Tetrahedral DNA engineered Janus nanoplatform for potentiated Zn²⁺ interference therapy and cGAS-STING activation via efficient delivery of exogenous DNA.

Authors

Mingya Tan, Meiling Liu, Xin Sun, Jiangyang Li, Linlin Huo, Mengke Fan, Jiayi Zhao, Chunlu Liu, Zhenghuan Zhao

Published in

Journal of controlled release : official journal of the Controlled Release Society. Pages 115464. Oct 28, 2026. Epub Oct 28, 2026.

Abstract

While zinc-ion interference therapy presents a compelling approach for cancer immunotherapy, poor intracellular bioavailability and weak innate immune activation restrict its therapeutic potential. To overcome these bottlenecks, we developed tetrahedral DNA-integrated ZnFe₂O₄-ZnO Janus nanoparticles (TDN-ZIZJP) to achieve spatiotemporal modulation of immunity. Distinct from conventional cubic nanoparticles, this nail-shaped Janus architecture amplifies cell-particle interactions, substantially improving tumor penetration and cellular uptake. This unique feature endows improved selectively dissolving of ZnO domain within the mildly acidic tumor microenvironment, resulting in a targeted intracellular surge of Zn²⁺. This enhanced ion flux provokes oxidative stress and endogenous DNA damage, thereby increasing the availability of endogenous cytosolic DNA. Moreover, the integrated tetrahedral DNA nanostructures serve as a robust reservoir, delivering abundant exogenous dsDNA directly into the cytoplasm. Zn²⁺-induced endogenous DNA release and TDN-derived exogenous dsDNA jointly increase the availability of cytosolic DNA substrates for cGAS. This dual-source DNA supply supports sustained cGAS-STING activation, thereby enhancing type I interferon signaling, promoting dendritic cell maturation and increasing cytotoxic T-cell infiltration. This study provides a new avenue that couples Zn²⁺-mediated ion interference and endogenous DNA damage with an exogenous dsDNA reservoir, providing a highly tunable platform for metal ion-regulated immunotherapy.

PMID:
42951258
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.

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