Programmable DNA Assemblies Reconstitute Supramolecular Protein Function.

Authors

Dhanush Gandavadi, Abhisek Dwivedy, Revathi Manoharaan, Seongmin Im, Saurabh Umrao, Chau Nguyen Minh Hoang, Kadmos Hammoud, Lauren Nguyen, Yang Zhao, Rohit Bhargava, Xing Wang

Published in

bioRxiv : the preprint server for biology. Sep 17, 2026. Epub Sep 17, 2026.

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 ( C ARD A ssembly on SCA ffold D NA), 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.

PMID:
42779922
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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