In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS–lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

在治疗严重创伤性脑损伤（TBI）时，涉及切除受损脑组织和脑内出血的紧急手术是首要任务。由原发性机械性脑损伤和手术损伤引发的氧化应激和能量代谢紊乱引起的继发性脑损伤也是 TBI 预后的决定因素。不幸的是，传统的术后静脉注射神经保护剂治疗的有效性常常受到神经保护剂全身递送时缺乏靶向性、及时性和副作用的限制。在这里，我们开发了可注射的智能自组装水凝胶（P-RT/2DG），可以通过术中应用于目标区域来实现精准治疗。 P-RT/2DG 水凝胶是通过将活性氧 (ROS) 响应的硫缩酮连接体 (RT) 整合到聚乙二醇中制备的。通过在降解过程中清除ROS并释放2-脱氧葡萄糖（2DG），这些水凝胶在抗氧化和能量代谢方面发挥作用，抑制TBI后ROS-乳酸的恶性循环，从而引发继发性损伤。体外和体内测试证实，P-RT/2DG 水凝胶不存在全身副作用，并且在减少水肿、神经细胞凋亡、神经炎症和维持血脑屏障方面具有神经保护功能。因此，我们的研究为 TBI 中的新型水凝胶提供了一种潜在的治疗策略。