. Our approach integrates new analytical methods, tools, and molecular characterizations into each design iteration. Machine learning will predict BBB permeability from in silico features, guiding TNC selection for further evaluation. By Phase II’s end, we aim to demonstrate a TNC capable of BBB penetration and efficacy in a mouse model, establishing predictability of BBB permeability from in silico characterizations. This positions us for IND-enabling studies, targeting a variety of therapeutic payloads and potentially transformative brain science applications.