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Herein, with minimal interference of the molecular backbone, we report a chiral engineering strategy to enhance the pH sensitivity of a tripeptide-drug conjugate (PDC). Specifically, homochiral PDC forms supramolecular nanofibers with a low pH dependence, whereas the heterochiral isomer with alternating D\/L residues exhibits a highly pH-dependent self-assembly. Importantly, in carbonic anhydrase IX (CAIX)-overexpressing tumor cells, fibrous assemblies of homochiral PDCs occur at the cell surface, while heterochiral PDCs form nanofibers within lysosomes via protonation. This process subsequently promoted lysosomal membrane permeabilization and enhanced CAIX inhibition, which turns into an efficient way of enhancing cellular Fenton reactions to evoke ferroptosis, thereby improving the antitumor efficacy in breast tumors. Overall, this work proposes a chiral engineering approach for enhancing the pH sensitivity of supramolecular assemblies, which establishes an efficient strategy for spatiotemporal control over supramolecular assemblies and offers alternative insights into the biological effects of heterochirality.<\/jats:p>","DOI":"10.1021\/jacs.6c09475","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:10:39Z","timestamp":1785849039000},"page":"32497-32508","source":"Crossref","is-referenced-by-count":0,"title":["Sensitizing\nSelf-Assembly of Peptide-Drug Conjugates\nvia Chiral Engineering to Evoke Tumor Ferroptosis"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6340-8489","authenticated-orcid":true,"given":"Jinmin","family":"Ye","sequence":"first","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]},{"name":"Jinan University , , ,","place":["Guangzhou, P. R. China, 510000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6989-0330","authenticated-orcid":true,"given":"Yangkai","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiao","family":"Fu","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Qiao","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingru","family":"Liu","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijian","family":"Liang","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huipeng","family":"Ma","sequence":"additional","affiliation":[{"name":"National Center for Nanoscience and Technology of China , , ,","place":["Beijing, P. R. China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, P. R. China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9698-8652","authenticated-orcid":true,"given":"Zhi","family":"Huang","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, P. R. 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