CeO2 nanozyme-embedded thermal-deformative polymer for site-specific chemotherapy via HIF-1α-P-gp/lipolysis axis reversal

The effective intracellular accumulation of doxorubicin (DOX) is crucial for improving antitumor efficacy, which is severely impeded by limited drug penetration, uncontrollable drug release, and drug resistance. In this study, a thermal-deformative polymer embedding ultrasmall ceria (CeO₂) was rationally designed for deep tumor drug shuttling and hypoxia reversal to improve chemotherapy. Structurally, the CeO₂ nanozyme was covalently grafted with a polymer of p(NIPAM-co-AM) that could sharply shrink for DOX loading, which was consolidated with polydopamine (PDA) film encapsulation. Thereafter, a tumor penetration guide of apolipoprotein A-I (apoA-I) conjugated iRGD peptide (apoA-I-iRGD) was further decorated onto the PDA shell via Michael addition for preparing CeO₂P/DOX@iAPDA. With the aid of apoA-I-iRGD, CeO₂P/DOX@iAPDA penetrated both the tumor spheroids (∼78 µm) and the tumors of the mouse model deeply. After internalization by tumor cells and triggering by low pH in lysosomes, rapid DOX release was achieved by peeling off the PDA shell and thermosensitive deformation of p(NIPAM-co-AM). CeO₂P/DOX@iAPDA provided 66.4 % tumor suppression in 4T1-derived tumor spheroids and 63.2 % in 4T1-tumor-bearing mice, respectively. Preliminary mechanistic research involving western blotting and immunohistochemistry revealed that CeO₂P/DOX@iAPDA reversed resistance through the through HIF-1α-P-gp/lipid axis. Collectively, this study intelligently integrated CeO₂ nanozymes, temperature-sensitive polymers, and imitated biochemical modifications to improve chemotherapy for breast cancer.