Redirecting nucleic acid-based nanostructures for immunotherapy and imaging

In the pursuit of addressing the complexity and heterogeneity of cancer, cancer therapy and diagnostics have experienced a transition in the fundamental concept of "one-size-fits-all" approach toward precision medicine in which each individual is treated according to the display of specific molecular or cellular biomarker features. By detecting, monitoring, and correlating biomarker expression with disease progression, the treatment can be tailored to target specific tumor associated antigens (TAA)s to maximize patient benefit, minimize adverse events, and deliver personalized cancer therapy on an ongoing basis. In the desire to improve the affinity and specificity for TAA targeting, the accumulative strength of multivalent and multispecific interactions has become recognized as a central principle of targeting. Several factors must be considered when designing efficient multivalent and multispecific systems, highlighting the complexity involved and the pivotal role played by the delivery platform. Nucleic acids serve as ideal platforms for multimerizing targeting ligands. This attribute stems from their modular, flexible, and programmable nature that enables the design of nanostructures in nearly any desired shape, with nanoscale precision and unmatched spatial control of ligand distribution and stoichiometry. The incorporation of dynamic mechanisms to undergo controlled reconfiguration of the nanostructures can drastically broaden their potential. In this dissertation, three projects are presented that all take advantage of the versatility and programmability of nucleic acids to construct tailored nanostructures for targeted therapy and diagnostics in precision medicine. The first project describes the establishment of a method for tightly controlling the circulatory half-life of imaging agents in vivo. For this purpose, we developed a DNA-based, PEGylated, near-infrared imaging agent that, through external actuated toehold-mediated strand displacement reactions, was cleared from circulation. In the second project, a biocompatible nucleic acid-based nanostructure, referred to as the Holliday Junction (HJ), was applied to create a multispecific T cell engager and modulator for T cell redirected cancer immunotherapy which led to efficient tumor cell killing. Finally, the third project applies the HJ to create a multivalent nuclear imaging agent that efficiently improved HER2-positive tumor cell targeting in vitro. Collectively, these projects demonstrate the utility of nucleic acids as building blocks for constructing modular and self-assembled nanostructures tailored to address the challenges of precision medicine.

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