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<p>Sonogenetic holds great potential for modulating cellular functions and behaviors. However, developing hypersensitive ultrasound (US)-responsive receptors remains a substantial challenge. Here, we combine AlphaFold3 prediction with molecular dynamics simulations to identify a hypersensitive Gpr114 protein variant (T-Gpr114) that responds to short-pulse US stimulation for activation. We further design sonogenetic macrophages (MΦ) by fusing T-Gpr114 to a synthetic genetic circuit, this circuit initiates expression of the transcription factor ID3 upon short-pulse US treatment. In vivo assays using female tumor-bearing mice demonstrate that sonogenetic-MΦ suppress tumor growth with no obvious systemic toxicity, and exhibit enhanced anti-tumor efficacy relative to cells with constitutive ID3 expression. Single-cell RNA sequencing reveals that sonogentic-MΦ potentiate the recruitment recruitment of CD8<sup>+</sup> T cells compared with constitutive ID3-overexpressing macrophages. In this work, this T-Gpr114-based US-hypersensitive gene circuit extends the scope of remote control over the activation of diverse cell types, thereby facilitating the programming of therapeutic cells.</p>

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Truncated Gpr114-based ultrasound-hypersensitive gene circuit for controlled expression of therapeutics

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • Pengying Wu,
  • Yubo Lai,
  • Yang Liu,
  • Zihang Li,
  • Zhaoyou Liu,
  • Lantian Wang,
  • Jieyuan An,
  • Yunnan Liu,
  • Shuzhe Wei,
  • Yue Sun,
  • Guodong Yang,
  • Lijun Yuan

摘要

Sonogenetic holds great potential for modulating cellular functions and behaviors. However, developing hypersensitive ultrasound (US)-responsive receptors remains a substantial challenge. Here, we combine AlphaFold3 prediction with molecular dynamics simulations to identify a hypersensitive Gpr114 protein variant (T-Gpr114) that responds to short-pulse US stimulation for activation. We further design sonogenetic macrophages (MΦ) by fusing T-Gpr114 to a synthetic genetic circuit, this circuit initiates expression of the transcription factor ID3 upon short-pulse US treatment. In vivo assays using female tumor-bearing mice demonstrate that sonogenetic-MΦ suppress tumor growth with no obvious systemic toxicity, and exhibit enhanced anti-tumor efficacy relative to cells with constitutive ID3 expression. Single-cell RNA sequencing reveals that sonogentic-MΦ potentiate the recruitment recruitment of CD8+ T cells compared with constitutive ID3-overexpressing macrophages. In this work, this T-Gpr114-based US-hypersensitive gene circuit extends the scope of remote control over the activation of diverse cell types, thereby facilitating the programming of therapeutic cells.