多模态联合治疗（MCT）是通过各种治疗方法的协同作用来消除肿瘤细胞的新兴方法。然而，复杂的肿瘤微环境（TME）由于H+离子、H2O2和谷胱甘肽（GSH）过度存在、缺乏O2和松弛性铁死亡等因素成为MCT治疗效果的关键障碍。为了克服这些限制，我们利用金纳米簇作为核心和钠藻酸盐（SA）/透明质酸（HA）复合凝胶的原位交联壳制备了具有优异生物相容性、稳定性和靶向功能的智能纳米杂化凝胶。获得的Au NCs-Cu2+@SA-HA核壳纳米杂化凝胶具有近红外光响应性，协同受益于光热成像引导的光热疗法（PTT）和光动力疗法（PDT）。与此同时，纳米杂化凝胶从中释放出的Cu2+离子不仅通过诱导铜死亡来避免铁死亡的松弛，还催化TME中的H2O2产生O2，同时改善缺氧微环境和PDT效果。此外，释放的Cu2+离子可以消耗过多的GSH形成Cu+离子，使氢氧自由基（·OH）产生以杀死肿瘤细胞，从而协同实现GSH消耗增强的PDT和化学动力疗法（CDT）。因此，我们研究中的新设计为通过TME调节增强PTT/PDT/CDT提供了另一种研究途径。版权所有©2023 Elsevier Inc.。

Multimodal combined therapy (MCT) is an emerging avenue to eliminate tumor cells by the synergistic effect of various therapeutic methods. However, the complex tumor microenvironment (TME) is becoming the key barrier to the therapeutic effect of MCT due to the excessive existence of H+ ions, H2O2, and glutathione (GSH), the lack of O2, and the relaxation of ferroptosis. To overcome these limitations, smart nanohybrid gels with excellent biocompatibility, stability and targeting function were prepared by using gold nanoclusters as cores and an in situ cross-linking composite gel of sodium alginate (SA)/hyaluronic acid (HA) as the shell. The obtained Au NCs-Cu2+@SA-HA core-shell nanohybrid gels possessed near-infrared light response synergistically benefitting photothermal imaging guided photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the H+-triggered release of Cu2+ ions from the nanohybrid gels not only induces cuproptosis to avoid the relaxation of ferroptosis, but also catalyzes H2O2 in the TME to generate O2 to simultaneously improve the hypoxic microenvironment and PDT effect. Furthermore, the released Cu2+ ions could consume the excessive GSH to form Cu+ ions effectively, which caused the formation of hydroxyl free radicals (·OH) to kill tumor cells, synergistically realizing GSH consumption-enhanced PDT and chemodynamic therapy (CDT). Hence, the novel design in our work provides another research avenue for cuproptosis-enhanced PTT/PDT/CDT via TME modulation.Copyright © 2023 Elsevier Inc. All rights reserved.