Genetically Engineered Membrane-Mimetic Liposome-Wrapped Violet Phosphorus Nanoplatform for Targeted Synergistic Ferroptosis/Photothermal/Immunotherapy of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), a highly prevalent malignancy, is mostly diagnosed at intermediate and advanced stages. Current monotherapies are limited by poor targeting, severe toxicity, drug resistance, and high metastatic risk, necessitating more effective precision therapeutic strategies. Photothermal therapy (PTT) and ferroptosis induction are promising for HCC treatment, but violet phosphorus nanoparticles (VPNs) alone confer limited PTT efficacy, while the ferroptosis inducers RSL3 and sulfasalazine (SSZ) are hampered by poor aqueous solubility, low biostability, and off-target toxicity, restricting their clinical translation. Herein, we constructed a glypican-3 (GPC3)-targeted multifunctional nanodelivery system for synergistic PTT-ferroptosis anti-HCC therapy. Liposomes coloading RSL3, SSZ and encapsulating VPNs (VRS@LP) were first synthesized. Macrophage membranes engineered to express the GPC3-specific single-chain antibody hGPC3 (M-hGPC3) were prepared via lentiviral transduction, then coated onto VRS@LP by mechanical extrusion to yield the targeted nanocarrier [email protected] nanocarrier achieves receptor-mediated endocytosis via specific hGPC3-GPC3 binding on HCC cells, with drug release triggered by the acidic lysosomal microenvironment. RSL3 inhibits glutathione peroxidase 4 (GPX4) activity, and SSZ blocks System xc – -mediated cystine uptake; their combination synergistically depletes intracellular glutathione (GSH) and potently induces ferroptosis in HCC cells. The nanoplatform-mediated PTT not only directly ablates tumor cells but also releases damage-associated molecular patterns (DAMPs), promoting dendritic cell maturation, T-cell activation, and tumor-associated macrophage polarization. Meanwhile, PTT-generated reactive oxygen species (ROS) synergize with ferroptosis to amplify oxidative injury and reduce HCC metastatic potential. The GPC3-targeted nanodelivery system enables precise synergistic PTT-ferroptosis therapy with high targeting efficiency, favorable biocompatibility and low systemic toxicity, significantly enhancing HCC therapeutic efficacy and suppressing metastasis. This work provides a potential strategy and experimental basis for precision HCC therapy, with promising clinical translational potential.