The combination of chemotherapy and photodynamic therapy provides a promising approach for enhanced tumor eradication by overcoming the limitations of each individual therapeutic modality. However, tumor is pathologically featured with extreme hypoxia together with the adaptable overexpression of anti-oxidants, such as glutathione (GSH), which greatly restricts the therapeutic efficiency. Here, a combinatorial strategy was designed to simultaneously relieve tumor hypoxia by self-oxygenation and reduce intracellular GSH level to sensitize chemo-photodynamic therapy. In our system, a novel multi-functional nanosystem based on MnO₂-doped graphene oxide (GO) was developed to co-load cisplatin (CisPt) and a photosensitizer (Ce6). With MnO₂ doping, the nanosystem was equipped with intelligent functionalities: (1) catalyzes the decomposition of H₂O₂ into oxygen to relieve the tumor hypoxia; (2) depletes GSH level in tumor cells, and (3) concomitantly generates Mn²⁺ to proceed Fenton-like reaction, all of which contribute to the enhanced anti-tumor efficacy. Meanwhile, the surface hyaluronic acid (HA) modification could facilitate the targeted delivery of the nanosystem into tumor cells, thereby resulting in amplified cellular toxicity, as well as tumor growth inhibition in nude mice model. This work sheds a new light on the development of intelligent nanosystems for synergistic combination therapy via regulating tumor microenvironment.

化学疗法与光动力疗法的结合通过克服每个个体治疗方式的局限性，为增强肿瘤根除提供了一种有前途的方法。然而，肿瘤的病理特征是极度缺氧以及抗氧化剂如谷胱甘肽（GSH）的适应性过表达，这极大地限制了治疗效率。在这里，设计了一种组合策略，以通过自加氧同时缓解肿瘤缺氧，并降低细胞内GSH的水平，从而使化学光动力疗法更为敏锐。在我们的系统中，开发了一种基于MnO ₂掺杂的氧化石墨烯（GO）的新型多功能纳米系统，以同时加载顺铂（CisPt）和光敏剂（Ce6）。含MnO ₂掺杂后，纳米系统具备了智能功能：（1）催化H ₂ O ₂分解为氧气，以减轻肿瘤的缺氧；（2）耗尽肿瘤细胞中的GSH水平，（3）伴随产生Mn ²⁺进行Fenton样反应，所有这些都有助于增强抗肿瘤功效。同时，表面透明质酸（HA）修饰可以促进纳米系统靶向递送至肿瘤细胞，从而导致放大的细胞毒性以及裸鼠模型中的肿瘤生长抑制作用。这项工作为通过调节肿瘤微环境进行协同治疗的智能纳米系统的开发提供了新的思路。