Hyaluronic acid-mediated artemisinin/ferrocene co-delivery Nanoplatform enhances immune checkpoint blockade response by triggering tumor cell immunogenic cell death via H₂O₂-independent Chemodynamic therapy.

Immune checkpoint blockade (ICB) therapy faces major challenges including low clinical response rates, while traditional chemodynamic therapy (CDT) is highly dependent on intratumoral hydrogen peroxide (H₂O₂) levels. To address these limitations, we constructed a pH-responsive hyaluronic acid (HA)-based nanosystem (HA-Fc@ART) for targeted cancer therapy. This nanoplatform achieves tumor-specific delivery through the specific interaction between HA and CD44 receptors overexpressed on tumor cells. Upon accumulation in the acidic tumor microenvironment (TME), the nanosystem undergoes Schiff base bond hydrolysis to precisely release artemisinin (ART) and ferrocene (Fc), avoiding off-target toxicity. Fc catalyzes the cleavage of the endoperoxide bridge in ART to generate singlet oxygen (1O₂) in an H₂O₂-independent manner. It simultaneously converts endogenous H₂O₂ into hydroxyl radicals (•OH) via the Fenton reaction. These dual pathways synergistically induce a reactive oxygen species (ROS) burst that efficiently eliminates cancer cells. Notably, HA-Fc@ART exhibits a high photothermal conversion efficiency of 35 ± 3%. The photothermal effect accelerates ROS production, and Fe(III) generated during the reaction depletes intracellular glutathione (GSH) to amplify oxidative damage. In vitro and in vivo experiments demonstrated that HA-Fc@ART possesses strong tumor-targeting ability. It effectively induces tumor immunogenic cell death (ICD) by releasing damage-associated molecular patterns (DAMPs). This process activates dendritic cell (DC) maturation, promotes macrophage M1 polarization, and enhances T cell infiltration into the TME. In the 4 T1 bilateral tumor model, the combination of HA-Fc@ART with photothermal therapy and anti-PD-L1 (αPD-L1) achieved complete ablation of primary tumors and significant inhibition of distant metastatic tumors. Histological analysis and hemolysis tests confirmed the nanosystem's excellent biosafety profile. This study provides a novel and efficient platform for improving the response rate of ICB therapy, offering new insights into the treatment of metastatic cancers.