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

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.