Self-Reporting Hierarchical DNA Nanoplatform for Tumor Cell-Selective Senescence Modulation and Immune Remodeling.

Authors

Wenya Dang, Jun Da, Jun Cao, Haolan Hu, Yuqi Xie, Lu Yu, Lu Wu, Linlin Wang, Jili Li, Yanlan Liu

Published in

Small methods. Pages e71110. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Therapy-induced senescence (TIS) promotes tumor resistance and recurrence through the senescence-associated secretory phenotype (SASP), but achieving tumor cell-selective senescence modulation remains a formidable challenge due to limited cellular specificity, insufficient spatiotemporal control, and the complexity of the secretory program. Here, we develop a self-reporting hierarchical DNA nanoplatform (Gal-lipo@S-CHA) that enables selective senescence reprogramming and immune remodeling in TIS tumor cells. In this design, a newly engineered β-galactosidase-responsive charge-reversal lipid carrier establishes the first layer of senescence selectivity by enabling preferential delivery and enhanced endosomal escape of a hierarchically gated catalytic DNA circuit. Subsequent intracellular decoding of GSH and microRNA-21, two tumor-associated and senescence-enriched molecular signatures, provides a second layer of tumor cell selectivity, activating the circuit specifically in pathological senescent tumor cells. The activated circuit simultaneously generates a fluorescence signal for real-time monitoring and assembles an NF-κB decoy to block NF-κB nuclear translocation, thereby suppressing downstream pro-tumorigenic SASP production at the upstream regulatory source. In vivo studies demonstrate that Gal-lipo@S-CHA effectively remodels the tumor immune microenvironment by enhancing natural killer cell infiltration and M1 macrophage polarization. Collectively, this framework establishes a new paradigm for selectively reprogramming pathological senescence, providing a versatile platform to support immunomodulatory cancer therapies.

PMID:
42865219
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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