Hyaluronic Acid-Modified Spherical MgO₂/Pd Nanocomposites Exhibit Superior Antitumor Effect through Tumor Microenvironment-Responsive Ferroptosis Induction and Photothermal Therapy

Metal peroxide nanomaterials as efficient hydrogen peroxide (H 2 O 2 ) self-supplying agents have attracted the attention of researchers for antitumor treatment. However, relying solely on metal peroxides to provide H 2 O 2 is undoubtedly insufficient to achieve optimal antitumor effects. Herein, we construct novel hyaluronic acid (HA)-modified nanocomposites (MgO 2 /Pd@HA NCs) formed by decorating palladium nanoparticles (Pd NPs) onto the surfaces of a magnesium peroxide (MgO 2 ) nanoflower as a highly effective nanoplatform for the tumor microenvironment (TME)-responsive induction of ferroptosis in tumor cells and tumor photothermal therapy (PTT). MgO 2 /Pd@HA NC could be well endocytosed into tumor cells with CD44 expression depending on the specific recognition of HA with CD44, and then, the nanocomposites can be rapidly decomposed in mild acid and hyaluronidase overexpressed TME, and plenty of H 2 O 2 was released. Simultaneously, Pd NPs catalyze self-supplied H 2 O 2 to generate abundant hydroxyl radicals ( • OH) and catalyze glutathione (GSH) into glutathione disulfide owing to its peroxidase and glutathione oxidase mimic enzyme activities, while the abundant • OH could also consume GSH in tumor cells and disturb the defense pathways of ferroptosis leading to the accumulation of lipid peroxidation and resulting in the occurrence of ferroptosis. Additionally, the superior photothermal conversion performance of Pd NPs in near-infrared II could also be used for PTT, synergistically cooperating with nanocomposite-induced ferroptosis for tumor inhibition. Consequently, the successfully prepared TME-responsive MgO 2 /Pd@HA NCs exhibited marked antitumor effect without obvious biotoxicity, contributing to thoroughly explore the nanocomposites as a novel and promising treatment for tumor therapy.