Antisense oligonucleotides can be employed as a potential approach to effectively treat cancer. However, the inherent instability and inefficient systemic delivery methods for antisense therapeutics remain major challenges to their clinical application. Here, we present a polymerized oligonucleotides (ODNs) that self-assemble during their formation through an enzymatic elongation method (rolling circle replication) to generate a composite nucleic acid/magnesium pyrophosphate sponge-like microstructure, or DNA microsponge, yielding high molecular weight nucleic acid product. In addition, this densely packed ODN microsponge structure can be further condensed to generate polyelectrolyte complexes with a favorable size for cellular uptake by displacing magnesium pyrophosphate crystals from the microsponge structure. Additional layers are applied to generate a blood-stable and multifunctional nanoparticle via the layer-by-layer (LbL) assembly technique. By taking advantage of DNA nanotechnology and LbL assembly, functionalized DNA nanostructures were utilized to provide extremely high numbers of repeated ODN copies for efficient antisense therapy. Moreover, we show that this formulation significantly improves nucleic acid drug/carrier stability during in vivo biodistribution. These polymeric ODN systems can be designed to serve as a potent means of delivering stable and large quantities of ODN therapeutics systemically for cancer treatment to tumor cells at significantly lower toxicity than traditional synthetic vectors, thus enabling a therapeutic window suitable for clinical translation.

Purpose Infants admitted to a level IV neonatal intensive care unit (NICU) who do not survive early childhood represent a population likely enriched for rare genetic disease; we therefore characterized their genetic diagnostic evaluation. Methods This is a retrospective analysis of infants admitted to our NICU between January 1, 2011 and December 31, 2015 who were deceased at the time of records review with an age at death of less than five years. Results 2,670 infants were admitted; 170 later died. 106/170 (62%) had an evaluation for a genetic or metabolic disorder. 47/170 (28%) had laboratory-confirmed genetic diagnoses made, though 14/47 (30%) diagnoses were made postmortem. Infants who were evaluated for a genetic disorder spent more time in the NICU (median 13.5 vs. 5.0 days, p = 0.003), were older at death (median 92.0 vs. 17.5 days p < 0.001), and had similarly-high rates of redirection of care (86% vs. 79%, p = 0.28). Conclusion Genetic disorders were suspected in many infants but found in a minority. Approximately one-third of diagnosed infants died prior to a laboratory-confirmed genetic diagnosis being made. This highlights the need to improve the genetic diagnostic evaluation in the NICU, particularly to aid in end-of-life decision-making.