Fully active zinc nitroprusside nanomedicine transforms cisplatin into chemoimmunotherapeutic agent for robust hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC) is notoriously resistant to conventional chemotherapy and immunotherapy. This study presents a strategy that reprograms cisplatin into a chemoimmunotherapeutic agent by combining it with ZnNO, a fully active nanomedicine composed of sodium nitroprusside and zinc ions. Mechanistically, ZnNO enhances cisplatin chemosensitivity by depleting glutathione and releasing nitric oxide, while Zn²⁺ restores cisplatin-induced immunogenic cell death by activating endoplasmic reticulum stress via the PERK-eukaryotic translation initiation factor 2α (eIF2α) pathway. This dual modulation reactivates antigen presentation and promotes in situ antitumor immunity. Co-encapsulation of ZnNO and cisplatin in a thermosensitive nanoemulsion hydrogel enables transarterial chemoimmunoembolization, achieving sustained drug release, vascular embolization, and immune activation that downregulates drug resistance markers (MRP2 and Slc22a1), upregulates immune genes (CD8a and Hspa1a), and activates mitogen-activated protein kinase (MAPK) signaling. Overall, this work redefines cisplatin therapy by overcoming resistance and enhancing immunity, offering a translational strategy for HCC.