Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer

Nie, Huifang; Xie, Xiaodong; Zhang, Doudou; Zhou, Yu; Li, Bifei; Li, Fengqiao; Li, Feiyang; Cheng, Yunlong; Mei, Hao; Meng, Huan; Jia, Lee

doi:10.1039/c9nr09011h

Cited by 166 publications

(107 citation statements)

References 33 publications

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“…If we try to increase the coupling amount of Ale, it could be possible to get a better antiosteoporosis effect of Ale-EVs. It has been reported that MSC derived exosomes and microparticles could stimulate the repair and regeneration of tissues such as kidney, heart, and bone [29][30][31][32]. In this study, our results also showed that EVs from MMSCs could promote cell proliferation and trigger osteogenic differentiation of MMSCs in vitro (Fig.…”

Section: Discussionsupporting

confidence: 75%

“…We can enrich MMSCsderived EVs with mRNAs or proteins that used to treat osteoporosis by genetic engineering technology [34][35][36], and strengthen the anti-osteoporosis effect of Ale-EVs. Besides, we also could load other drugs such as nucleic acid drugs [32,37], small molecule drugs [38] into the target-delivery system to achieve the purpose of combined treatment of osteoporosis…”

Section: Discussionmentioning

confidence: 99%

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Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy

Wang¹,

Yao

Cai

et al. 2020

Preprint

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Background Osteoporosis (OP) is one of the most common chronic diseases, but the drugs used to treat OP have strong side effects. Recently, bone regeneration in stem cell derivatives represented by extracellular vesicles (EVs) has provided a new strategy for the prevention and treatment of OP. EVs derived from mouse mesenchymal stem cells (mMSCs) have a positive effect on bone regeneration, yet their clinical application has been hampered by the lack of bone-targeting. Alendronate (Ale) has a specifically affinity for bone tissue through a high affinity with hydroxyapatite. Herein, we used copper-free "click chemistry” to combine EVs with Ale together for OP targeted therapy. Bone targeting was facilitated via Ale binding to hydroxyapatite, which is highly expressed on the bone surface. Methods In vitro, bone targeting of Ale-EVs was confirmed by flow cytometry. Also, Ex vivo ﬂuorescent imaging data revealed strong ﬂuorescent signals in bone tissues in mice treated with Ale-EVs-DiD compared to bone tissues of mice treated with EVs-DiD. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Besides, our results showed that Ale-EVs could promote the proliferation and differentiation of mouse mesenchymal stem cells in vitro. And it had the antiosteoporotic effects in ovariectomy (OVX)-induced osteoporosis rat model. Conclusions A novel bone-targeting nanoparticle delivery system was developed for osteoporosis therapy. We used the Ale-N3 to modify mMSCs derived EVs by copper-free "click chemistry” to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy

Wang¹,

Yao

Cai

et al. 2020

Preprint

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“…It has been reported that MSC-derived exosomes and microparticles could stimulate the repair and regeneration of tissues such as kidney, heart, and bone. [33][34][35][36][37] Exosomes contain functional mRNAs, lncRNA, tRNA and miRNAs, as well as proteins. In addition, these contents play a positive role in osteogenic differentiation and proliferation.…”

mentioning

confidence: 99%

“…We can enrich mMSCs-derived EVs with mRNAs or proteins to treat osteoporosis by genetic engineering technology, [57][58][59] and strengthen the antiosteoporosis effect of Ale-EVs. Besides, we also could load other drugs such as nucleic acid drugs, 36,60 small molecule drugs 61 into the target-delivery system to achieve the purpose of combined treatment of osteoporosis.…”

