Most brain diseases including brain tumor and dementia are fatal without current therapeutic solutions. [1] Small interfering RNA (siRNA) technology has demonstrated inherent advantages and significant potential for treating numerous tumor types, [2] owing to its high specificity, low dose requirement and relatively simple drug development process. [3] The rapid development of nanotechnology and material sciences has led to a myriad of nanocarriers being explored for siRNA delivery, [4] and promoting the preclinical potential of siRNA in treating genetically based diseases. siRNA delivery carriers, such as cationic polymers, [5] are predominately amine-abundant and can compress siRNAs into nanoparticles via electrostatic interaction between positive-charged amine groups (NH 3 + ) of polymer and negative-charged phosphate group (PO 3 4− ) of siRNA. However, the abundant presence of charged biomacromolecules in blood, can interfere with the association between cationic polymers and siRNAs, [6] making siRNA nanomedicines that solely rely on electrostatic interaction for stabilization at risk of dissociation in vivo, thereby Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@ siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple-interaction stabilization together with inbuilt self-destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases. siRNA DeliveryThe ORCID identification number(s) for the author(s) of this article can be found under https://doi.
We designed a unique nanocapsule for efficient single CRISPR-Cas9 capsuling, noninvasive brain delivery and tumor cell targeting, demonstrating an effective and safe strategy for glioblastoma gene therapy. Our CRISPR-Cas9 nanocapsules can be simply fabricated by encapsulating the single Cas9/sgRNA complex within a glutathione-sensitive polymer shell incorporating a dual-action ligand that facilitates BBB penetration, tumor cell targeting, and Cas9/sgRNA selective release. Our encapsulating nanocapsules evidenced promising glioblastoma tissue targeting that led to high PLK1 gene editing efficiency in a brain tumor (up to 38.1%) with negligible (less than 0.5%) off-target gene editing in high-risk tissues. Treatment with nanocapsules extended median survival time (68 days versus 24 days in nonfunctional sgRNA-treated mice). Our new CRISPR-Cas9 delivery system thus addresses various delivery challenges to demonstrate safe and tumor-specific delivery of gene editing Cas9 ribonucleoprotein for improved glioblastoma treatment that may potentially be therapeutically useful in other brain diseases.
report of a versatile siRNA micelle platform for GBM treatment which can be potentially applied for the treatment of other brain disorders.Research data are not shared.
A superior biocompatible spherical nucleic acid (SNA) conjugate was fabricated by grafting siRNA onto the surface of a core composed of a spherical DNA nanostructure that we have termed a DNA nanoclew (DC). After uptake by cultured cancer cells, SNA nanoparticles release engrafted siRNAs by cleavage of the intracellular Dicer enzyme. Moreover, in vitro experiments reveal that such SNAs demonstrate potent gene knockdown at both mRNA and protein levels, while with negligible cytotoxicity.
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