In situ generation of hydroperoxide-rich-peptide-based nano-assemblies for self-amplified magnetic resonance imaging-guided synergistic tumor chemo/chemodynamic/ferroptotic therapy.

Conventional chemotherapy for hepatocellular carcinoma (HCC) often suffers from nonspecific delivery and consequent off-target toxicity, resulting in diminished efficacy. The rational design of theranostic nanoplatforms, which integrate biomedical imaging with therapeutic functions, can circumvent the intrinsic limitations of conventional chemotherapeutic agents. This approach enhances the efficacy of synergistic chemotherapy-based cancer treatments and advances the development of personalized medicine. Herein, we report the facile construction of a versatile theranostic nanoplatform (D@LADFe) for tumor-specific magnetic resonance (MR) imaging and synergistic chemo/chemodynamic/ferroptotic therapy. The nanoplatform D@LADFe was formed by encapsulating doxorubicin (DOX) and coordinating iron (Fe3+) into chimeric peptide (LAD) nanoparticles. The LAD nanoparticles comprise the therapeutic peptide KLAK-YSV, a dopamine-derived DOPA moiety, and hydrophobic linoleic acid (LA). Upon uptake by cancer cells, D@LADFe nanoparticles undergo gradual decomposition, facilitating the on-demand release of DOX and Fe3+ ions. Intracellular Fe3+ ions function as endogenous contrast agents, enabling tumor-specific MR imaging. Concomitantly, the high concentration of glutathione (GSH) reduces Fe3+ to Fe2+, which then catalyze the conversion of hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (•OH) via the Fenton reaction. This reaction not only drives chemodynamic therapy (CDT) but also initiates a cascade of downstream effects, including glutathione (GSH) depletion, membrane lipid peroxidation (LPO) and cancer cell ferroptosis. Subsequent LPO targets the unsaturated double bonds in the LA moiety of LAD, amplifying the in situ production of toxic singlet oxygen (1O2) via the Russell mechanism, facilitated by the self-amplified nanoreactor (LA(OOH)D) and Fe2+. These D@LADFe nanoparticles exhibited excellent Fenton-reaction efficiency with a Michaelis-Menten constant (Km) and maximum velocity (Vmax) of 11.5 × 10-3 M and 7.8 × 10-8 M s-1, respectively. Furthermore, DOX selectively accumulates in tumor tissues and induces cellular apoptosis by interfering with DNA replication, downregulating adenosine triphosphate (ATP) production, and upregulating mitochondrial reactive oxygen species (ROS). This cascade ultimately elevates cellular ROS levels, triggering ferroptosis. In vitro assays demonstrated that D@LADFe treatment significantly increased Hepa1-6 cell apoptosis to 87 %, exceeding the apoptotic rates in the single-treatment groups and the control groups. Finally, in vivo studies substantiated that intravenously administered D@LADFe nanoparticles significantly tumor growth suppression versus monotherapies (CT, CDT, or ferroptosis alone), ascribing to their multimodal mechanism. Given its favorable biocompatibility and biosafety, this work proposes a rational design strategy to employ a novel self-assembling peptide-based nanoplatform for tumor-specific MR imaging and multimodal therapeutic applications.