pH-activatable copper-biomineralized proenzyme for synergistic chemodynamic/ chemo-immunotherapy against aggressive cancers
pH-activatable copper-biomineralized proenzyme for synergistic chemodynamic/ chemo-immunotherapy against aggressive cancers
复制标题
pH 可激活的铜生物矿化酶原，用于针对侵袭性癌症的协同化学动力学/化学免疫疗法
DOI：
10.1002/adma.202210201
复制
发表时间：
2023
影响因子：
29.4
通讯作者：
Chen Huabing
中科院分区：
文献类型：
--
作者：
Li Ting;Zhang Ying;Zhu Jie;Zhang Fangrui;Xu An'an;Zhou Tian;Li Yaoqi;Liu Ming;Ke Hengte;Yang Tao;Tang Yong'an;Tao Jing;Miao Liyan;Deng Yibin;Chen Huabing
人工酶已经证明了对多种恶性肿瘤的治疗益处，但它们的抗肿瘤效力仍然受到非选择性催化、低原子利用效率和不期望的脱靶毒性的严重损害。在本文中，我们报告了单个白蛋白纳米笼（CuCH-NC）内的过氧化物酶样生物矿化的碱式碳酸铜（II）纳米晶体作为pH可激活的酶原，以实现对侵袭性三阴性乳腺癌（TNBC）的肿瘤选择性和协同化学动力学/化学免疫疗法。这些CuCH-NC表现出pH敏感的Cu 2+释放，其自发地经历谷胱甘肽（GSH）介导的还原成Cu+物质，用于以单原子样方式催化H2 O2演变成羟基自由基，从而引起化学动力学细胞损伤，同时激活无毒的双硫仑以产生细胞毒性复合物，从而通过阻断细胞增殖和放大细胞凋亡产生选择性化疗损伤。CuCH-NC表现出相当大的肿瘤靶向能力，具有较深的穿透深度，从而通过协同化学动力学/化学疗法提供对原位乳腺肿瘤的优选功效，以及良好的体内安全性。此外，CuCH-NC在双硫仑组合后引起明显的免疫原性细胞死亡效应并上调PD-L1表达，因此与抗PD-L1抗体协同激活适应性和先天性免疫，以及减轻免疫抑制，最终产生针对原发性和转移性TNBC的有效抗肿瘤功效。这些结果为智能和高性能的酶原提供了见解，用于协同治疗侵袭性癌症。
Artificial enzymes have demonstrated therapeutic benefit against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic utilization efficiency, and undesired off-target toxicity. Herein, we report that the peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2O2 into hydroxyl radicals in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieved immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.