Coordination Self-Assembly of a Carrier-Free Hyaluronic Acid-Modified Nanoplatform for Augmented Photothermal/Chemodynamic Therapy and Robust Antimetastatic Immunity

Although photothermal therapy (PTT) and chemodynamic therapy (CDT) show promise for tumor treatment, their efficacy is significantly limited by the tumor microenvironment’s antioxidant defenses and thermoresistance mechanisms. Furthermore, while nanotechnology provides a viable strategy to enhance these therapies, conventional nanocarriers are frequently plagued by low drug loading capacity, premature leakage, and potential carrier-induced toxicity. To overcome these limitations, we developed a carrier-free nanoplatform (LF@HA NPs) through coordination self-assembly of luteolin (Lut) and Fe 3+, further modified with hyaluronic acid (HA) for enhanced stability and active targeting. This innovative system achieves exceptional encapsulation efficiency (90.46%) and drug loading efficiency (85.86%) that substantially surpass those of conventional systems. In addition, the nanoplatform displays dual responsiveness to both glutathione (GSH) and NIR lasers, enabling precisely controlled drug release and photothermal conversion. Under near-infrared irradiation, the platform simultaneously enables PTT and Fe 3+ -mediated CDT. The released Fe 3+ depletes GSH to disrupt redox balance, while Lut inhibits both heat shock protein 90 (HSP90) and hypoxia inducible factor-1α (HIF-1α), establishing a self-reinforcing therapeutic cycle that overcomes treatment resistance. Importantly, the synergistic effect induces immunogenic cell death (ICD), activating systemic antitumor immunity and suppressing metastasis. This work not only provides an integrated platform combining high drug loading, self-amplifying therapy, and immune activation but also establishes a foundation for developing natural product-based coordination nanomedicines.