Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H₂O₂) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H₂O₂ and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO₂-based multifunctional nanocomposite with a surface coating of Cu²⁺ and L-buthionine sulfoximine (BSO) (named CaO₂@Cu–BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO₂ nanoparticles subsequently decompose to produce H₂O₂, alleviating the insufficient supply of endogenous H₂O₂ in the tumor microenvironment (TME). Furthermore, Cu²⁺ detached from the surface of CaO₂ is reduced by H₂O₂ and GSH to Cu⁺ and ROS. Then, Cu⁺ catalyzes H₂O₂ to generate highly cytotoxic ˙OH and Cu²⁺, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu²⁺ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO₂ by TME releases a large amount of free Ca²⁺, resulting in the accumulation and overload of Ca²⁺ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.

中文翻译：

---

一种产生 ROS 风暴的纳米复合材料，通过 H2O2 自供应、GSH 消耗和钙超载来增强化学动力学治疗

_{从过氧化氢（H 2} O ₂ ）催化产生有毒羟基自由基（˙OH）是化学动力学疗法（CDT）中肿瘤治疗的有效策略。然而，实体瘤微环境的固有特征（以有限的H ₂ O ₂和过度表达的谷胱甘肽（GSH）为特征）严重阻碍了细胞内˙OH的积累，带来了重大挑战。为了规避这些关键问题，在这项工作中，设计了一种具有 Cu ²⁺和L-丁硫氨酸亚砜亚胺 (BSO)表面涂层的CaO ₂基多功能纳米复合材料（命名为 CaO ₂ @Cu–BSO），用于增强 CDT。利用肿瘤的弱酸性环境，纳米复合材料逐渐崩解，暴露的CaO ₂纳米颗粒随后分解产生H ₂ O ₂ ，​​缓解肿瘤微环境(TME)内源性H ₂ O ₂供应不足。此外，从CaO ₂表面脱离的Cu ^2+被H ₂ O ₂和GSH还原为Cu ⁺和ROS。然后，Cu ⁺催化H ₂ O ₂生成高细胞毒性的˙OH和Cu ²⁺，形成有效CDT的循环催化作用。同时，GSH 被 Cu ²⁺离子耗尽，以消除可能的 ˙OH 清除作用。此外，TME分解CaO ₂释放出大量游离Ca ²⁺ ，导致肿瘤细胞内Ca ²⁺积累和超载以及线粒体损伤，进一步提高CDT疗效并加速肿瘤细胞凋亡。此外，BSO 是一种分子抑制剂，通过阻断 γ-谷氨酰半胱氨酸合成酶来减少 GSH 的产生。总之，该策略可以通过肿瘤治疗中的 ROS 风暴生成策略来提高 CDT 效率。实验结果证实并证明了体外和体内良好的肿瘤抑制效果。