mentioning

confidence: 99%

<p>Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy</p>

Wang¹,

Yao²,

Cai

et al. 2020

IJN

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Background: Current drugs used for osteoporosis therapy show strong adverse effects. Stem cell-derived extracellular vesicles (EVs) provide another choice for osteoporosis therapy. Mouse mesenchymal stem cells (mMSCs)-derived EVs promote bone regeneration; however, their clinical application is limited due to non-specific tissue targeting. Alendronate specifically targets bone tissue via hydroxyapatite. Therefore, EVs were combined with alendronate to generate Ale-EVs by "click chemistry" to facilitate EVs targeting bone via alendronate/hydroxyapatite binding. Methods: Ale-EVs were characterized based on size using dynamic light scattering analysis and morphology was visualized by transmission electron microscopy. Hydroxyapatite affinity of Ale-EVs was detected by flow cytometry. Bone targeting of Ale-EVs was tested by ex vivo fluorescent imaging. Cell viability was assessed by using WST-8 reduction assay kit for testing the ability of Ale-EVs to promote mMSCs proliferation. Alkaline phosphatase experiment was used to detect ability of Ale-EVs to promote differentiation of mouse mesenchymal stem cells in vitro. Western blotting and Q-PCR assay were used to detect the early marker of osteogenic differentiation. Antiosteoporotic effects of Ale-EVs were detected in ovariectomy (OVX)-induced osteoporosis rat model. The safety of the Ale-EVs in vivo was measured by H&E staining and serum markers assay. Results: In vitro, Ale-EVs had high affinity with hydroxyapatite. Also, ex vivo data indicated that Ale-EVs-DiD treatment of mice induced strong fluorescece in bone tissues compared with EVs-DiD group. Furthermore, results suggested that Ale-EVs promoted the growth and differentiation of mouse MSCs. They also protected against osteoporosis in ovariectomy (OVX)-induced osteoporotic rats. Ale-EVs were well tolerated and no side effects were found, indicating that Ale-EVs specifically target bone and can be used as a new therapeutic in osteoporosis treatment. Conclusion: We used the Ale-N3 to modify mouse mesenchymal stem cells-derived extracellular vesicles by copper-free "click chemistry" to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.

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“…In addition, a recent study reported that exosome transportation was an important regulator in the formation and progression of lung cancer, and that the inhibition of exosomes could inhibit tumor proliferation. 32 In this study, microscopic observation showed that the fluorescently-labeled exosomes were able to enter the lung cancer cells. We separated and isolated G-MDSC-derived exosomes and found that exosomes promoted the proliferation of lung cancer in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 65%

<p>G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer</p>

Zhou

Yao

Zheng

et al. 2020

OTT

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Background: The immune environment of lung cancer is complex, and the critical immune factors that promote lung cancer progression need to be explored. Granulocytic myeloidderived suppressor cells (G-MDSCs) are regarded as immune suppressing cells. However, they also promote tumor progression through other ways, which needs to be explored further. Therefore, we sought to study the regulatory mechanisms underlying the cancer promoting function of G-MDSCs in lung cancer. Methods: G-MDSCs were isolated from lung cancer tissues using flow cytometry. Exosomes were separated from the G-MDSCs supernatant by ultracentrifugation and verified using flow cytometry, Western blot, and transmission electron microscopy (TEM). RNA sequencing was used to identify the differential miRNAs and genes. Real-time quantitative real-time PCR (RT-qPCR) confirmed these results. The proliferation rate was assessed using the CCK-8 assay. Lentiviral vectors were used to alter the expression of the miRNAs and genes to analyze their effects on lung cancer progression. Results: G-MDSCs secreted more exosomes in the lung cancer tissues, which promoted cancer progression by accelerating proliferation. Micro RNA-143-3p (miR-143-3p) increased in G-MDSCs derived exosomes and downregulated integral membrane protein 2B (ITM2B) by targeting the 3ʹ-untranslated region (UTR) region. Overexpression of miR-143-3p enhanced proliferation by inhibiting transcription of ITM2B to activate the PI3K/Akt signaling pathway, which can be blocked by deguelin. This phenomenon was further confirmed by accelerated tumor growth and worse prognosis in mice. Conclusion: The key findings of this study highlight the potential of the G-MDSC-derived exosomes and the miR-143-3p/ITM2B axis as therapeutic targets and clinical indicators of lung cancer.

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Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer

Abstract: Engineered exosomes have become popular drug delivery carriers for cancer treatment. Systemic injection of organotropic exosome carrier leads to efficient targeting and efficacious anti-cancer outcome.

Cited by 166 publications

References 33 publications

Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy

Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy

<p>Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy</p>

<p>G-MDSCs-Derived Exosomal miRNA-143-3p Promotes Proliferation via Targeting of ITM2B in Lung Cancer</p>

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