Programmable DNA Assemblies Reconstitute Supramolecular Protein Function
- 1University of Illinois at Urbana-Champaign
Abstract
Biological processes are often regulated through reactions involving supramolecular protein complexes organized with nanoscale precision, such as the apoptosome that activates procaspase-9 through defined stoichiometry to induce apoptosis. Here we report designer CASCAD (CARD Assembly on SCAffold DNA), a self-assembled DNA nanoplatform that spatially organizes caspase recruitment domains (CARDs), exhibiting catalytic intracellular caspase-9 activation. By functioning like a natural apoptosome, CASCAD enhances caspase-9 oligomerization and promotes valency-dependent enzymatic activation. Further, after incorporating targeting aptamers and membrane-interacting peptides for cellular uptake and cytosolic delivery, CASCAD has successfully reconstituted apoptosome function and downstream apoptotic signaling in in-vitro 2D and 3D cultures. Our molecular design paradigm establishes CASCAD as versatile and programmable DNA nanomaterial for reconstructing signaling pathways driven by diverse supramolecular complexes, including inflammasomes and myddosomes, providing a general chemical framework for engineering cellular signaling and directing cellular function and fate.
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BibTeX
@misc{gandavadi2026programmable,
title = {{Programmable DNA Assemblies Reconstitute Supramolecular Protein Function}},
author = {D. Gandavadi and A. Dwivedy and R. Manoharaan and S. Im and S. Umrao and C. Hoang and K. Hammoud and L. Nguyen and Y. Zhao and R. Bhargava and X. Wang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751908},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751908v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Programmable DNA Assemblies Reconstitute Supramolecular Protein Function
AU - D. Gandavadi
AU - A. Dwivedy
AU - R. Manoharaan
AU - S. Im
AU - S. Umrao
AU - C. Hoang
AU - K. Hammoud
AU - L. Nguyen
AU - Y. Zhao
AU - R. Bhargava
AU - X. Wang
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751908
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751908v1
AB - Biological processes are often regulated through reactions involving supramolecular protein complexes organized with nanoscale precision, such as the apoptosome that activates procaspase-9 through defined stoichiometry to induce apoptosis. Here we report designer CASCAD (CARD Assembly on SCAffold DNA), a self-assembled DNA nanoplatform that spatially organizes caspase recruitment domains (CARDs), exhibiting catalytic intracellular caspase-9 activation. By functioning like a natural apoptosome, CASCAD enhances caspase-9 oligomerization and promotes valency-dependent enzymatic activation. Further, after incorporating targeting aptamers and membrane-interacting peptides for cellular uptake and cytosolic delivery, CASCAD has successfully reconstituted apoptosome function and downstream apoptotic signaling in in-vitro 2D and 3D cultures. Our molecular design paradigm establishes CASCAD as versatile and programmable DNA nanomaterial for reconstructing signaling pathways driven by diverse supramolecular complexes, including inflammasomes and myddosomes, providing a general chemical framework for engineering cellular signaling and directing cellular function and fate.
ER -