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Here, we demonstrate that a chimeric peptide (RS\u2010FS), consisting of HCC\u2010targeting RS and nanostructure\u2010forming motifs (FS), self\u2010assembles into nanospheres at neutral pH and transforms into nanofibers under acidic and reductive conditions. These nanofibers specifically localize to tumors and disrupt tumor cell lysosomes, thus enhancing doxorubicin's activity in human HCC cells in vitro and orthotopic HCC mice in vivo after RS\u2010FS\u2010doxorubicin treatment. Importantly, intravenous RS\u2010FS potentiated oral Lenvatinib's antitumor activity up to 61\u2010fold, and eradicated tumors in orthotopic HCC mice via HCC cell\u2010specific lysosome disruption. Potent antitumor effects were also achieved with intravenous RS\u2010FS and oral Epimedium brevicornu Maxim. \u2010derived extracellular vesicles in orthotopic HCC mice, with markedly reduced tumor growth and increased cytotoxic T infiltration, in which RS\u2010FS\u2010mediated lysosome disruption promoted drug release and autophagic flux blockade. Our study demonstrates that RS\u2010FS self\u2010assembles into nanospheres or nanofibers in response to stimuli and enables tumor cell\u2010specific lysosome disruption, resulting in enhanced drug release, autophagic flux blockade, and antitumor activities of diverse therapeutics in HCC mice, and thus provides a generalizable peptide adjuvant for sensitizing HCC\u2010targeted therapeutics.<\/jats:p>","DOI":"10.1002\/adma.73468","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T08:14:05Z","timestamp":1779351245000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Self\u2010Assembly of Stimuli\u2010Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo"],"prefix":"10.1002","volume":"38","author":[{"given":"Renwei","family":"Jing","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology The 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