Accurate intranuclear delivery of smart nanoplatforms synergistically enhances hepatocellular carcinoma therapy by remodeling tumor microenvironment

Delivering chemotherapeutic agents precisely to tumors and modifying the tumor microenvironment (TME) remain major challenges in cancer therapy. Here, we developed an intelligent nanoplatform based on hepatocellular carcinoma (HCC)-targeting peptide (9R-P201)-modified hollow manganese dioxide (HMnO 2 )-coated copper sulfide (CuS) nanoparticles (CuS@HMnO 2 @9R-P201 NPs) for enhanced HCC treatment. The HMnO 2 structure enabled high loading of doxorubicin (DOX) and indocyanine green (ICG). Upon exposure to 808 nm laser irradiation, the HMnO 2 shells interacted with hydrogen peroxide (H 2 O 2 ) and protons (H + ) in TME to generate Mn 2+ and oxygen (O 2 ), alleviating hypoxia and triggering the release of ICG, DOX, and CuS. CuS enhanced the photothermal effect, while DOX allowed imaging-guided therapy. This nanoplatform demonstrates precise targeting and multimodal therapeutic potential, supporting its clinical translation.