Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

Teng, Xin-Qi; Qu, Jian; Li, Guohua; Zhuang, Hai-Hui; Qu, Qiang

doi:10.3389/fcell.2022.824299

Cited by 7 publications

(3 citation statements)

References 147 publications

(175 reference statements)

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“…However, a significant challenge persists in achieving effective systemic delivery, particularly for the targeted treatment of GBM [ 49 ]. Current siRNA research focuses on chemically modifying the siRNA backbone and employing various delivery vehicles to achieve effective targeting of siRNA to glioma cells.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Chen,

Liu,

Fang

et al. 2024

J Transl Med

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Background Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5’-C; antisense strand, 3’-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. Methods IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5’-C; antisense strand, 3’-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-β and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. Results IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-β and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. Conclusions This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5’-C; antisense strand, 3’-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.

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Section: Discussionmentioning

confidence: 99%

“…Viral vectors, nanomaterials, dendrimers, siRNA-conjugated systems, and other extracellular vesicles have substantially attracted attention as potential delivery tools. These innovative strategies aim to enhance the stability and cellular uptake of siRNA, ultimately maximizing its therapeutic potential [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Chen,

Liu,

Fang

et al. 2024

J Transl Med

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“…RNA interference (RNAi) is an endogenous, real-time RNA editing tool. The three subclasses of RNAi include small interfering RNA (siRNA), short hairpin RNA (shRNA), and micro RNA (miRNA) which can be exogenously delivered to silence targeted mRNA sequences [ 84 , 85 , 86 ]. In a medulloblastoma mouse model, Guo et al employed MB-FUS to aid delivery of an siRNA targeting the mRNA coding for the Smoothened (SMO) protein, whose function is critical to the Sonic Hedgehog Pathway [ 64 ].…”

Section: Mb-fus As a Delivery Methods (Preclinical)mentioning

confidence: 99%

Advances in Focused Ultrasound for the Treatment of Brain Tumors

et al. 2023

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Employing the full arsenal of therapeutics to treat brain tumors is limited by the relative impermeability of the blood–brain and blood–tumor barriers. In physiologic states, the blood–brain barrier serves a protective role by passively and actively excluding neurotoxic compounds; however, this functionality limits the penetrance of therapeutics into the tumor microenvironment. Focused ultrasound technology provides a method for overcoming the blood–brain and blood–tumor barriers through ultrasound frequency to transiently permeabilize or disrupt these barriers. Concomitant delivery of therapeutics has allowed for previously impermeable agents to reach the tumor microenvironment. This review details the advances in focused ultrasound in both preclinical models and clinical studies, with a focus on its safety profile. We then turn towards future directions in focused ultrasound-mediated therapies for brain tumors.

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Multifunctional Fluoropolymer‐Engineered Magnetic Nanoparticles to Facilitate Blood‐Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma

Forgham,

Zhu,

Huang

et al. 2024

Advanced Science

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Patients with brain cancers including medulloblastoma lack treatments that are effective long‐term and without side effects. In this study, a multifunctional fluoropolymer‐engineered iron oxide nanoparticle gene‐therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood‐brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) – as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity – meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment‐focused MRI‐siRNA theranostics for the better treatment and diagnosis of medulloblastoma.

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Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

Cited by 7 publications

References 147 publications

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas

Advances in Focused Ultrasound for the Treatment of Brain Tumors

Multifunctional Fluoropolymer‐Engineered Magnetic Nanoparticles to Facilitate Blood‐Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma

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