Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)‐based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature‐sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti‐CD47 monoclonal antibodies, when incorporated into subsurface‐injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high‐grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site‐specific modification with hydrolysable “azidoester” adapters, allowing for user‐defined release profiles from the hydrogel. Hydrogel‐generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T‐cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel‐based delivery system for local protein therapeutic administration to meet diverse clinical needs.

中文翻译：

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多功能组织注射水凝胶，能够延长生物活性蛋白治疗剂的水解释放

水凝胶因其适应性强的结构、高含水量和生物相容性而广泛应用于医疗保健领域，FDA 批准的应用范围从脊髓再生到局部治疗递送。然而，临床水凝胶遇到了与治疗暴露不一致、释放窗口不可修改以及表面下聚合物插入困难相关的挑战。为了解决这些问题，我们设计了可注射的生物相容性水凝胶作为局部治疗库，利用聚乙二醇（PEG）基水凝胶，通过生物正交 SPAAC 手柄进行网络聚合和功能化。我们的水凝胶溶液以温度敏感的方式原位聚合，持久存在于组织中，并促进生物活性治疗剂在地下位置的输送。重组抗 CD47 单克隆抗体在掺入皮下注射的水凝胶溶液中时，表现出针对啮齿类动物大脑中浸润性高级别神经胶质瘤异种移植物的细胞毒活性，这证明了我们方法的有效性。为了增强凝胶的多功能性，重组蛋白货物可以使用可水解的“叠氮酯”适配器进行位点特异性修饰，从而允许用户定义水凝胶的释放曲线。水凝胶生成的小鼠 CXCL10 梯度，通过叠氮酯连接体连接到瘤内注射的水凝胶溶液，导致 CD8 的显着募集+“冷”同基因黑色素瘤模型中的 T 细胞和肿瘤生长的减弱。这项研究强调了一种高度可定制的、基于水凝胶的递送系统，用于局部蛋白质治疗给药，以满足不同的临床需求。