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<p>Efficient intracellular delivery of therapeutic biomolecules, including messenger RNA, plasmid DNA, and CRISPR–Cas9 systems, is critical for advancing cell-based therapies and genome editing. However, conventional approaches, such as lipid-based nanocarriers and electroporation, often suffer from low cell viability, limited efficiency, and poor scalability. Microfluidic droplet-based cell squeezing offers a promising alternative by transiently permeabilizing membranes, enabling high delivery efficiency with reduced cytotoxicity and reagent consumption. Nevertheless, existing implementations are susceptible to clogging, which compromises operational reliability and reproducibility. Here, we present a z-axis droplet-squeezing platform that reconfigures the constriction geometry from a horizontal to a vertical orientation, effectively preventing clogging. This design maintains stable mechanoporation, facilitating efficient, carrier-free delivery of diverse biomolecules, with efficiencies reaching &gt; 98% for mRNA delivery, &gt; 80% for plasmid DNA transfection, and ~ 69% for CRISPR–Cas9 genome editing. Overall, this study introduces a clog-resistant, scalable, and high-performance mechanoporation platform for tunable and efficient intracellular delivery, establishing a foundation for next-generation genome engineering and cell-based therapeutic manufacturing.</p>

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Vertical Droplet-Squeezing Platform for Highly Efficient Biomolecular Delivery

  • 期刊论文

  • 发表日期：

    2026年2月26日

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  • Juhee Lee,
  • Aram J. Chung

摘要

Efficient intracellular delivery of therapeutic biomolecules, including messenger RNA, plasmid DNA, and CRISPR–Cas9 systems, is critical for advancing cell-based therapies and genome editing. However, conventional approaches, such as lipid-based nanocarriers and electroporation, often suffer from low cell viability, limited efficiency, and poor scalability. Microfluidic droplet-based cell squeezing offers a promising alternative by transiently permeabilizing membranes, enabling high delivery efficiency with reduced cytotoxicity and reagent consumption. Nevertheless, existing implementations are susceptible to clogging, which compromises operational reliability and reproducibility. Here, we present a z-axis droplet-squeezing platform that reconfigures the constriction geometry from a horizontal to a vertical orientation, effectively preventing clogging. This design maintains stable mechanoporation, facilitating efficient, carrier-free delivery of diverse biomolecules, with efficiencies reaching > 98% for mRNA delivery, > 80% for plasmid DNA transfection, and ~ 69% for CRISPR–Cas9 genome editing. Overall, this study introduces a clog-resistant, scalable, and high-performance mechanoporation platform for tunable and efficient intracellular delivery, establishing a foundation for next-generation genome engineering and cell-based therapeutic manufacturing.