Ma Qiming, Xu Shenglin, Wang Qian, Que Yukang, He Peng, Yang Rui, Wang Hao, Wu Ziheng, Xiao Longze, Yuan Xingshi, Li Xingxing, Xu Tangbing, Hu Yong
Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
ACS Appl Mater Interfaces. 2024 Dec 11;16(49):67424-67443. doi: 10.1021/acsami.4c16287. Epub 2024 Nov 27.
Pyroptosis has gained attention for its potential to reinvigorate the immune system within the tumor microenvironment. However, current approaches employing pyroptosis inducers suffer from limitations. They primarily rely on single agents, lack precise targeting, and potentially disrupt the intricate bone formation microenvironment, hindering local repair of tumor-induced bone defects. Therefore, a therapeutic strategy is urgently needed that can effectively trigger pyroptosis while simultaneously promoting bone regeneration. This research introduces an all-in-one construct designed to address these limitations. It combines a cell-camouflaged shell with an autosynergistic reactive oxygen species (ROS) generating polymer. This construct incorporates a hollow core of manganese dioxide (HMnO) embedded with the photosensitizer IR780 and disguised by the cell membrane of an M1 macrophage. The M1 macrophage membrane grants the construct stealth-like properties, enabling it to accumulate selectively at the tumor site. Upon laser irradiation, IR780 acts as an exogenous trigger for ROS generation while simultaneously converting the light energy into heat. Additionally, the hollow structure of HMnO serves as an efficient carrier for IR780. Furthermore, Mn ions released from HMnO deplete glutathione (GSH) within the tumor, further amplifying ROS production. This synergistic cascade ultimately culminates in pyroptosis induction through caspase-3-mediated cleavage of gasdermin E (GSDME) upon laser activation. Meanwhile, the depletion of GSH by HMnO within the tumor microenvironment (TME) leads to the generation of Mn ions. These Mn ions establish a supportive milieu, which promotes the transformation of bone marrow mesenchymal stem cells (BMSCs) into mature bone cells. This, in turn, promotes the repair of bone defects in rat femurs. Our findings strongly indicate that pyroptosis may be a strategy for osteosarcoma treatment, which presents a robust and versatile approach for targeted therapy and tissue regeneration in this patient population.
细胞焦亡因其在肿瘤微环境中重振免疫系统的潜力而受到关注。然而，目前使用细胞焦亡诱导剂的方法存在局限性。它们主要依赖单一药物，缺乏精确靶向性，并且可能破坏复杂的骨形成微环境，阻碍肿瘤诱导的骨缺损的局部修复。因此，迫切需要一种能够有效触发细胞焦亡同时促进骨再生的治疗策略。本研究引入了一种一体化构建体来解决这些局限性。它将细胞伪装外壳与自协同产生活性氧（ROS）的聚合物相结合。该构建体包含一个嵌入光敏剂IR780的二氧化锰空心核（HMnO），并由M1巨噬细胞的细胞膜伪装。M1巨噬细胞膜赋予该构建体类似隐身的特性，使其能够在肿瘤部位选择性积聚。在激光照射下，IR780作为ROS产生的外源性触发因素，同时将光能转化为热能。此外，HMnO的空心结构是IR780的有效载体。此外，从HMnO释放的锰离子消耗肿瘤内的谷胱甘肽（GSH），进一步放大ROS的产生。这种协同级联最终通过激光激活后caspase-3介导的gasdermin E（GSDME）裂解导致细胞焦亡的诱导。同时，肿瘤微环境（TME）中HMnO对GSH的消耗导致锰离子的产生。这些锰离子建立了一个支持性环境，促进骨髓间充质干细胞（BMSC）向成熟骨细胞的转化。这反过来又促进了大鼠股骨骨缺损的修复。我们的研究结果有力地表明，细胞焦亡可能是骨肉瘤治疗的一种策略，为该患者群体的靶向治疗和组织再生提供了一种强大而通用的方法。
