Glioma-targeted delivery of exosome-encapsulated antisense oligonucleotides using neural stem cells.
Glioma-targeted delivery of exosome-encapsulated antisense oligonucleotides using neural stem cells.
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DOI：
10.1016/j.omtn.2021.12.029
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Kortylewski M
中科院分区：
文献类型：
--
作者：
Adamus T;Hung CY;Yu C;Kang E;Hammad M;Flores L;Nechaev S;Zhang Q;Gonzaga JM;Muthaiyah K;Swiderski P;Aboody KS;Kortylewski M
神经干细胞（neural stem cells，NSCs）对缺氧肿瘤区域的趋化性为药物的递送提供了机会。在这里，我们证明了神经干细胞有效地将靶向致癌和致耐受性信号转导和转录激活因子3（STAT 3）蛋白的反义寡核苷酸（ASO）转运到胶质瘤微环境中。为了能够通过NSC进行自发的、清道夫受体介导的内吞作用，我们使用先前描述的CpG-STAT 3ASO缀合物。在摄取和内体逃逸后，CpG-STAT 3ASO与CD 63+囊泡共定位，随后与CD 63 + CD 81+外泌体共定位。在3天内，NSC分泌负载高达80%的CpG-STAT 3AS 0的外来体。与天然NSC外泌体相比，负载CpG-STAT 3 ASO的外泌体有效地刺激人树突状细胞或小鼠巨噬细胞的免疫活性，诱导核因子κB（NF-κB）信号传导和白细胞介素-12（IL-12）产生。使用原位GL 261肿瘤，我们证实了与裸寡核苷酸相比，NSC介导的递送改善了寡核苷酸从远处注射部位转移到胶质瘤微环境中。相应地，NSC递送的CpG-STAT 3AS 0增强了胶质瘤相关小胶质细胞的活化。最后，我们证明了NSC介导的CpG-STAT 3ASO递送导致小鼠中针对GL 261胶质瘤的增强的抗肿瘤作用。瘤周注射5 × 105个离体负载CpG-STAT 3ASO的NSC比单独等量的寡核苷酸更有效地抑制皮下肿瘤生长。基于这些结果，我们预期NSC和NSC衍生的外泌体将提供临床相关策略以改善用于神经胶质瘤治疗的寡核苷酸治疗剂的递送和安全性。在这里，我们证明了神经干细胞对缺氧肿瘤区域的向性允许寡核苷酸递送。分泌外泌体包裹的CpG-STAT 3AS 0的NSCs诱导小鼠抗胶质瘤的抗肿瘤效应。我们认为，神经干细胞介导的寡核苷酸治疗转移是一个更安全，更有效的治疗脑肿瘤的机会。
Tropism of neural stem cells (NSCs) to hypoxic tumor areas provides an opportunity for the drug delivery. Here, we demonstrate that NSCs effectively transport antisense oligonucleotides (ASOs) targeting oncogenic and tolerogenic signal transducer and activator of transcription 3 (STAT3) protein into glioma microenvironment. To enable spontaneous, scavenger receptor-mediated endocytosis by NSCs, we used previously described CpG-STAT3ASO conjugates. Following uptake and endosomal escape, CpG-STAT3ASO colocalized with CD63+ vesicles and later with CD63+CD81+ exosomes. Over 3 days, NSCs secreted exosomes loaded up to 80% with CpG-STAT3ASO. Compared to native NSC exosomes, the CpG-STAT3ASO-loaded exosomes potently stimulated immune activity of human dendritic cells or mouse macrophages, inducing nuclear factor κB (NF-κB) signaling and interleukin-12 (IL-12) production. Using orthotopic GL261 tumors, we confirmed that NSC-mediated delivery improved oligonucleotide transfer from a distant injection site into the glioma microenvironment versus naked oligonucleotides. Correspondingly, the NSC-delivered CpG-STAT3ASO enhanced activation of glioma-associated microglia. Finally, we demonstrated that NSC-mediated CpG-STAT3ASO delivery resulted in enhanced antitumor effects against GL261 glioma in mice. Peritumoral injections of 5 × 105 NSCs loaded ex vivo with CpG-STAT3ASO inhibited subcutaneous tumor growth more effectively than the equivalent amount of oligonucleotide alone. Based on these results, we anticipate that NSCs and NSC-derived exosomes will provide a clinically relevant strategy to improve delivery and safety of oligonucleotide therapeutics for glioma treatment. Here, we demonstrate that tropism of neural stem cells to hypoxic tumor areas allows for oligonucleotide delivery. NSCs secreting exosome-encapsulated CpG-STAT3ASOs induced antitumor effects against glioma in mice. We believe that NSC-mediated transfer of oligonucleotide therapeutics is an opportunity for safer and more effective treatment of brain tumors.
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影响因子：
16
作者：
Mateescu B;Kowal EJ;van Balkom BW;Bartel S;Bhattacharyya SN;Buzás EI;Buck AH;de Candia P;Chow FW;Das S;Driedonks TA;Fernández-Messina L;Haderk F;Hill AF;Jones JC;Van Keuren-Jensen KR;Lai CP;Lässer C;Liegro ID;Lunavat TR;Lorenowicz MJ;Maas SL;Mäger I;Mittelbrunn M;Momma S;Mukherjee K;Nawaz M;Pegtel DM;Pfaffl MW;Schiffelers RM;Tahara H;Théry C;Tosar JP;Wauben MH;Witwer KW;Nolte-'t Hoen EN
通讯作者：
Nolte-'t Hoen EN
影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
10.8
作者：
Kooijmans, Sander A. A.;Stremersch, Stephan;Vader, Pieter
通讯作者：
Vader, Pieter