Thermosensitive RGD-modified liposomes co-loading Fe3O4 and sorafenib for synergistic photothermal-chemotherapy of hepatocellular carcinoma.

Sorafenib (SRF) therapy for hepatocellular carcinoma (HCC) is limited by dose-limiting toxicities, inadequate tumor exposure, and the inability to confine drug action spatiotemporally, leading to suboptimal efficacy and a narrow therapeutic window. Here we report an RGD-functionalized DPPC-based thermosensitive liposomal theranostic system co-encapsulating Fe3O4 nanoparticles and SRF (RGD-Fe3O4/SRF@TSL) to enable MRI-guided window selection and near-infrared (NIR)-triggered, on-demand chemotherapy potentiation. The nanosystem is colloidally stable (208 nm) and exhibits a phase transition at 41 °C. Accordingly, SRF release is sharply temperature-gated, reaching 88% at 45 °C but only 26% at 37 °C within 18 h (3.4-fold enhancement). Fe3O4 confers strong T2 MRI contrast (r2 = 136.4 mM-1 s-1) and photothermal conversion (η = 24.73%), enabling noninvasive tracking of tumor accumulation and controllable local heating that elevates tumor-surface temperature to 56 °C within 5 min under 808 nm irradiation. Dynamic MRI identifies a pronounced tumor signal drop at ∼12 h post-injection, providing an imaging-defined irradiation window. RGD decoration improves cellular internalization (DiO-positive cells 80.6% vs. 55.8% at 3 h) and, together with NIR activation, increases ROS-associated signals, mitochondrial depolarization, and apoptosis (up to 46.4%) in vitro. In Hepa1-6 tumor-bearing mice, the image-guided combined regimen markedly suppresses tumor growth, reducing endpoint tumor weight from 1.1 g (PBS) to 0.1 g (91% reduction) without obvious acute toxicity under the tested conditions. This work establishes an operational "MRI-defined window → mild hyperthermia → thermosensitive release" paradigm to localize SRF action and improve the efficacy-toxicity balance for HCC therapy.