Control of the Assembly and Disassembly of Spherical Nucleic Acids Is Critical for Enhanced Gene Silencing
Bibliographic record
Abstract
Spherical nucleic acids─nanospheres with nucleic acids on their corona─have emerged as a promising class of nanocarriers, aiming to address the shortcomings of traditional nucleic therapeutics, namely, their poor stability, biodistribution, and cellular entry. By conjugating hydrophobic monomers to a growing nucleic acid strand in a sequence-defined manner, our group has developed self-assembled spherical nucleic acids (SaSNAs), for unaided, enhanced gene silencing. By virtue of their self-assembled nature, SaSNAs can disassemble under certain conditions in contrast to covalent or gold nanoparticle SNAs. Gene silencing involves multiple steps including cellular uptake, endosomal escape, and therapeutic cargo release. Whether assembly vs disassembly is advantageous to any of these steps has not been previously studied. In this work, we modify the DNA and hydrophobic portions of SaSNAs and examine their effects on stability, cellular uptake, and gene silencing. When the linkages between the hydrophobic units are changed from phosphate to phosphorothioate, we find that the SaSNAs disassemble better in endosomal conditions and exhibit more efficacious silencing, despite having cellular uptake similar to that of their phosphate counterparts. Thus, disassembly in the endolysosomal compartments is advantageous, facilitating the release of the nucleic acid cargo and the interactions between the hydrophobic units and endosomal lipids. We also find that SaSNAs partially disassemble in serum to bind albumin; the disassembled, albumin-bound strands are less efficient at cellular uptake and gene silencing than their assembled counterparts, which can engage scavenger receptors for internalization. When the DNA portion is cross-linked by G-quadruplex formation, disassembly decreases and cellular uptake significantly increases. However, this does not translate to greater gene silencing, again illustrating the need for disassembly of the SaSNAs when they are in the endosome. This work showcases the advantages of the dual nature of SaSNAs for gene silencing, requiring extracellular assembly and disassembly inside the cell compartments.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".