Dual-Targeted Biomimetic Nanoparticles for Enhanced Delivery of Polyphyllin B Synergistically Induce Ferroptosis and Immunogenic Cell Death in Gastric Cancer

Gastric cancer (GC) is one of the most common malignant tumors in the world, which is resistant to conventional chemotherapy drugs. Although polyphyllin B (PB) exhibits antitumor activity against GC, its clinical application is limited by systemic toxicity and poor target specificity. Here, we developed a dual-targeting nanoparticle (Ma/HA@NP) coated with a gastric cancer cell membrane (Ma) and hyaluronic acid (HA) to enhance biocompatibility, immune evasion, and homologous targeting. Ma/HA@NPs preserve the immune evasion and homologous targeting properties of both components. Upon endocytosis, Ma/HA@NPs react with cysteine to release PB, deplete glutathione (GSH), and reduce the enzymatic activity of glutathione peroxidase 4 (GPX4), leading to ferroptosis activation. Compared to single PB, Ma/HA@NPs not only enhance PB release but also trigger immunogenic cell death, promoting dendritic cell maturation and cytotoxic T lymphocyte activation. Moreover, interferon-γ release further suppresses cysteine uptake, synergistically amplifying ferroptosis. <i>In vivo,</i> intravenous administration of Ma/HA@NPs-PB in an orthotopic GC model achieved an 85.4% tumor inhibition rate with reduced systemic toxicity compared to free PB. Together, this dual-targeting platform enhances PB delivery and synergizes ferroptosis with immunogenic cell death (ICD) activation, offering a promising strategy for the treatment of gastric cancer.