Dual-Targeted Biomimetic Nanoparticles for Enhanced Delivery of Polyphyllin B Synergistically Induce Ferroptosis and...

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. In vivo, 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.