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Intracellular peptide effectors acting at defined subcellular sites require activation logic that follows this order, yet many responsive carriers couple multiple functional changes to one trigger. Here, we report sequential unmasking peptide release architecture (SUPRA), a covalent brush\u2010on\u2010brush (BOB) bottlebrush polymer that distributes two orthogonal biochemical inputs across two structural layers: a mitochondria\u2010disrupting KLAK peptide inner brush densely grafted onto a glutathione\u2010cleavable polydisulfide backbone, and an acid\u2010labile PEG outer brush that masks the construct during circulation. Acidity first removes the outer mask to expose a membrane\u2010interactive peptide\u2010brush state, whereas cytosolic reduction deconstructs the backbone and relieves brush confinement. Architecture\u2010disrupted control and intracellular perturbation\/FRET studies support a sequential pathway of acid\u2010triggered endolysosomal escape followed by reductive scaffold deconstruction and mitochondrial accumulation of KLAK\u2010bearing species. SUPRA extends circulation, accumulates in tumors, induces tumor\u2010cell death with immunogenic features, sensitizes tumors to PD\u20101 blockade, and produces no detectable anti\u2010PEG antibody response under the tested dosing schedule. These results establish covalent BOB architectures as a design strategy for programming the sequence, not only the occurrence, of intracellular activation events.<\/jats:p>","DOI":"10.1002\/anie.4777081","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:09:27Z","timestamp":1789528167000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Covalent Brush\u2010on\u2010Brush Polymer Programs Ordered Intracellular Activation of a Mitochondria\u2010Disrupting Peptide"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9499-0451","authenticated-orcid":false,"given":"Rui","family":"Xu","sequence":"first","affiliation":[{"name":"College &amp; Hospital of Stomatology Anhui Medical University, Anhui Province Key Laboratory of Oral Diseases Research  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4195-1641","authenticated-orcid":false,"given":"Lubin","family":"Ning","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9595-3515","authenticated-orcid":false,"given":"Laixi","family":"Zhao","sequence":"additional","affiliation":[{"name":"College &amp; Hospital of Stomatology Anhui Medical University, Anhui Province Key Laboratory of Oral Diseases Research  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilin","family":"Lu","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Xu","sequence":"additional","affiliation":[{"name":"College &amp; Hospital of Stomatology Anhui Medical University, Anhui Province Key Laboratory of Oral Diseases Research  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2754-6009","authenticated-orcid":false,"given":"Fei","family":"Jia","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.3c00705"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS00686J"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c02238"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010023\u201001016\u2010x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010024\u201001785\u20100"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010022\u201001243\u20100"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202111839"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2025.118339","article-title":"KLAK Peptide in Anticancer Therapy: Achieving Cancer Cell Apoptosis via Mitochondrial Membrane Disruption Using Homing Domains Introduction and Other Modifications","volume":"302","author":"Kotal\u00edk K.","year":"2026","journal-title":"European Journal of Medicinal Chemistry"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010025\u201001909\u20100"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.04.003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.8b02830"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nantod.2024.102147"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010022\u201001310\u20101"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202508639"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025856\u20101"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202103438"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja311961k"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja501581b"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b00039"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b08957"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.2c01125"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/la0343977"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565\u2010022\u201001085\u20105"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c22249"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c14199"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010025\u201001855\u2010y"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav9322"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.1c14285"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja5088216"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b05064"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c13285"},{"key":"e_1_2_8_33_1","article-title":"Ex Vivo Red Blood Cell Hemolysis Assay for the Evaluation of pH\u2010Responsive Endosomolytic Agents for Cytosolic Delivery of Biomacromolecular Drugs","volume":"73","author":"Evans B. 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