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Although doxorubicin (Dox) is a potent and widely used chemotherapeutic agent, its application in liver cancer is severely constrained by nonspecific biodistribution, rapid systemic elimination, and dose-dependent cardiotoxicity, necessitating the development of safer and more efficient delivery systems. Herein, we report a peptide-based artificial viral capsid system constructed through the coassembly of \u03b2-annulus peptides with a novel perfluoroether (PFE)-modified \u03b2-annulus peptide as a biocompatible nanoplatform for the delivery of Dox to liver cancer cells. The artificial capsids spontaneously form directly in buffer or biological media, overcoming formulation limitations associated with toxic organic solvents or complex processing. In this design, \u03b2-annulus peptides provide the structural scaffold and encapsulation reservoir, whereas PFE modification introduces hydrophobicity and cell-penetrating capability, thereby enhancing intracellular delivery without added toxicity. The resulting PFE-modified capsids exhibit a uniform spherical morphology with an average diameter of \u223c150 nm, as confirmed by dynamic light scattering and transmission electron microscopy, and efficiently encapsulate Dox during self-assembly. Compared with unmodified capsids and free Dox, the PFE-modified capsids show markedly improved intracellular delivery and considerably enhanced anticancer activity in human liver cancer (HepG2) cells, along with reduced cytotoxicity toward normal cells. This virus-mimetic, fully peptide-based nanocarrier integrates biocompatibility, efficient drug encapsulation, and enhanced intracellular transport, providing a versatile materials platform for safer and more effective liver cancer chemotherapy.<\/jats:p>","DOI":"10.1021\/acsomega.6c04693","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:02:01Z","timestamp":1786536121000},"page":"49855-49871","source":"Crossref","is-referenced-by-count":0,"title":["Perfluoroether\nPeptide-Modified Artificial Viral Capsid\nfor Enhanced Doxorubicin Delivery to Liver Cancer Cells"],"prefix":"10.1021","volume":"11","author":[{"given":"Avijit","family":"Ghosh","sequence":"first","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Wada","sequence":"additional","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunari","family":"Takaki","sequence":"additional","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Inaba","sequence":"additional","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]},{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohsuke","family":"Aikawa","sequence":"additional","affiliation":[{"name":"Nihon University , , 30-1 Oyaguchi-Kamicho , Itabashi-ku, ,","place":["Tokyo, Japan, 173-8610"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ota","sequence":"additional","affiliation":[{"name":"AGC Inc Materials Integration Laboratories , Tsurumi-ku ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Hirata","sequence":"additional","affiliation":[{"name":"AGC Inc Materials Integration Laboratories , Tsurumi-ku ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Okazoe","sequence":"additional","affiliation":[{"name":"AGC Inc Materials Integration Laboratories , Tsurumi-ku ,","place":["Yokohama, Japan, 230-0045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5472-7860","authenticated-orcid":true,"given":"Kazunori","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]},{"name":"Tottori University , , ,","place":["Tottori, Japan, 680-8552"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026083119143983200_cit1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41392-024-02072-z","article-title":"Liver Diseases:\nEpidemiology, Causes, Trends and Predictions","volume":"10","author":"Gan","year":"2025","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026083119143983200_cit2","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1186\/s12876-025-04264-5","article-title":"Global Burden\nof Cirrhosis and Other Chronic Liver\nDiseases Caused by Specific Etiologies from 1990 to 2021","volume":"25","author":"Zhang","year":"2025","journal-title":"BMC Gastroenterol."},{"key":"2026083119143983200_cit3","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular Carcinoma: Signaling Pathways and Therapeutic\nAdvances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduction Targeted Ther."},{"key":"2026083119143983200_cit4","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular Carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat.\nRev. 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