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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Methods

AAV-DJ enables efficient, function-preserving neuronal transduction for circuit interrogation in human cortical and thalamic organoids

  • Shota Adachi1
  • Masatoshi Nishimura1
  • Kosuke Yamaguchi1
  • Akinori Y. Sato1
  • Ryosuke F. Takeuchi1
  • Fumitaka Osakada1,2,3,4,5
5 affiliations
  1. 1Laboratory of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan
  2. 2Laboratory of Neural Information Processing, Institute for Advanced Research, Nagoya University, Nagoya, Japan
  3. 3Research Institute for Quantum and Chemical Innovation, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Japan
  4. 4iGCORE, Nagoya University, Nagoya, Japan
  5. 5PRESTO/CREST, Japan Science and Technology Agency, Saitama, Japan
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Abstract

Neural organoids provide tractable models of human brain development, function, and disease, but adeno-associated viral vector (AAV)-based gene delivery is limited by inefficient transduction and insufficient comparative evaluation of the natural and engineered capsids. Here, we evaluated seven AAV capsids (AAV-2, -6, -9, -DJ, -2-retro, -PHP.eB, and -Cap-Mac) for transduction efficiency, cell type tropism, cytotoxicity, and functional integrity in human cortical and thalamic organoids. AAV-Cap-Mac demonstrated the highest transduction efficiency, with broad cellular tropism, but caused cytotoxicity and decreased neuronal activity. By contrast, AAV-DJ yielded efficient neuronal transduction, with preserved calcium dynamics and minimal cytotoxicity, which enabled rabies virus-based circuit tracing and all-optical physiology. Our findings reveal a capsid-dependent trade-off between transduction efficiency and functional integrity and identify AAV-DJ as an optimal serotype for robust gene delivery and physiological interrogation in organoid-based neuroscience. Combining AAV-DJ with emerging molecular and circuit-level technologies in organoids should facilitate mechanistic and translational studies of the human brain.

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Cite

BibTeXRIS
BibTeX
@article{adachi2026aavdj,
  title = {{AAV-DJ enables efficient, function-preserving neuronal transduction for circuit interrogation in human cortical and thalamic organoids}},
  author = {Shota Adachi and Masatoshi Nishimura and Kosuke Yamaguchi and Akinori Y. Sato and Ryosuke F. Takeuchi and Fumitaka Osakada},
  journal = {Cell Reports Methods},
  year = {2026},
  month = aug,
  doi = {10.1016/j.crmeth.2026.101546},
  url = {https://doi.org/10.1016/j.crmeth.2026.101546},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - AAV-DJ enables efficient, function-preserving neuronal transduction for circuit interrogation in human cortical and thalamic organoids
AU  - Shota Adachi
AU  - Masatoshi Nishimura
AU  - Kosuke Yamaguchi
AU  - Akinori Y. Sato
AU  - Ryosuke F. Takeuchi
AU  - Fumitaka Osakada
PY  - 2026
DA  - 2026/08/13
JO  - Cell Reports Methods
DO  - 10.1016/j.crmeth.2026.101546
UR  - https://doi.org/10.1016/j.crmeth.2026.101546
AB  - Neural organoids provide tractable models of human brain development, function, and disease, but adeno-associated viral vector (AAV)-based gene delivery is limited by inefficient transduction and insufficient comparative evaluation of the natural and engineered capsids. Here, we evaluated seven AAV capsids (AAV-2, -6, -9, -DJ, -2-retro, -PHP.eB, and -Cap-Mac) for transduction efficiency, cell type tropism, cytotoxicity, and functional integrity in human cortical and thalamic organoids. AAV-Cap-Mac demonstrated the highest transduction efficiency, with broad cellular tropism, but caused cytotoxicity and decreased neuronal activity. By contrast, AAV-DJ yielded efficient neuronal transduction, with preserved calcium dynamics and minimal cytotoxicity, which enabled rabies virus-based circuit tracing and all-optical physiology. Our findings reveal a capsid-dependent trade-off between transduction efficiency and functional integrity and identify AAV-DJ as an optimal serotype for robust gene delivery and physiological interrogation in organoid-based neuroscience. Combining AAV-DJ with emerging molecular and circuit-level technologies in organoids should facilitate mechanistic and translational studies of the human brain.
SN  - 2667-2375
ER  -