The value of a new way to develop not just drugs, but interfaces to the body is unprecedented in redefining conventional healthcare systems while addressing its most devastating flaws/points of friction.

• novel therapeutics are required in silico and in vitro to test and treat personalized diseases + accomodate for said response
• a new interface → we input a molecule/programmable voyager into the body and it stays dormant, and it can be invasively activated either on command or automatically based on data it collects + streams back to personal monitor
• by better understanding our bodies and providing immediate yet dormant immune bases for easy engineering (ie. beyond just CRISPR for gene editing), we can effectively solve many logistical and data-collection problems
• to speed up discovery, monitoring, and get a much higher resolution of the effects of said drugs, we can add programmable hooks that can alter the behaviour of a drug at absolute times
• Programmable nanostructures: RNA could be used as vessels for shipping therapeutic molecules into cells, but we want to go beyond just molecules and engineer chemical signals that can be read and monitored + altered
• researchers in US showed by experiment that RNA assemblies designed on computers were stable and could accomodate multiple siRNAs with broad therapeutic function (as they helped control gene function)
  • potential could be modelling gene expression levels as an indicator [timestamps are critical]
  • RNA is present naturally in large quantities in cell → synthetic RNA is a potentially attractive candidate for bio-compatible therapeutics
  • through computer-aided design, we can speedtrack evolution (this was done by University of California, Santa Barbara, and National Cancer Institute in Maryland)
    • created self-assembling hexagonal nanorings of RNA [quasi-digital → what does this mean]
• generating shape of hexagon requries careful selection of RNA sequences to avoid particles self-assembling into its preferred structural conformation (based on available energy)
• team adapted structural elements from bacterial RNA known as kissing-loop complexes → each side of one of their 15nm hexagons is RNA unit ending in a loop that meets or kisses another loop at a corner of the hexagon → each kiss is 120 deg. at loop point
  • biggest issue is delivery and stability (what enzyme would unpackage and release molecular contents of therapy
  • making nanoparticles stable and protected in the body is difficult [living things and systems alike depend on non-eternal molecules]
• Forming this into a toolset: paper tackles chromosomal translocations (copy number variations) which are point mutations that account for 58% of pathogenic genetic variants causing disease → programmable nucleases such as CRISPR-Cas while effective are not the final iteration of the tech (use homologous recombineering, can introduce off-target mutations, immunogenicity)
• while CRISPR does use a Guide-RNA, why can't we also use Guide-RNA as the programmable basis for our interface → this guide-RNA can recruit exogenously expressed human Adenosine-Deaminase acting on RNA (known as ADAR) enzymes to target transcripts responsible for guanosine-adenosine mutations + catalyze said modifications
  • you can repair or re-engineer start and stop codons + splice-site mutations via exogenously delivered ADARs and its associated guide-RNA
  • exogenous delivery for these ADARs lead to transcriptome-wide off-targets + enzymatic activity only present for certain RNA motifs (i.e. adenosines flanked by a 5' guanosine is very low) which limits usefulness based on design
    • to combat this, designed split-ADAR system through specificity profiles [identifying key targets is important to design] → also carries out high throughput mutagenesis screen to identify ADAR variants with enhanced activity at adenosines flanked by a 5' guanosine
• based on gene therapy, recruitment of endogenous ADAR enzymes for editing transcript creates minimal perturbation for target cells → the "base or terminal of operations" can be a novel circular guide RNA to recruit these ADAR enzymes