Li Tianyu, Zhang Ya, Li Cong, Song Yanwei, Jiang Tiaoyan, Yin Yipengchen, Chang Meiqi, Song Xinran, Zheng Xiaojun, Zhang Wenqing, Yu Zhongdan, Feng Wei, Zhang Qin, Ding Li, Chen Yu, Wang Sheng
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, P. R. China.
Adv Mater. 2025 Jul;37(26):e2503138. doi: 10.1002/adma.202503138. Epub 2025 Apr 26.
Rectal cancer surgery is challenging due to the complex anatomy, making it difficult to achieve clear surgical margins. Radiotherapy (RT) plays a crucial role, especially in treating locally recurrent rectal cancer and preserving anal function. However, its effectiveness is often limited by tumor hypoxia, particularly prevalent in hypoxic regions near the bowel wall in colorectal cancer. Hypoxia contributes to both radiation resistance and apoptosis resistance, compromising RT outcomes. To overcome hypoxia-driven radiotherapy resistance, this work designs and engineers a radiotherapy-sensitizing bioplatform for efficient cancer RT. It combines lanthanum oxide nanoparticles (LaO NPs) with cyanobacteria, which produces oxygen through photosynthesis. This bioplatform uniquely reduces tumor hypoxia, enhances radiation deposition, and improves RT efficacy. LaO NPs further enhance reactive oxygen species (ROS) production induced by radiation, triggering pyroptosis via the ROS-NLRP3-GSDMD pathway, while RT amplifies pyroptosis through GSDME, circumventing tumor apoptosis resistance. The further integrated thermosensitive hydrogels ensure precise localization of the bioplatform, reducing systemic toxicity and improving therapeutic specificity. Compared to conventional therapies, this dual-action system addresses hypoxia, RT resistance, and apoptosis resistance more effectively. In vivo and in vitro hypoxia models validate its potent anti-tumor efficacy, offering valuable insights for refining clinical treatment paradigms.
由于解剖结构复杂，直肠癌手术具有挑战性，难以实现清晰的手术切缘。放射治疗（RT）起着关键作用，特别是在治疗局部复发性直肠癌和保留肛门功能方面。然而，其有效性常常受到肿瘤缺氧的限制，尤其是在结直肠癌肠壁附近的缺氧区域普遍存在。缺氧导致放射抗性和凋亡抗性，损害了放疗效果。为了克服缺氧驱动的放疗抗性，这项工作设计并构建了一种用于高效癌症放疗的放疗增敏生物平台。它将氧化镧纳米颗粒（LaO NPs）与通过光合作用产生氧气的蓝细菌相结合。这种生物平台独特地减少肿瘤缺氧，增强辐射沉积，并提高放疗疗效。LaO NPs进一步增强辐射诱导的活性氧（ROS）生成，通过ROS-NLRP3-GSDMD途径触发细胞焦亡，而放疗通过GSDME放大细胞焦亡，规避肿瘤凋亡抗性。进一步整合的热敏水凝胶确保生物平台精确定位，降低全身毒性并提高治疗特异性。与传统疗法相比，这种双作用系统更有效地解决了缺氧、放疗抗性和凋亡抗性问题。体内和体外缺氧模型验证了其强大的抗肿瘤疗效，为完善临床治疗模式提供了有价值的见解。
