A pH-activatable copper-biomineralized proenzyme for synergistic chemodynamic/chemo-immunotherapy
Artificial enzymes have demonstrated therapeutic benefits 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.
Figure 1. Schematic illustration of biomineralized CuCH-NCs as the proenzyme for cancer-specific cooperative therapy. (A) Synthetic process of biomineralized CuCH-NCs. (B) In vivo cooperative chemodynamic-chemoimmunotherapy of CuCH-NCs in combination with DSF and aPD-L1. Upon internalization into tumor cells, CuCH-NCs undergo a cascade reaction to yield considerable hydroxyl radicals, and DSF activation for further amplifying apoptosis and ICD effect at tumor. Meanwhile, the CuCH-NCs/DSF/aPD-L1 combination yielded preferable antitumor potency via activating adaptive and innate immunity, and relieving immunosuppression.
References: Ting Li, Ying Zhang, Jie Zhu, Fangrui Zhang, An'an Xu, Tian Zhou, Yaoqi Li, Ming Liu, Hengte Ke, Tao Yang, Yong'an Tang, Jing Tao*, Liyan Miao*, Yibin Deng*, Huabing Chen*, Adv Mater 2023, 2210201
The original link: https://doi.org/10.1002/adma.202210201