Programming DNA Circuits for Controlled Immunostimulation through CpG Oligodeoxynucleotide Delivery,Journal of the American Chemical Society

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Programming DNA Circuits for Controlled Immunostimulation through CpG Oligodeoxynucleotide Delivery
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-06-02 , DOI: 10.1021/jacs.2c09359
Aman Ishaqat _{1,

2} , Xiaofeng Zhang ₂ , Qing Liu ₃ , Lifei Zheng ₃ , Andreas Herrmann _{1,

2}

Affiliation

Herein, we present a DNA circuit programmed for the delivery of CpG oligodeoxynucleotides (CpG ODNs) with the pharmacological immunostimulation function. The circuit employs a complementary DNA (cDNA) strand to deactivate the biological function of CpG ODNs via hybridization, while T7 exonuclease mediates the activation by hydrolyzing the cDNA and releasing the CpG ODN as an active moiety. We investigated the influence of several factors on the kinetic profile and temporal behavior of the circuit. These include the design of the cDNA strand, the concentration of the DNA duplex, and the concentration of T7 exonuclease. The DNA circuit’s in vitro activation resulted in toll-like receptor 9 stimulation in the HEK-engineered cell line, as well as tumor necrosis factor-alpha release by J774A.1 macrophages. By programming the DNA circuit to control the release of the CpG ODN, we achieved an altered pharmacological profile with acute and potent immunostimulation, in comparison to a system without controlled CpG ODN release, which exhibited a slow and delayed response. Our findings demonstrate the potential of DNA circuits in controlling the pharmacological activity of DNA strands for controlled drug delivery.

中文翻译：

通过 CpG 寡脱氧核苷酸递送控制免疫刺激的 DNA 电路编程

在此，我们提出了一个 DNA 电路，该电路被编程为具有药理学免疫刺激功能的 CpG 寡脱氧核苷酸 (CpG ODN) 的递送。该电路采用互补 DNA (cDNA) 链通过杂交使 CpG ODN 的生物学功能失活，而 T7 核酸外切酶通过水解 cDNA 并释放 CpG ODN 作为活性部分来介导激活。我们调查了几个因素对电路的动力学曲线和时间行为的影响。这些包括 cDNA 链的设计、DNA 双链体的浓度和 T7 核酸外切酶的浓度。DNA 电路的体外激活导致 HEK 工程细胞系中的 toll 样受体 9 刺激，以及 J774A.1 巨噬细胞释放肿瘤坏死因子-α。通过对 DNA 回路进行编程以控制 CpG ODN 的释放，我们通过急性和有效的免疫刺激实现了药理学特征的改变，与没有受控 CpG ODN 释放的系统相比，后者表现出缓慢和延迟的反应。我们的研究结果证明了 DNA 回路在控制 DNA 链的药理活性以实现受控药物递送方面的潜力。

更新日期：2023-06-02

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