Tumor-specific glyco-detonators: A neuraminidase-3-gated programmable DNA Nanoarchitectonics for liver cancer-exclusive chemotherapy.

The silent progression and lack of reliable biomarkers for early-stage hepatocellular carcinoma (HCC) often lead to late-stage diagnoses, where conventional chemotherapies are highly toxic and offer limited efficacy. To bridge this diagnostic-therapeutic gap, we designed a DNA nanocomputer that functions as a biological logic gate, converting a pathological marker into a therapeutic command. This "dual-lock" system uses sialic acid 'caps' to mask galactose ligands on a DNA scaffold. Tumor-overexpressed neuraminidase 3 (NEU3) first cleaves the caps, exposing galactose to trigger asialoglycoprotein receptor (ASGPR)-mediated internalization, thus completing an HCC-exclusive activation cascade. In orthotopic HCC models, the system suppressed tumor growth by 82 % and abrogated the off-target hepatotoxicity of free doxorubicin. Its specificity was confirmed by differential cytotoxicity between HCC and normal hepatocytes and by spatially confined tumor apoptosis. By programming a therapeutic response to a tumor-specific enzymatic circuit, this work establishes a new paradigm for metabolically guided nanomedicine, transforming a pathological hallmark into a therapeutic trigger to resolve the precision-toxicity dichotomy of conventional chemotherapy.