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Herein, we establish uracil\u2010DNA glycosylase (UDG) and apurinic\/apyrimidinic endonuclease 1 (APE1) as diagnostic biomarkers for early\u2010stage HCC and develop a lock\u2010open strategy based on an\n                    <jats:bold>\n                      <jats:styled-content>A<\/jats:styled-content>\n                    <\/jats:bold>\n                    ND\n                    <jats:bold>\n                      <jats:styled-content>l<\/jats:styled-content>\n                    <\/jats:bold>\n                    ogic\u2010gated,\n                    <jats:bold>\n                      <jats:styled-content>e<\/jats:styled-content>\n                    <\/jats:bold>\n                    ntropy\u2010driven DNA\n                    <jats:bold>\n                      <jats:styled-content>n<\/jats:styled-content>\n                    <\/jats:bold>\n                    anowalker (ALEN) for highly sensitive detection of their enzymatic activities. ALEN integrates sequential UDG\/APE1 processing with miR\u201021 gating to achieve on\u2010track signal amplification. In the locked state, circuit leakage is minimized. Upon UDG\/APE1 processing and miR\u201021 gating, ALEN is unlocked to initiate walker propagation, reactant regeneration, and spatially confined amplification selectively in tumor cells. This ability overcomes critical limitations of conventional entropy\u2010driven DNA circuits, including low efficiency, limited turnover, and excessive leakage. When encapsulated in aptamer\u2010functionalized lipid nanoparticles, ALEN gains robust biostability, biocompatibility, and HCC\u2010specific accumulation. Using in vitro cellular models and in vivo mouse models of HCC, we confirmed that ALEN enables highly sensitive, cell type\u2010specific discrimination of the activities of UDG and APE1, as well as timely and sensitive sensing of their dynamic fluctuations. Our results demonstrate that ALEN facilitates HCC diagnosis and monitoring of tumor progression, highlighting its promise as a clinical management tool.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71417","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:22:18Z","timestamp":1785730938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lock\u2010Open: An AND Logic\u2010Gated, Entropy\u2010Driven DNA Nanowalker for Highly Sensitive Detection of UDG and APE1 Activities in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Zongying","family":"Li","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine The Second Affiliated Hospital of Chongqing Medical University  Chongqing P. 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