CD44 and Mitochondria Dual-Targeted Polydopamine Nanoplatform for Combined Chemotherapy, Photothermal Ablation, and Immunogenic Cell Death Induction in Liver Cancer

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy characterized by inadequate drug delivery to tumor sites, insufficient immune activation, and poor response to conventional monotherapies. To overcome these limitations, we developed a pH and near-infrared (NIR) responsive nanoplatform (DOX@MPDA-TPP@HA) by encapsulating doxorubicin (DOX) into mesoporous polydopamine (MPDA) nanoparticles functionalized with triphenylphosphonium (TPP) and hyaluronic acid (HA) to achieve mitochondrial and CD44 dual-targeting. This system enables combined chemotherapy and photothermal therapy, while simultaneously promoting immunogenic cell death and enhancing antitumor immunity. In vitro and in vivo experiments demonstrated that the nanoplatform exhibits acid and NIR-triggered drug release, efficient photothermal conversion, and enhanced cellular uptake in tumor cells. Treatment significantly increased calreticulin exposure and high-mobility group box 1 (HMGB1) release, both recognized as hallmarks of immunogenic cell death. Flow cytometry revealed a marked increase in the maturation of CD11c⁺CD80⁺CD86⁺ dendritic cells in tumor-draining lymph nodes, elevated intratumoral CD8⁺ cytotoxic T lymphocyte infiltration, and a reduction in CD4⁺Foxp3⁺ regulatory T cells. Enzyme-linked immunosorbent assay (ELISA) confirmed the elevated secretion of proinflammatory cytokines including interleukin-6, interleukin-12, tumor necrosis factor-alpha, and interferon-gamma, suggesting immune reprogramming of the tumor microenvironment.