State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha 410082 P.R. China.
State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, Hunan University, Changsha 410082 P.R. China.
Acta Biomater. 2021 Aug;130:138-148. doi: 10.1016/j.actbio.2021.05.027. Epub 2021 May 31.
Precise delivery of therapeutic protein drugs that specifically modulate desired cellular responses is critical in clinical practice. However, the spatiotemporal regulation of protein drugs release to manipulate the target cell population in vivo remains a huge challenge. Herein, we have rationally developed an injectable and Near-infrared (NIR) light-responsive MXene-hydrogel composed of TiC, agarose, and protein that enables flexibly and precisely control the release profile of protein drugs to modulate cellular behaviors with high spatiotemporal precision remotely. As a proof-of-concept study, we preloaded hepatic growth factor (HGF) into the MXene@hydrogel (MXene@agarose/HGF) to activate the c-Met-mediated signaling by NIR light. We demonstrated NIR light-instructed cell diffusion, migration, and proliferation at the user-defined localization, further promoting angiogenesis and wound healing in vivo. Our approach's versatility was validated by preloading tumor necrotic factor-α (TNF-α) into the composite hydrogel (MXene@agarose/TNF-α) to promote the pro-apoptotic signaling pathway, achieving the NIR light-induced programmed cell deaths (PCD) of tumor spheroids. Taking advantage of the deep-tissue penetrative NIR light, we could eradicate the deep-seated tumors in a xenograft model exogenously. Therefore, the proposed MXene-hydrogel provides the impetus for developing therapeutic synthetic materials for light-controlled drug release under thick tissue, which will find promising applications in regenerative medicine and tumor therapy. STATEMENT OF SIGNIFICANCE: Current stimuli-responsive hydrogels for therapeutic proteins delivery mainly depend on self-degradation, passive diffusion, or the responsiveness to cues relevant to diseases. However, it remains challenging to spatiotemporally deliver protein-based drugs to manipulate the target cell population in vivo in an "on-demand" manner. Therefore, we have rationally constructed an injectable and Near-infrared (NIR) light-responsive composite hydrogel by embedding TiC MXene and protein drugs within an agarose hydrogel to enable the remote control of protein drugs delivery with high spatiotemporal precision. The NIR light-controlled release of the growth factor or cytokine has been carried out to regulate receptor-mediated cellular behaviors under deep tissue for skin wound healing or cancer therapy. This system will provide the potential for precision medicine through the development of intelligent drug delivery systems.
精准递送具有特定细胞调节功能的治疗性蛋白药物在临床实践中至关重要。然而，调控蛋白药物释放以在体内操纵目标细胞群体的时空仍是一个巨大的挑战。在此，我们合理设计了一种可注射的近红外（NIR）光响应性 MXene-水凝胶，由 TiC、琼脂糖和蛋白质组成，可灵活、精确地控制蛋白药物的释放曲线，从而实现对细胞行为的高时空精度远程调控。作为概念验证研究，我们将肝细胞生长因子（HGF）预装载到 MXene@水凝胶（MXene@琼脂糖/HGF）中，通过 NIR 光激活 c-Met 介导的信号通路。我们证明了 NIR 光引导的细胞在预定位置扩散、迁移和增殖，进一步促进了体内的血管生成和伤口愈合。通过将肿瘤坏死因子-α（TNF-α）预装载到复合水凝胶（MXene@琼脂糖/TNF-α）中以促进促凋亡信号通路，我们验证了我们方法的多功能性，实现了 NIR 光诱导的肿瘤球程序性细胞死亡（PCD）。利用深部组织穿透性的 NIR 光，我们可以在异种移植模型中外源性消除深部肿瘤。因此，所提出的 MXene-水凝胶为开发用于厚组织中光控药物释放的治疗性合成材料提供了动力，这将在再生医学和肿瘤治疗中具有广阔的应用前景。
目前用于治疗性蛋白药物递送的刺激响应性水凝胶主要依赖于自降解、被动扩散或对与疾病相关的信号的响应。然而，以“按需”方式在体内时空递送达药物仍具有挑战性。因此，我们通过将 TiC MXene 和蛋白药物嵌入琼脂糖水凝胶中，合理构建了一种可注射的近红外（NIR）光响应性复合水凝胶，从而能够以高时空精度远程控制蛋白药物的递送。已经进行了生长因子或细胞因子的 NIR 光控释放，以调节深层组织中受受体介导的细胞行为，用于皮肤伤口愈合或癌症治疗。该系统通过开发智能药物递送系统，为精准医学提供了潜力。
