Perfluoroether Peptide-Modified Artificial Viral Capsid for Enhanced Doxorubicin Delivery to Liver Cancer Cells

Hepatocellular carcinoma is difficult to treat owing to poor tumor selectivity, rapid hepatic clearance, intrinsic drug resistance, and the high susceptibility of healthy liver tissue to off-target toxicity. 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 β-annulus peptides with a novel perfluoroether (PFE)-modified β-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, β-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 ∼150 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.