文献：Enhanced mRNA delivery using ultrasound-delivered click reactive anchors

作者：Emilio Di Ianni, Jueun Jeon, Huiyu Hu, Jeremy M. Quintana, Chanseo Lee, Edwina Abou Haidar, Sedra Mohammadi, Ayrton Zargani-Piccardi, Mohammed Mahamdeh, Iván Coto Hernández, Thomas S.C. Ng, Koen Breyne, Hakho Lee, Xandra O. Breakefield, Miles A. Miller

文献链接：https://www.biorxiv.org/content/10.1101/2025.01.28.635330v1.abstract

摘要：

Therapeutic nucleic acid delivery has many potential applications, but it remains challenging to target extrahepatic tissues in a flexible and image-guided manner. To address this issue, we report a bioorthogonal pre-targeting strategy that uses focused ultrasound to promote the delivery of mRNA-loaded lipid nanoparticles (mRNA-LNP). We synthesized amphiphilic click reactive anchors (ACRAs) consisting of a phospholipid PEG-conjugate functionalized with transcyclooctene (TCO) or its companion reactive partner methyltetrazine (mTz), yielding ACRA-TCO and ACRA-mTz. ACRA derivatives were screened for cellular activity, yielding functionalized DOPE-PEG (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- (polyethylene glycol)) derivatives outperforming those containing saturated lipid or branched PEG. Nanobubbles encapsulating ultrasound-responsive gas precursor delivered ACRA-TCO to targeted cells and tissues using focused ultrasound, and this pre-targeting promoted the subsequent delivery of mRNA- LNP functionalized with companion ACRA-mTz. In cell cultures and in mice, ultrasound pre-targeting enhanced the accumulation of mTz-functionalized small molecule and nanoparticle compounds by 75% and 3.6-fold, respectively, and increased gene expression using mRNA-LNP in vivo. Taken together, this report presents a modular, ultrasound-enabled strategy for enhancing nucleic acid delivery in targeted tissues.

一种生物正交预靶向策略，该策略利用聚焦超声促进载mRNA的脂质纳米颗粒（mRNA-LNP）的递送。我们合成了两亲点击反应锚（ACRA），其由磷脂PEG共轭物组成，该共轭物用反式环辛烯（TCO）或其伴随反应性配体甲基四嗪（mTz）功能化，从而生成ACRA-TCO和ACRA-mTz。对ACRA衍生物进行了细胞活性筛选，

结果发现功能化的DOPE-PEG（1,2-二油酰-sn-甘油-3-磷酸乙醇胺-N-（聚乙二醇））衍生物的性能优于含有饱和脂质或支链PEG的衍生物。纳米气泡包裹超声响应气体前体，利用聚焦超声将ACRA-TCO递送至目标细胞和组织，这种预靶向作用促进了随后递送经ACRA-mTz功能化的mRNA-LNP。

在细胞培养物和小鼠体内，超声预靶向作用分别使mTz功能化的小分子和纳米颗粒化合物的积累增加了75%和3.6倍，并提高了mRNA-LNP在体内的基因表达。综上所述，本报告提出了一种模块化、超声赋能的策略，用于增强核酸在目标组织中的递送。

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