Sodium hyaluronate-modified FeIII-shikonin self-assembly nanoparticle for effective tumor therapy and reduced tumor metastasis.

Tumor metastasis constitutes a major obstacle in cancer treatment and affects patients' quality of life. In this study, we synthesized FeIII-shikonin nanoparticles (SF NPs) through a one-step self-assembly process utilizing shikonin (SK) and FeIII. Following the synthesis of nanoparticles, the challenges associated with the poor water solubility and the low bioavailability of SK, as well as its toxicity and adverse effects on normal tissues, could be addressed, thereby enhancing its applicability. Additionally, the synergistic effect between SK and FeIII could be achieved. These nanoparticles were subsequently modified with sodium hyaluronate (HA) to obtain tumor-targeted HSF NPs, characterized by a particle size of 171.2 nm and a zeta potential of -39.85 mV. SK could reduce LA production to improve the tumor microenvironment by downregulating PKM2 activity. Additionally, SK has been observed to downregulate MMP9 expression, resulting in decreased tumor metastasis. The exposure of tumor cells to SK and FeIII induced ferroptosis by disrupting iron ion balance and redox homeostasis. In vivo antitumor activity assessments in CT26-bearing mice demonstrated that the HSF NPs achieved a tumor growth inhibition rate of 76.94 %. By integrating these therapeutic mechanisms, HSF NPs effectively inhibited the growth of orthotopic tumors and the dissemination of metastatic tumors.