Zhou Hao, Bao Peng, Lin Yan-Tong, Meng Ran, Yan Xiao, Deng Xin-Chen, Huang Qian-Xiao, Chen Wei-Hai, Zhang Xian-Zheng
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan, 430072, PR China.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan, 430072, PR China.
Biomaterials. 2025 Jun;317:123075. doi: 10.1016/j.biomaterials.2024.123075. Epub 2024 Dec 30.
As a promising tumor treatment, chemodynamic therapy (CDT) can specifically catalyze HO into the cytotoxic hydroxyl radical (·OH) via Fenton/Fenton-like reaction. However, the limited HO and weakly acidic pH in tumor microenvironment (TME) would severely restrict the therapeutic efficiency of CDT. Here, a weakly acid activated, HO self-supplied, hyaluronic acid (HA)-functionalized Ce/Cu bimetallic nanoreactor (CBPNs@HA) is elaborately designed for complementary chemodynamic-immunotherapy. In this nanoreactor, the component of peroxide group and Ce/Cu bimetals played the role of HO self-supply and synergistic catalytic Fenton-like reaction, respectively. Specifically, CBPNs@HA can sensitively respond to TME (pH 6.8) and rapidly degrade to generate Ce, Cu and HO. The high-valence Ce would be reduced by the intracellular glutathione (GSH) to generate Ce and this process could be accelerated by Cu via synergistic effect of Ce/Cu. Particularly, the low-valence metallic ions (Ce and Cu) can react with the produced HO to generate a multitude of reactive oxygen species (ROS). These cascaded effects can significantly amplify oxidative stress and seriously disturb the redox balance of tumor cells, inducing the potent immunogenic cell death (ICD) to release tumor-specific antigens and thereby activating the powerful antitumor immune responses. After combined with immune checkpoint blockade (ICB), CBPNs@HA can significantly heighten antitumor effects to inhibit the growth of primary and metastatic tumors, and dramatically prolong the survival lifetime of 4T1 tumor-bearing mice to 60 days. This work provides a materials-based strategy for enhanced CDT and highlights new opportunities for complementary chemodynamic-immunotherapy.
作为一种很有前景的肿瘤治疗方法，化学动力疗法（CDT）可以通过芬顿/类芬顿反应将过氧化氢（H₂O₂）特异性催化为具有细胞毒性的羟基自由基（·OH）。然而，肿瘤微环境（TME）中有限的H₂O₂和弱酸性pH会严重限制CDT的治疗效果。在此，精心设计了一种弱酸性激活、H₂O₂自供应、透明质酸（HA）功能化的Ce/Cu双金属纳米反应器（CBPNs@HA）用于互补化学动力免疫治疗。在这个纳米反应器中，过氧化物基团和Ce/Cu双金属组分分别起到了H₂O₂自供应和协同催化类芬顿反应的作用。具体而言，CBPNs@HA能够对TME（pH 6.8）敏感响应并快速降解以生成Ce、Cu和H₂O₂。高价态的Ce会被细胞内的谷胱甘肽（GSH）还原生成Ce³⁺，并且这个过程可以通过Ce/Cu的协同作用被Cu²⁺加速。特别地，低价态金属离子（Ce³⁺和Cu²⁺）可以与生成的H₂O₂反应产生大量活性氧（ROS）。这些级联效应能够显著放大氧化应激并严重扰乱肿瘤细胞的氧化还原平衡，诱导强烈的免疫原性细胞死亡（ICD）以释放肿瘤特异性抗原，从而激活强大的抗肿瘤免疫反应。与免疫检查点阻断（ICB）联合后，CBPNs@HA可以显著增强抗肿瘤效果以抑制原发性和转移性肿瘤的生长，并将4T1荷瘤小鼠的生存寿命显著延长至60天。这项工作为增强CDT提供了一种基于材料的策略，并突出了互补化学动力免疫治疗的新机遇。
