Controllable All-in-One Biomimetic Hollow Nanoscaffold Initiating Pyroptosis-Mediated Antiosteosarcoma Targeted Therapy and Bone Defect Repair

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 (HMnO₂) 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 HMnO₂ serves as an efficient carrier for IR780. Furthermore, Mn⁴⁺ ions released from HMnO₂ 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 HMnO₂ within the tumor microenvironment (TME) leads to the generation of Mn²⁺ ions. These Mn²⁺ 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.