Tumor\nMicroenvironment-Responsive Biodegradable Nanomedicine\nfor Self-Enhanced Synergistic Chemo‑, Photothermal, and Chemodynamic\nTherapy

The\nnanoscale multidrug codelivery system for synergistic therapy\nis an effective strategy for tumor treatment. However, the low drug\ndelivery efficiency and poor therapeutic effects limit its application.\nHere, based on the coordination effect of Artemisinin (Art), quercetin\n(Qc), and Fe<sup>3+</sup>, we had constructed a safe and efficient\ncarrier-free hyaluronic acid (HA)-modified Art–Fe–Qc\nnanoparticles (AFQ@HA NPs) for enhanced chemotherapy/photothermal\ntherapy (PTT)–chemodynamic therapy (CDT) synergistic therapy,\nwhich achieved an ultrahigh drug loading efficiency and a multifunction\nanticancer strategy. The results showed that high drug loading was\nachieved based on drug coordination self-assembly, with Art and Qc\ncontents of 38.6 and 42.7%, respectively. At the same time, based\non the Qc–Fe coordination molecular network, the system had\nexcellent photothermal conversion performance with an efficiency of\n57.3% and could effectively inhibit the expression of HSP70, achieving\nenhanced PTT. Further, under the stimulation of excessive H<sub>2</sub>O<sub>2</sub> and glutathione (GSH) in the tumor microenvironment,\nthe AFQ@HA NPs were continuously degraded, while releasing Art and\nFe<sup>3+</sup>/Fe<sup>2+</sup> to achieve iron ion-enhanced CDT.\nThe results of in vitro and in vivo experiments showed that AFQ@HA\nNPs could achieve chemotherapy–PTT–CDT synergistic therapy\nin response to tumor microenvironment by passively targeting and actively\ntargeting tumor cells with CD44, demonstrating its excellent targeted\nantitumor effects.