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Cell BiologybioRxiv
Preprint

Mechanically-mediated low-pressure cell membrane poration enables tunable intracellular delivery of traditionally impermeable cargoes in high throughput and clinical scale formats

Sophia M. HirschiD, Darby Kreienberg, Zhihui Song, Alain Larocque, Yi ZuoiD, Rachel Conover, Eleni JaeckleiniD, Karen Gonzalez, Ain Imchen, Sean Franco, Michael A. Evans, R. Alexander WesselhoeftiD, Matthew SwiatnickiiD, Hicham ZegzoutiiD, Kirill ChesnoviD, Marius WernigiD, Neil S. Dhawan, Cameron Pye, Scott M. Loughhead, Jacquelyn L. Sikora Hanson, Alec Barclay, Armon Sharei

Abstract

Traditional intracellular delivery methods suffer from cargo inefficiencies, non-linear delivery kinetics, and cellular trauma. We designed a mechanically-mediated poration platform governed by deterministic, passive diffusion operating at low pressure which enables dose-dependent, cargo-agnostic intracellular delivery and preserves cellular homeostasis; key advantages include high-fidelity multiplexing, transient cell engineering, and direct-to-biology live-cell target engagement enabling development of novel intracellular delivery applications across drug discovery and cell therapy. We demonstrate examples including live-cell DEL discovery and MOA studies, complex and rapid cell therapy manufacturing, and assay development in sensitive primary cell types.

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