Qi Hedong, Li Xue, Ma Jing, Sun Jiacheng, Liu Yating, Wang Xin, Fan Kelong, Shu Chunying, Wang Chunru
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Sci Bull (Beijing). 2025 Apr 30;70(8):1275-1294. doi: 10.1016/j.scib.2025.02.034. Epub 2025 Feb 25.
Subcellular inter-organellar crosstalk among lysosome, endoplasmic reticulum (ER), and mitochondrion is crucial for cancer cell survival and is a promising target in cancer treatment; however, efficiently disrupting these interactive networks is challenging. Herein, a communication interception strategy is presented, which specifically disrupts inter-organellar crosstalk by lysosomal contents leakage along with their trajectory and pre-activates autophagic flux to augment the lysosome-associated autophagy blocking for preventing the self-repair of this subcellular disorder. Briefly, fullerenols containing multiple hydroxyl groups (MF) tear the lysosomal phospholipid membrane through direct interaction, which causes lysosomal contents (calcium ions and cathepsins) to leak into the cytoplasm, subsequently leading to endoplasmic reticulum stress and mitochondrial dysfunction with redox imbalance and metabolic reprogramming. mTOR inhibitors activate and amplify autophagy, then impaired lysosomes prevent their fusion with autophagosome, and thus autophagy is paralyzed along with autolysosome accumulation. Consequently, the cellular homeostasis is compromised by destroyed inter-organellar networks without self-repair by autophagy, thereby triggering PANoptotic processes and leading to a remarkable anti-tumor therapeutic efficacy in vitro and in vivo. This strategy demonstrates the selective cytotoxicity of non-toxic nanomaterials that interfere with subcellular inter-organellar crosstalk, offering a novel method for designing tumor therapies.
溶酶体、内质网（ER）和线粒体之间的亚细胞细胞器间串扰对癌细胞存活至关重要，是癌症治疗中有前景的靶点；然而，有效破坏这些相互作用网络具有挑战性。在此，提出一种通信拦截策略，其通过溶酶体内容物沿其轨迹泄漏特异性破坏细胞器间串扰，并预激活自噬通量以增强溶酶体相关的自噬阻断，从而防止这种亚细胞紊乱的自我修复。简而言之，含有多个羟基的富勒烯醇（MF）通过直接相互作用撕裂溶酶体磷脂膜，导致溶酶体内容物（钙离子和组织蛋白酶）泄漏到细胞质中，随后导致内质网应激和线粒体功能障碍，伴有氧化还原失衡和代谢重编程。mTOR抑制剂激活并放大自噬，然后受损的溶酶体阻止其与自噬体融合，因此自噬随着自噬溶酶体积累而瘫痪。因此，细胞内稳态因细胞器间网络被破坏且无法通过自噬进行自我修复而受损，从而触发PAN凋亡过程，并在体外和体内产生显著的抗肿瘤治疗效果。该策略证明了干扰亚细胞细胞器间串扰的无毒纳米材料的选择性细胞毒性，为设计肿瘤治疗方法提供了一种新方法。
