Self‐Assembly of Stimuli‐Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo

Self‐Assembly of Stimuli‐Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo

Advanced Materials

10.1002/adma.73468

https://doi.org/10.1002/adma.73468

Renwei Jing, Xiaorong Kong, Jin Zhang, Jiaxue Li, Xingjie He, Zhongqiu Yang, Yi Wang, Leijie Zhang, Qian Wang, Yiqi Seow, HaiFang Yin

21 May 2026

Jing, R., Kong, X., Zhang, J., Li, J., He, X., Yang, Z., Wang, Y., Zhang, L., Wang, Q., Seow, Y., & Yin, H. (2026). Self‐Assembly of Stimuli‐Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo. Advanced Materials. Portico. https://doi.org/10.1002/adma.73468

ABSTRACT Lysosome sequestration or drug‐triggered autophagic flux curtails antitumor drug potency in hepatocellular carcinoma (HCC) and can potentially be reversed with tumor cell‐specific lysosomal disruption. Here, we demonstrate that a chimeric peptide (RS‐FS), consisting of HCC‐targeting RS and nanostructure‐forming motifs (FS), self‐assembles 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‐FS‐doxorubicin treatment. Importantly, intravenous RS‐FS potentiated oral Lenvatinib's antitumor activity up to 61‐fold, and eradicated tumors in orthotopic HCC mice via HCC cell‐specific lysosome disruption. Potent antitumor effects were also achieved with intravenous RS‐FS and oral Epimedium brevicornu Maxim. ‐derived extracellular vesicles in orthotopic HCC mice, with markedly reduced tumor growth and increased cytotoxic T infiltration, in which RS‐FS‐mediated lysosome disruption promoted drug release and autophagic flux blockade. Our study demonstrates that RS‐FS self‐assembles into nanospheres or nanofibers in response to stimuli and enables tumor cell‐specific 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‐targeted therapeutics.

Publisher Copyright

This research is supported by core funding from: GIS
Grant Reference no. : NA

This is the peer reviewed version of the following article: Jing, R., Kong, X., Zhang, J., Li, J., He, X., Yang, Z., Wang, Y., Zhang, L., Wang, Q., Seow, Y., & Yin, H. (2026). Self‐Assembly of Stimuli‐Responsive Peptide Enhances Therapeutics by Specifically Disrupting Hepatocellular Carcinoma Lysosomes In Vivo. Advanced Materials. Portico. https://doi.org/10.1002/adma.73468 , which has been published in final form at https://doi.org/10.1002/adma.73468. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

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