MIRA supplement

Principal Investigator/Program Director (Last, First, Middle): Afonin, Kirill, A PROJECT SUMMARY What if healthcare providers were equipped with biocompatible, biodegradable, robust, and affordable treatment options that combine therapeutic modalities with controlled mechanisms of action? What if this

versatile technology had learning capacity and could be educated to recognize patient-specific diseases and interfere with their progression by redirecting fundamental cellular processes? What if the very same formulation could offer an additional means of control over patients’ immune responses and further advance favorable

therapeutic outcomes with minimal toxicities? These next generation therapies would then become a game changer in helping to prevent, detect, diagnose, and treat diseases and disabilities at their source. With the support from MIRA (R35) funding, we envision a data-driven platform, SMART NANPs (specific, modular,

adjustable, reproducible, and targeted nucleic acid nanoparticles), encoded by self-assembling nucleic acids. By controlling the flow of genetic information across all forms of life, nucleic acids have become instrumental in acquiring new knowledge about major cellular processes and origins of diseases. Besides their diverse biological

roles, these biopolymers can be programmed into NANPs with specified physicochemical properties and functionalities that dictate NANPs’ biological actions with endless possibilities for reprogramming cellular behavior through molecular signaling. We recently discovered that different architectural parameters and

compositions of NANPs, delivered to primary human immune cells, can activate monocytes and dendritic cells to produce type I and type III interferons. This pioneering work on NANPs’ immunorecognition highlighted an unforeseen clinical application for this technology in the field of vaccines and immunotherapy. A defined

structure-function relationship for any given NANP would then allow conditional actuation of its immunorecognition or any other therapeutic activity through a set of embedded architectural codes. With this notion, we introduced two orthogonal concepts of therapeutic NANPs which can be conditionally activated in

human cancer cells to release pre-programmed therapeutics. By uniting these breakthroughs and other preliminary findings from my lab, as highlighted in the current application, and integrating them into a unified network of SMART NANPs with programmable control of biodistribution, immunological activity, and therapeutic

modules, we will advance the current repertoire of therapies against infectious diseases and cancers (through NANP-based vaccines and immunotherapies), cardiovascular diseases (through regulated coagulation by thrombin-targeting NANPs), and address drug overdose and safety issues (through the biodegradable nature of

NANPs and their controlled deactivation). To maximize the successful translation of this technology, the proposed program will employ a multidisciplinary approach that spans the fields of nucleic acid nanotechnology, immunology, drug delivery, translational oncology, and machine learning. The long-term goal of this program is

to elevate SMART NANPs to the level of clinical use.