Cation‐Free siRNA Micelles as Effective Drug Delivery Platform and Potent RNAi Nanomedicines for Glioblastoma Therapy

Jiang, Tong; Qiao, Yonghan; Ruan, Weimin; Zhang, Dongya; Yang, Qingshan; Wang, Guoying; Chen, Qunzhi; Zhu, Fengping; Yin, Jinlong; Zou, Yan; Ran, Qian; Zheng, Meng

doi:10.1002/adma.202104779

Cited by 65 publications

(50 citation statements)

References 63 publications

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“…Viral vectors and cationic nanoparticles not only have certain toxicity but also induce immunogenic responses. Furthermore, excessive cationic components readily cause decomposition of the carrier particles at the glomerular basement membrane, resulting in renal clearance of ncRNAs ( 175 ). Although scientific researchers have made great efforts to design a variety of promising noncationic nucleic acid carriers (octameric ribonucleoprotein, exosomes, spherical nucleic acids and siRNA conjugates) to load ncRNAs ( 183 , 184 ), viral vectors and cationic nanoparticles are still the most commonly used delivery methods in ncRNA therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Nanoparticles with addition of the Ang polypeptide possess obvious brain targeting characteristics and do not destroy the integrity of the BBB. However, the targeting effect of Ang polypeptide modification is ineffective in normal glial cells with LRP-1 deficiency ( 175 ). Mahmoudi et al ( 176 ) attempted to use arginine-glycine-aspartate (RGD) peptide-modified liposomes as delivery carriers of curcumin for the targeted treatment of glioma.…”

Section: Future Perspectivesmentioning

confidence: 99%

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NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

et al. 2022

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As the most common primary tumour of the central nervous system, gliomas have a high recurrence rate after surgical resection and are resistant to chemotherapy, particularly high-grade gliomas dominated by glioblastoma multiforme (GBM). The prognosis of GBM remains poor despite improvements in treatment modalities, posing a serious threat to human health. At present, although drugs such as temozolomide, cisplatin and bevacizumab, are effective in improving the overall survival of patients with GBM, most patients eventually develop drug resistance, leading to poor clinical prognosis. The development of multidrug resistance has therefore become a major obstacle to improving the effectiveness of chemotherapy for GBM. The ability to fully understand the underlying mechanisms of chemotherapy resistance and to develop novel therapeutic targets to overcome resistance is critical to improving the prognosis of patients with GBM. Of note, growing evidence indicates that a large number of abnormally expressed noncoding RNAs (ncRNAs) have a central role in glioma chemoresistance and may target various mechanisms to modulate chemosensitivity. In the present review, the roles and molecular mechanisms of ncRNAs in glioma drug resistance were systematically summarized, the potential of ncRNAs as drug resistance markers and novel therapeutic targets of glioma were discussed and prospects for glioma treatment were outlined. ncRNAs are a research direction for tumor drug resistance mechanisms and targeted therapies, which not only provides novel perspectives for reversing glioma drug resistance but may also promote the development of precision medicine for clinical diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

et al. 2022

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“…For GBM therapy, RNA interference (RNAi) therapy can specifically suppress GBM growth through silencing oncogene expression with high efficacy, negligible toxicity, and low-dose requirements. [27,28] Transglutaminase 2 (TG2), a multifunctional enzyme that is widely distributed in human bodies, was best known for its Ca 2+ -dependent catalytic crosslinking of proteins through ε-(γ-glutamyl)-lysine isopeptide bonds. [29,30] With a more profound understanding of cancers, several studies have established it as a validated biomarker for GBM, [31][32][33] which was overexpressed in GBM and the aberrant expression level was associated with cancer progression.…”

Section: Introductionmentioning

confidence: 99%

TfR Aptamer Enhanced Blood‐Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma

Yao

Chen

et al. 2022

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Engineering a versatile nanocomplex integrating effective penetration of the blood‐brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)‐triggered self‐assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer‐modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO2 is decomposed to release KKGKGQQ‐tetraphenylethene (Pep‐TPE) and siRNA. Owing to TG2 dependence, the non‐emissive Pep‐TPE would be self‐aggregated to induce the emission turn‐on in GBM that contain overexpressed TG2. The resulting aggregation‐induced emission fluorescence imaging with a high signal‐to‐noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as‐prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.

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“…However, challenges for siRNA therapeutics lie in the effective delivery and enhancing the treatment effects [18]. Emerging studies have demonstrated that novel nanotechbased strategies can robustly enhance drug and siRNA delivery, which offers synergetic treatment potentials for multiple diseases [19][20][21][22][23][24]. Cationic polymeric vectors are the most studied siRNA delivery vectors [25].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, difficulties, such as high cytotoxicity, low transfection efficiency, and uncontrollable and untraceable gene transfer, still hamper its progression into clinical applications of gene therapy [26]. The high cytotoxicity of a cationic vector is generally attributed to the plentiful positive charge and non-biodegradable accumulation of the vector [21,27]. Low delivery efficiency and poor vector unpacking are the major limiting steps for high-performance gene delivery.…”

Section: Introductionmentioning

confidence: 99%

Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells

et al. 2022

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Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs’ local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.

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Cation‐Free siRNA Micelles as Effective Drug Delivery Platform and Potent RNAi Nanomedicines for Glioblastoma Therapy

Abstract: 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.

Cited by 65 publications

References 63 publications

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

TfR Aptamer Enhanced Blood‐Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma

Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells

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