PO.CH01.04 · 化学

通过离子导入利用面部神经通路将双模态球形核酸靶向皮内递送至脑部以发挥抗胶质瘤效应

Harnessing facial neuronal pathways via iontophoresis for targeted intradermal delivery of bimodal spherical nucleic acids to the brain for anti-glioma  effect

编号 6392 展板 24 时间 4/21 02:00–05:00 区域 Section 38 主讲 Davin Hickman-Chow, BS

分会场 Drug Delivery

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作者与单位 Authors & Affiliations

Akanksha S. Mahajan¹, Davin Hickman-Chow², Gaelen Clayton³, Seunghyun Kim¹, Rachel Jarvis¹, Emma Shen¹, Clara Foltz¹, Cao Dai Phung¹, Eric Leuthardt⁴, Alexander Stegh⁵

¹Taylor Family Department of Neurosurgery, The Brain Tumor Center, Washington University in St. Louis, Saint Louis, MO,²Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO,³Department of Mechanical Engineering,, Washington University in St. Louis, Saint Louis, MO,⁴Department of Neuroscience, Neurosurgery, Mechanical Engineering, Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO,⁵Taylor Family Department of Neurosurgery, The Brain Tumor Center, Department of Neuroscience, Washington University in St. Louis, Saint Louis, MO

摘要 Abstract

中文摘要

背景：胶质母细胞瘤（GBM）由于药物跨血脑屏障（BBB）递送的障碍及其高度免疫抑制性的肿瘤微环境（TME），仍是最具侵袭性的脑肿瘤之一。这些限制阻碍了治疗药物向肿瘤部位的渗透。虽然鼻内策略利用三叉神经/嗅觉途径，但黏膜纤毛清除和脱靶暴露限制了其临床转化。在此，我们开发了一种基于面部真皮离子导入的系统，通过面部神经-淋巴网络递送免疫调节纳米颗粒，以绕过BBB并重塑TME。方法：为克服影响旨在调节肿瘤相关免疫和外周免疫的免疫疗法的递送障碍，我们整合了两种方法。首先，我们确立离子导入作为一种微创方法，以绕过BBB并增强经面部皮内（i.d.）注射递送的治疗药物的转运。其次，我们设计了一种双模态球形核酸（bi-SNA）平台，可激活cGAS并抑制STAT3。Bi-SNA由一个15 nm的金核构成，其表面功能化有带STAT3诱饵序列的发夹寡核苷酸，从而实现cGAS激活和STAT3隔离的同步进行。Bi-SNA在多种HGG模型中引发强效抗肿瘤免疫，并优于cGAS激动剂单药治疗。设计了专用的离子导入设备用于使用小鼠GBM模型的临床前评估，并对离子导入参数（电流密度、波形、电极放置）进行了优化，以实现受控的经皮SNA转运。通过带ICG标记SNA的3D荧光CT-IVIS测量生物分布，通过ICP-MS测量金水平，通过多光谱流式细胞术测量免疫调节。结果：使用离子导入进行的皮内Bi-SNA递送显著抑制了肿瘤进展，耗竭了免疫抑制性髓系细胞，并增加了效应T细胞的募集/激活。IVIS成像显示SNA从面部平面向脑部转运增加了2倍且动力学更快，未检测到全身扩散，并优先沿上颌-嗅觉和颞下颌通道蓄积。ICP-MS显示，与被动皮内递送相比，12小时内脑部和三叉神经中的金沉积高出约20倍。结论：离子导入增强的皮内递送为脑靶向免疫治疗提供了一种强大的非侵入性策略，利用神经通路绕过BBB并重塑GBM TME。这为可供患者适配、居家使用的脑肿瘤纳米治疗递送奠定了基础。

查看英文原文 English abstract

Background: Glioblastoma (GBM) remains one of the most aggressive brain tumors due to barriers in drug delivery across the blood-brain barrier (BBB) and its profoundly immunosuppressive tumor microenvironment (TME). These limitations restrict therapeutic penetration into tumor sites. While intranasal strategies exploit trigeminal/olfactory routes, mucociliary clearance and off-target exposure have limited clinical translation. Here, we developed a facial dermal iontophoresis-based system to deliver immune-modulating nanoparticles through the facial neuro-lymphatic network to bypass the BBB and reprogram the TME. Methods: To overcome delivery barriers affecting immunotherapies intended to modulate tumor-associated and peripheral immunity, we integrated two approaches. First, we established iontophoresis as a minimally invasive method to bypass the BBB and enhance the transport of therapeutics delivered via facial intradermal (i.d.) injection. Second, we engineered a bimodal Spherical Nucleic Acid (bi-SNA) platform that activates cGAS and inhibits STAT3. Bi-SNAs consist of a 15-nm gold core functionalized with a hairpin oligonucleotide with STAT3-decoy sequences, enabling simultaneous cGAS activation and STAT3 sequestration. Bi-SNAs elicit potent antitumor immunity in multiple HGG models and outperform cGAS-agonist monotherapies. A dedicated iontophoresis device was designed for preclinical assessment using murine GBM models, and iontophoretic parameters (current density, waveform, electrode placement) were optimized for controlled transdermal SNA transport. Biodistribution was measured by 3D fluorescence CT-IVIS with ICG-labeled SNAs, gold levels by ICP-MS, and immune modulation by multispectral flow cytometry. Results: I.d. Bi-SNA delivery with iontophoresis significantly suppressed tumor progression, depleted immunosuppressive myeloid cells, and increased recruitment/activation of effector T cells. IVIS imaging showed a two-fold increase and faster kinetics of SNA trafficking from facial planes to the brain without detectable systemic spread, with preferential accumulation along maxillary-olfactory and temporomandibular conduits. ICP-MS revealed ~20-fold higher gold deposition in the brain and trigeminal nerve within 12 hours compared with passive i.d. delivery. Conclusions: Iontophoresis-enhanced i.d. delivery provides a powerful non-invasive strategy for brain-targeted immunotherapy, leveraging neuronal pathways to bypass the BBB and reprogram the GBM TME. This establishes a foundation for patient-adaptable, at-home nanotherapeutic delivery for brain tumors.

利益披露 Disclosure

A. S. Mahajan, None.. D. Hickman-Chow, None.. G. Clayton, None.. S. Kim, None.. R. Jarvis, None.. E. Shen, None.. C. Foltz, None.. C. Dai Phung, None. E. Leuthardt, Sora Imaging Solutions Stock, Other Intellectual Property. Neurolutions Stock, Other Intellectual Property, consultant. Inner Cosmos Stock, Other Intellectual Property. Cordance Stock. Aurenar Stock, Other Intellectual Property. Face to Face Biometrics Stock, equity. Acera Stock, equity. Caeli Vascular Stock, Other Intellectual Property, equity. Petal Surgical Stock. Silent Surgical Stock. Monteris Medical Stock, consultant. A. Stegh, Exicure Stock.

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