School of Materials Science and Engineering, Zhengzhou University, 100 Science Road, Zhengzhou 450001, China; State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China; Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Biomater. 2022 Nov;153:494-504. doi: 10.1016/j.actbio.2022.09.024. Epub 2022 Sep 15.
The field of nanomedicine-catalyzed tumor therapy has achieved a lot of progress; however, overcoming the limitations of the tumor microenvironment (TME) to achieve the desired therapeutic effect remains a major challenge. In this study, a nanocomposite hydrogel (GH@LDO) platform combining the nanozyme CoMnFe-layered double oxides (CoMnFe-LDO) and natural enzyme glucose oxidase (GOX) was engineered to remodel the TME to enhance tumor catalytic therapy. The CoMnFe-LDO is a nanozyme that can convert endogenous HO into reactive oxygen species (ROS) and O to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Meanwhile, GOX can catalyze the conversion of glucose and O to gluconic acid and HO, which not only represses the ATP production of tumor cells to achieve starvation therapy (ST), but also decreases the pH value of TME and supplies extra HO to enhance the CDT effect. Furthermore, this well-designed CoMnFe-LDO possessed a high photothermal conversion efficiency of GH@LDO (66.63%), which could promote the generation of ROS to enhance the CDT effect and achieve photothermal therapy (PTT) under near-infrared light irradiation. The GH@LDO hydrogel performes cascade reaction which overcomes the limitation of the TME and achieves satisfactory CDT/ST/PTT synergetic effects in vitro and in vivo. This work provides a new strategy for remodeling the TME using nanomedicine to achieve precise tumor cascaded catalytic therapy. STATEMENT OF SIGNIFICANCE: At present, the focus of tumor therapy has begun to shift from monotherapy to combination therapy for improving the overall therapeutic effect. In this study, we synthesized a CoMnFe-LDO nanozyme composed of multiple transition metal oxides, which demonstrated improved peroxidase and oxidase activities as well as favorable photothermal conversion capability. The CoMnFe-LDO nanozyme was compounded with an injectable GH hydrogel crosslinked by GOX and horseradish peroxidase (HRP). This nanocomposite hydrogel overcame the limitations of weak acidity, HO, and O levels in the TME and achieved synergetic CDT, ST, and PTT effects based on the cascaded catalytic actions of CoMnFe-LDO and GOX to HO and glucose.
纳米医学催化肿瘤治疗领域已经取得了很多进展；然而，克服肿瘤微环境 (TME) 的限制以达到理想的治疗效果仍然是一个主要挑战。在这项研究中，构建了一种纳米复合水凝胶 (GH@LDO) 平台，该平台结合了纳米酶 CoMnFe 层状双氧化物 (CoMnFe-LDO) 和天然酶葡萄糖氧化酶 (GOX)，以重塑 TME 以增强肿瘤催化治疗。CoMnFe-LDO 是一种纳米酶，可将内源性 HO 转化为活性氧 (ROS) 和 O，从而实现化学动力学治疗 (CDT) 并减轻缺氧微环境。同时，GOX 可催化葡萄糖和 O 的转化为葡萄糖酸和 HO，不仅抑制肿瘤细胞的 ATP 产生以实现饥饿治疗 (ST)，还降低 TME 的 pH 值并提供额外的 HO 以增强 CDT 效果。此外，这种精心设计的 CoMnFe-LDO 具有 GH@LDO 的高光热转换效率 (66.63%)，可促进 ROS 的产生以增强 CDT 效果，并在近红外光照射下实现光热治疗 (PTT)。GH@LDO 水凝胶进行级联反应，克服了 TME 的限制，在体外和体内实现了令人满意的 CDT/ST/PTT 协同效应。这项工作为利用纳米医学重塑 TME 以实现精确的肿瘤级联催化治疗提供了一种新策略。
目前，肿瘤治疗的重点已开始从单一疗法转向联合疗法，以提高整体治疗效果。在这项研究中，我们合成了一种由多种过渡金属氧化物组成的 CoMnFe-LDO 纳米酶，该纳米酶具有增强的过氧化物酶和氧化酶活性以及良好的光热转换能力。CoMnFe-LDO 纳米酶与 GOX 和辣根过氧化物酶 (HRP) 交联的可注射 GH 水凝胶复合。这种纳米复合水凝胶克服了 TME 中弱酸性、HO 和 O 水平的限制，并基于 CoMnFe-LDO 和 GOX 对 HO 和葡萄糖的级联催化作用，实现了协同的 CDT、ST 和 PTT 效应。
