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嵌合抗原受体(CAR)T细胞疗法在血液系统恶性肿瘤中疗效显著,但在实体瘤应用中面临肿瘤异质性、免疫抑制微环境和在靶脱瘤毒性等挑战。合成Notch受体(synNotch)作为一种模块化的跨膜信号传导工具,通过将抗原识别与定制化的转录激活程序人工耦联,赋予T细胞整合多重信号、执行布尔逻辑运算的能力。将synNotch与CAR等效应模块结合,可构建“与”、“非”、“或”等逻辑门控回路,可实现对肿瘤微环境的精确识别与响应,极大提升CAR-T细胞的靶向特异性。本文系统综述了synNotch受体的结构演进与逻辑门控设计原理;重点阐明了其在提升细胞疗法靶向特异性、克服实体瘤抗原异质性、动态调控肿瘤微环境以及扩展至其他免疫细胞工程化领域的最新应用进展,并探讨了当前该技术在载体系统构建、受体信噪比优化等方面面临的挑战及未来的发展方向。
Chimeric antigen receptor(CAR)T-cell therapy has demonstrated remarkable efficacy in hematological malignancies;however,its application in solid tumors is confronted with significant challenges,including tumor heterogeneity,the immunosuppressive microenvironment,and on-target off-tumor toxicity.As a highly modular transmembrane signal transduction tool,the synthetic Notch(synNotch)receptor innovatively links antigen recognition with customized transcriptional activation programs,thereby empowering T cells with the capacity to integrate multiple signals and perform Boolean logic operations.By combining synNotch with effector modules such as CARs,logic-gated circuits,including AND,NOT,and OR gates,can be constructed,which enables precise discrimination of and response to the tumor microenvironment,substantially enhancing the targeting specificity of CAR-T cells.This review systematically summarizes the structural evolution of synNotch receptors and the principles of logic-gated design.Furthermore,it highlights recent advances in their application for enhancing the targeting specificity of cell-based therapies,overcoming solid tumor antigen heterogeneity,dynamically regulating the tumor microenvironment,and extending to the engineering of other immune cell types.Finally,we discuss current challenges,such as the construction of vector systems and the optimization of receptor signal-to-noise ratios,as well as future directions for this technology.
肿瘤治疗仍然是生物医学研究的一个突出领域。围绕各种化学治疗(化疗)药物和其他治疗药物的不良反应和靶向疗效的研究推动了各种药物载体的发展。这些载体聚焦于提高肿瘤部位的药物浓度,最大限度地减少全身不良反应,并改善治疗效果。在已报道的递送系统中,可注射水凝胶由于其微创的药物递送特性,已成为化疗药物体内递送的重要载体形式。文章系统地总结了可注射水凝胶的类型和特征,并进一步概括了可注射水凝胶装载药物的方式,同时深入讨论可注射水凝胶在治疗肿瘤的各种药物的递送应用。文章对原位注射水凝胶在治疗肿瘤方面存在的潜在性挑战和可能的解决方案提供了动态前瞻性的参考。可注射的水凝胶作为药物传递系统用于肿瘤治疗具有良好的发展前景。
Tumor treatment remains a prominent area of biomedical research.The researches surrounding the adversereactions and targeted efficacy of various chemotherapy drugs and other therapeutic drugs have driven the development of various drug carriers.These carriers focus on increasing drug concentration at tumor site,minimizing systemic adverse reactions,and improving treatment outcomes.In the reported delivery systems,injectable hydrogels have become an important carrier for the delivery of chemotherapeutic drugs in vivo due to their minimally invasive characteristics.This review systematically summarized the types and characteristics of injectable hydrogels,and further summarized their drug loading methods.At the same time,the application of injectable hydrogels in the delivery of various drugs for tumor treatment was discussed in depth.This review provides dynamic and prospective reference for the potential challenges and possible solutions of the in situ injectable hydrogels for tumor therapy.Injectable hydrogels as drug delivery systems are with good prospects for tumor treatment.