Lyu Meng, Zhang Tianfu, Bao Zhirong, Li Pei, Chen Mingzhu, Quan Hong, Wang Cunchuan, Xia Ligang, Li Yang, Tang Benzhong
Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, China.
School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China.
Biomaterials. 2025 Sep;320:123281. doi: 10.1016/j.biomaterials.2025.123281. Epub 2025 Mar 20.
FLASH radiotherapy, which involves the delivery of an ultra-high radiation dose rate exceeding 40 Gy/s, has emerged as a promising tumor ablation strategy. While this approach generally spares normal tissues, the incomplete killing of tumors may sometimes lead to recurrence due to the immunosuppressive tumor microenvironment (TME). Herein, an aggregation-induced-emission luminogen (AIEgen)-alginate hydrogel was used to sensitize colon cancer via photodynamic therapy (PDT). Flower-like calcium carbonate nanoparticles, doped with an AIEgen termed CQu, were designed and applied as a cocktail with sodium alginate. When exposed to the acidic TME, Ca is released from this structure, resulting in sodium alginate termed FA forming a hydrogel in situ within the TME. This hydrogel also captures high concentrations of CQu in the local TME. Under laser irradiation, the CQu can generate sustained reactive oxygen species (ROS) production, thereby facilitating Ca influx and causing mitochondrial damage. Through a single injection of established FA hydrogel, followed by PDT and FLASH radiotherapy, immunogenic tumor cell death was induced which promoted antitumor immunity, thereby protecting against tumor recurrence while realizing abscopal effect. The results highlight the potential to improve the sensitivity of tumor cells to FLASH radiotherapy through sustained ROS production and Ca overload, thereby yielding optimal immunotherapy outcomes.
闪速放疗涉及超过40 Gy/s的超高辐射剂量率的输送，已成为一种有前景的肿瘤消融策略。虽然这种方法通常能使正常组织免受辐射，但由于免疫抑制性肿瘤微环境（TME），肿瘤有时无法被完全杀死，可能导致复发。在此，一种聚集诱导发光剂（AIEgen）-海藻酸盐水凝胶被用于通过光动力疗法（PDT）使结肠癌致敏。设计了掺杂名为CQu的AIEgen的花状碳酸钙纳米颗粒，并将其与海藻酸钠作为混合剂应用。当暴露于酸性TME时，Ca从该结构中释放出来，导致名为FA的海藻酸钠在TME中原位形成水凝胶。这种水凝胶还能在局部TME中捕获高浓度的CQu。在激光照射下，CQu可产生持续的活性氧（ROS），从而促进Ca内流并导致线粒体损伤。通过单次注射已制成的FA水凝胶，随后进行PDT和闪速放疗，诱导了免疫原性肿瘤细胞死亡，从而促进抗肿瘤免疫，在实现远隔效应的同时防止肿瘤复发。结果突出了通过持续产生ROS和Ca过载来提高肿瘤细胞对闪速放疗敏感性的潜力，从而产生最佳的免疫治疗效果。
