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While mitochondria\u2010targeted peptide\u2010based nanoassemblies offer a promising platform for controllable delivery, achieving mitochondria\u2010specific responses and programmable subcellular apoptotic regulation remains a critical yet underexplored challenge. Herein, we report controllable mitochondria\u2010targeted DNA\u2010peptide nanoassemblies co\u2010assembled from an enterokinase (ENTK)\u2010responsive cationic peptide\u2014incorporating a DDDDK substrate motif targeted to the perimitochondrial ENTK\u2014and a multifunctional DNAzyme chimera (DC) through DNAzyme\u2010catalyzed dityrosine crosslinking, thereby enabling mitochondria\u2010specific and programmable subcellular apoptotic regulation. In addition, the DC integrates a hemin\u2010intercalated G\u2010quadruplex (G4\/hemin) that catalyzes H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010dependent reactive oxygen species (ROS) generation and an antisense oligonucleotide (ASO) targeting antisense long noncoding mitochondrial RNAs (ASncmtRNAs). Upon selective peptide cleavage by perimitochondrial ENTK, the DNA\u2010peptide nanoassemblies undergo subcellular\u2010specific disassembly and payload release, resulting in mitochondria\u2010localized ROS generation and synergistic ASO\u2010mediated ASncmtRNA knockdown, accompanied by suppression of the anti\u2010apoptotic protein survivin. These coordinated effects collectively induce mitochondria\u2010mediated apoptosis and achieve effective tumor suppression. This work establishes a DNAzyme\u2010catalyzed covalent assembly strategy that integrates the molecular programmability of nucleic acids with the biological specificity of peptides, providing a modular and highly tunable platform for organelle\u2010targeted nanosystems and enabling sophisticated spatiotemporal combination therapy.\n                  <\/jats:p>","DOI":"10.1002\/anie.2929190","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:35:23Z","timestamp":1790670923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA\u2010Peptide Nanoassembly for Mitochondria\u2010Specific and Programmable Subcellular Apoptotic Regulation"],"prefix":"10.1002","author":[{"given":"Fuqiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Anhui Province Key Laboratory of Biomedical Materials and Chemical Measurement Anhui Province Key Laboratory of Chem\u2010Biosensing Ministry of Education Key Laboratory of Functional Molecular Solids College of Chemistry and Molecular Sciences Anhui Normal University  Wuhu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-4408","authenticated-orcid":false,"given":"Xi","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics School of Pharmacy National Center for Translational Medicine (Shanghai) Hefei Branch Anhui Academy of Chinese Medicine Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanru","family":"Sun","sequence":"additional","affiliation":[{"name":"Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Metabolic Diseases College of Life Sciences Anhui Normal University  Wuhu 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