AbstractNucleic acid delivery offers tremendous potential for the treatment of acquired and hereditary diseases. Despite limited successes, the use of nucleic acid therapies has been hampered by the lack of safe and efficient delivery approaches. To address this challenge, Epps, Sullivan, and coworkers developed a new nucleic acid delivery framework predicated on a photo-responsive cationic block copolymer (BCP) that enabled tunable nucleic acid binding and precise spatiotemporal control over gene expression. This innovative platform, in which the polymer moieties directly responsible for nucleic acid complexation could be cleaved from the polymer upon photo-stimulation, significantly enhancing nucleic acid release. Furthermore, temporal control over polyplex disassembly facilitated the development of a simple, and potentially universal, kinetic modeling scheme for intracellular small interfering RNA (siRNA), messenger RNA, and protein concentrations, and that model was quantitatively validated using various genes across several animal cell lines and human primary cells. This versatile BCP-based framework easily accommodated: anionic excipients that increased siRNA potency by ~200% (on a per mass basis) over comparable polyplex systems; quantum dots that unlocked theranostic applications without impacting silencing performance; and small-molecule lipid co-formulations that enhanced transfection in human primary cells. Altogether, the system described herein shows great promise for the clinical translation of gene therapeutics.A new nucleic acid delivery framework, predicated on a photo-responsive cationic block copolymer (BCP), was used to precisely tune nucleic acid binding and provide spatiotemporal control over gene expression. This innovative platform leveraged a macromolecular design in which the polymer moieties directly responsible for nucleic acid complexation were cleaved from the polymer upon photo-stimulation, significantly enhancing nucleic acid release. Temporal control over polyplex disassembly facilitated development of a potentially universal, kinetic modeling scheme for gene silencing. Furthermore, this versatile BCP-based framework easily accommodated anionic excipients and quantum dot imaging constructs.

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用于可调核酸递送和有效基因沉默的稳健光响应嵌段共聚物框架的设计和开发

摘要核酸递送为治疗获得性和遗传性疾病提供了巨大的潜力。尽管取得了有限的成功，但由于缺乏安全有效的递送方法，核酸疗法的使用受到了阻碍。为了应对这一挑战，Epps、Sullivan 和同事开发了一种新的核酸递送框架，该框架基于光响应阳离子嵌段共聚物 (BCP)，该框架能够实现可调节的核酸结合和对基因表达的精确时空控制。在这个创新平台中，直接负责核酸复合的聚合物部分可以在光刺激下从聚合物上裂解下来，从而显着增强核酸的释放。此外，对 polyplex 分解的时间控制促进了一种简单且可能通用的、细胞内小干扰 RNA (siRNA)、信使 RNA 和蛋白质浓度的动力学建模方案，并且该模型使用多种动物细胞系和人类原代细胞中的各种基因进行了定量验证。这种基于 BCP 的多功能框架很容易适应： 与可比的复合系统相比，将 siRNA 效力提高约 200%（按质量计）的阴离子赋形剂；量子点在不影响沉默性能的情况下解锁了治疗诊断应用程序；和小分子脂质复合制剂，可增强人类原代细胞的转染。总而言之，本文描述的系统对基因治疗的临床转化显示出巨大的希望。 一种新的核酸递送框架，基于光响应阳离子嵌段共聚物（BCP），用于精确调整核酸结合并提供对基因表达的时空控制。这一创新平台利用了大分子设计，其中直接负责核酸复合的聚合物部分在光刺激下从聚合物上裂解下来，显着增强了核酸释放。对复合物分解的时间控制促进了基因沉默的潜在通用动力学建模方案的开发。此外，这种基于 BCP 的多功能框架可轻松容纳阴离子赋形剂和量子点成像结构。显着增强核酸释放。对复合体分解的时间控制促进了基因沉默的潜在通用动力学建模方案的开发。此外，这种基于 BCP 的多功能框架可轻松容纳阴离子赋形剂和量子点成像结构。显着增强核酸释放。对复合体分解的时间控制促进了基因沉默的潜在通用动力学建模方案的开发。此外，这种基于 BCP 的多功能框架可轻松容纳阴离子赋形剂和量子点成像结构。