Cell penetrating peptide-functionalized small interfering RNA nanoparticles knock down HER expression in breast cancer cells
Bibliographic record
Abstract
Efficient delivery of small interfering RNA (siRNA) remains a major challenge in gene therapy, particularly due to poor cellular uptake, enzymatic degradation, and endosomal entrapment of the cargo.Cell penetrating peptides (CPPs) offer a promising strategy for intracellular delivery of nucleic acids; however, peptide-based gene delivery carriers possess limited nucleic acid condensation capability, demonstrating reduced transfection efficacies in mammalian cells.This study aimed to enhance siRNA delivery efficacies of CPP-based siRNA therapeutics by combining nucleic acid condensation efficacies of methylated protamine with the cell permeation capabilities of cyclic peptides to improve physiological stability, cellular uptake, and gene silencing efficacies in HER2 + breast cancer cells.Cyclic CPPs (cCPPs) of different cationic and amphipathic characters (namely, cTAT, cKALA, and cC105Y) were synthesized by solid phase peptide synthesis.Methylated protamine/siRNA complexes of net neutral nanoparticles (NNPs) obtained at nitrogen-to-phosphate ratio of 1 were functionalized with cCPPs at various cCPP/ siRNA w/w ratios, and the sizes and net charges of the formulated nanoparticles were analyzed using dynamic light scattering and a zeta potential instrument, respectively.cCPP-functionalized NNPs demonstrated improved nucleic acid condensation efficacy and protection against enzymatic degradation compared with bare NNPs.cCPP-NNPs formulated using various types of peptides overall demonstrated superior siRNA transfection efficacies with ~60% HER2 gene silencing efficacies in HER2 + breast cancer cells.cC105Y-NNPs particularly showed improved physiological stability and cellular uptake compared with the other cCPP-functionalized nanoparticles.Endosomal escape remained a limiting factor in the gene expression efficacies of cCPP-NNPs, and incorporation of an endosomedisrupting agent improved HER2 gene knockdown efficacies (~80%) to levels that were comparable to the Lipofectamine control.Furthermore, the potential of cCPP-NNPs for simultaneous knockdown of HER2 and HER3 was demonstrated to improve the anticancer efficacies of the nanoparticle for HER2 + breast cancer treatment.Significance Statement: Cyclic cell penetrating peptide-functionalized nanoparticles with improved physiological stability and optimized nucleic acid condensation and release efficacies formulated by simple deposition of cationic peptides on protamine small interfering RNA complexes demonstrate superior gene knockdown and anticancer efficacies in breast cancer cells.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".