Lin Qian, He Yueyang, Li Yang, Sun Qiuyue, Li Fu-Nan, Lin Jinyan, Zhu Xuan
Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, PR China.
Cancer Center and Department of Breast and Thyroid Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, PR China.
J Colloid Interface Sci. 2025 Aug 15;692:137545. doi: 10.1016/j.jcis.2025.137545. Epub 2025 Apr 7.
The high redox levels within tumors position chemodynamic therapy (CDT) as a promising therapeutic approach. However, the CDT efficiency of dihydroartemisinin (DHA) is limited by rapid clearance from bloodstream, along with inadequate endogenous ferrous ions within tumor microenvironment and heightened anti-oxidative defense inside tumor cells. To overcome these limitations, we developed an innovative virus-like hollow mesoporous manganese nanocage, loaded with DHA and subsequently cloaked with red cell membrane, designed to trigger a tumor-microenvironment-responsive free radical generation, synergized with glutathione (GSH) exhaustion for enhanced CDT efficacy. Upon accumulation in tumor tissues via the enhanced penetration and retention (EPR) effect, the high concentration of GSH in cancer cells initiates the degradation of the nanocages. This process specifically and efficiently released both Mn and DHA while simultaneously depleting GSH. The released Mn further catalyzed the conversion of DHA to generate large amounts of highly toxic carbon-center (•C) radicals accompanied by the generation of Mn. The •C radical generation led to severe mitochondria dysfunction and DNA damage, potentially causing cancer cell death. The concurrently generated Mn continued to depelete intracellular GSH and induce lipid peroxidation, thereby weakening cancer cells' anti-oxidative defenses and amplifing oxidative stress. The viability of 4T1 cells treated with DHA@vhmMN@RM was significantly lower (about 30 %) than other groups. This work presents a novel nanosystem that specifically enhances the therapeutic effect of CDT by leveraging a tumor microenvironment-responsive free radical generation, coupled with GSH exhaustion, offering a new avenue for targeted drug delivery and synergistic cancer therapy.
肿瘤内的高氧化还原水平使化学动力疗法（CDT）成为一种有前景的治疗方法。然而，双氢青蒿素（DHA）的CDT效率受到从血液中快速清除的限制，同时肿瘤微环境中内源性亚铁离子不足以及肿瘤细胞内抗氧化防御增强。为了克服这些限制，我们开发了一种创新的病毒样中空介孔锰纳米笼，装载DHA并随后用红细胞膜包裹，旨在引发肿瘤微环境响应性自由基生成，与谷胱甘肽（GSH）耗竭协同作用以增强CDT疗效。通过增强渗透和滞留（EPR）效应在肿瘤组织中积累后，癌细胞中高浓度的GSH引发纳米笼的降解。这个过程特异性且高效地释放了Mn和DHA，同时消耗了GSH。释放的Mn进一步催化DHA的转化，产生大量高毒性的碳中心（•C）自由基并伴随Mn的生成。•C自由基的产生导致严重的线粒体功能障碍和DNA损伤，可能导致癌细胞死亡。同时产生的Mn继续消耗细胞内GSH并诱导脂质过氧化，从而削弱癌细胞的抗氧化防御并放大氧化应激。用DHA@vhmMN@RM处理的4T1细胞的活力明显低于其他组（约30%）。这项工作提出了一种新型纳米系统，通过利用肿瘤微环境响应性自由基生成以及GSH耗竭来特异性增强CDT的治疗效果，为靶向药物递送和协同癌症治疗提供了一条新途径。
