Nuclear-targeted smart nanoplatforms featuring double-shell hollow mesoporous copper sulfide coated with manganese dioxide synergistically potentiate chemotherapy and immunotherapy in hepatocellular carcinoma cells

Smart nanoplatforms designed for nuclear-targeted delivery of chemotherapeutic agents to tumor sites are pivotal in advancing tumor treatment and immunotherapy. Herein, we introduced a novel nuclear-targeting double-shell smart nanoplatform (HMCuS/Pt/ICG@MnO₂@9R-P201 (HMCPIM9P)), which synergistically enhances chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), immunotherapy and chemodynamic therapy (CDT). The core of this nanoplatform consists of double-shell multifunctional nanoparticles (HMCuS@MnO₂) that enable targeted delivery of the photosensitizer Indocyanine Green (ICG) and the chemotherapeutic agent cisplatin (Pt). By effectively consuming glutathione (GSH), these nanoparticles boost the chemotherapeutic efficacy of Pt. Additionally, the manganese ion (Mn²⁺) present activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) pathway, bolstering adaptive immune responses against tumors and elevating the level of tumor-infiltrating CD8+ T cells. The incorporation of the hepatoma-targeting peptide (9R-P201 peptide) allows the system to exhibit FOXM1 receptor-mediated nuclear targeting properties specifically in hepatocellular carcinoma (HCC). Notably, when combined with near-infrared (NIR) light, HMCPIM9P demonstrated a remarkable tumor inhibition rate of 95.6 %, fostered a robust immune response, and significantly inhibited tumor growth and recurrence. Overall, the smart nanoplatform boasts active nuclear targeting capabilities, enabling the enrichment of chemotherapeutic agents at tumor sites, and holds great potential for synergistic applications in enhancing chemotherapy and immunotherapy for HCC.