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

Author

Listed:
  • Catarina Rebelo

    (University of Coimbra
    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
    University of Coimbra)

  • Sónia L. C. Pinho

    (University of Coimbra)

  • Lino Ferreira

    (University of Coimbra
    University of Coimbra)

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).

Suggested Citation

  • Catarina Rebelo & Tiago Reis & Joana Guedes & Cláudia Saraiva & Artur Filipe Rodrigues & Susana Simões & Liliana Bernardino & João Peça & Sónia L. C. Pinho & Lino Ferreira, 2022. "Efficient spatially targeted gene editing using a near-infrared activatable protein-conjugated nanoparticle for brain applications," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31791-6
    DOI: 10.1038/s41467-022-31791-6
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    References listed on IDEAS

    as
    1. Holly A. Rees & Alexis C. Komor & Wei-Hsi Yeh & Joana Caetano-Lopes & Matthew Warman & Albert S. B. Edge & David R. Liu, 2017. "Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
    2. Hyunjin Jung & Seong-Wook Kim & Minsoo Kim & Jongryul Hong & Daseuli Yu & Ji Hye Kim & Yunju Lee & Sungsoo Kim & Doyeon Woo & Hee-Sup Shin & Byung Ouk Park & Won Do Heo, 2019. "Noninvasive optical activation of Flp recombinase for genetic manipulation in deep mouse brain regions," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Joo Ho Lee & Jeong Eun Lee & Jee Ye Kahng & Se Hoon Kim & Jun Sung Park & Seon Jin Yoon & Ji-Yong Um & Woo Kyeong Kim & June-Koo Lee & Junseong Park & Eui Hyun Kim & Ji-Hyun Lee & Joon-Hyuk Lee & Won-, 2018. "Human glioblastoma arises from subventricular zone cells with low-level driver mutations," Nature, Nature, vol. 560(7717), pages 243-247, August.
    4. Hampus Rietz & Hampus Hedlund & Sten Wilhelmson & Pontus Nordenfelt & Anders Wittrup, 2020. "Imaging small molecule-induced endosomal escape of siRNA," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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