Efficient spatially targeted gene editing using a near-infrared activatable protein-conjugated nanoparticle for brain applications

Catarina Rebelo, Tiago Reis, Joana Guedes, Cláudia Saraiva, Artur Filipe Rodrigues, Susana Simões, Liliana Bernardino, João Peça, Sónia L. C. Pinho () and Lino Ferreira ()
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Catarina Rebelo: University of Coimbra
Tiago Reis: University of Coimbra
Joana Guedes: University of Coimbra
Cláudia Saraiva: University of Beira Interior
Artur Filipe Rodrigues: University of Coimbra
Susana Simões: University of Coimbra
Liliana Bernardino: University of Beira Interior
João Peça: University of Coimbra
Sónia L. C. Pinho: University of Coimbra
Lino Ferreira: University of Coimbra

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Spatial control of gene expression is critical to modulate cellular functions and deconstruct the function of individual genes in biological processes. Light-responsive gene-editing formulations have been recently developed; however, they have shown limited applicability in vivo due to poor tissue penetration, limited cellular transfection and the difficulty in evaluating the activity of the edited cells. Here, we report a formulation composed of upconversion nanoparticles conjugated with Cre recombinase enzyme through a photocleavable linker, and a lysosomotropic agent that facilitates endolysosomal escape. This formulation allows in vitro spatial control in gene editing after activation with near-infrared light. We further demonstrate the potential of this formulation in vivo through three different paradigms: (i) gene editing in neurogenic niches, (ii) gene editing in the ventral tegmental area to facilitate monitoring of edited cells by precise optogenetic control of reward and reinforcement, and (iii) gene editing in a localized brain region via a noninvasive administration route (i.e., intranasal).

Date: 2022
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DOI: 10.1038/s41467-022-31791-6

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