Lab of Molecular Imaging and Translational Medicine (MITM), Engineering Research Center of Molecular & Neuroimaging, School of Life Science and Technology, International Joint Research Center for Advanced Medical Imaging and Intelligent Diagnosis and Treatment, Ministry of Education, Xidian University, Xi'an, 710126, Shaanxi, P. R. China.
Guangzhou Institute of Technology, Xidian University, Guangzhou, 510555, Guangdong, P. R. China.
J Nanobiotechnology. 2024 Nov 1;22(1):670. doi: 10.1186/s12951-024-02843-4.
Mn-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO level in the system. Although the physiological buffers (HCO/HCO) provide certain amounts of HCO, the acidity of the tumor microenvironment (TME) would seriously affect the HCO ionic equilibrium (HCO ⇌ H + HCO). As a result, HCO level in the tumor region is actually insufficient to support effective Mn-mediated CDT.
In this study, a robust nanomodulator MnFeO@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO is presented to enhance therapeutic efficacy of Mn-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO ionic equilibrium to the positive direction, significantly boosting the generation of the HCO. Most importantly, such HCO supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFeO of PrSMZ to exert the remarkable antitumor effect on mouse models.
This work addresses the challenge of insufficient HCO in the TME for Mn-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn-mediated CDT agents to treat cancer effectively.
Mn 介导的化学动力学疗法（CDT）作为一种有前途的癌症治疗方式，严重依赖于系统中的 HCO 水平。尽管生理缓冲剂（HCO/HCO）提供了一定量的 HCO，但肿瘤微环境（TME）的酸度会严重影响 HCO 的离子平衡（HCO ⇌ H + HCO）。因此，肿瘤区域的 HCO 水平实际上不足以支持有效的 Mn 介导的 CDT。
在这项研究中，提出了一种具有原位自我调节 HCO 能力的强大纳米调节剂 MnFeO@ZIF-8（PrSMZ），以增强 Mn 介导的 CDT 的治疗效果。在酸性肿瘤微环境下，PrSMZ 可以作为质子海绵，将 HCO 的离子平衡向正方向移动，显著增加 HCO 的生成。最重要的是，PrSMZ 的这种 HCO 供应能力可以通过其 ZIF-8 壳层厚度进行精细调节，从而使活性氧（ROS）的产生增加 1000 倍。PrSMZ 内芯 MnFeO 所具有的谷胱甘肽（GSH）耗竭能力和光热效应进一步放大了 ROS 依赖性 CDT 疗效，从而对小鼠模型发挥了显著的抗肿瘤作用。
这项工作解决了 TME 中 Mn 介导的 Fenton 催化剂中 HCO 不足的挑战，并为设计高性能 Mn 介导的 CDT 试剂以有效治疗癌症提供了有前景的策略。
