Huang Ri, Wang Feifei, Fu He, Qi Xinming, Xing Guozhen, Ren Jin, Cheng Liang, Meng Fenghua, Zhong Zhiyuan
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
Biomacromolecules. 2023 Nov 13;24(11):5353-5363. doi: 10.1021/acs.biomac.3c00813. Epub 2023 Oct 23.
The silencing of disease-causing genes with small interfering RNA () offers a particularly effective therapeutic strategy for different disorders; however, its clinical efficacy relies on the development of nontoxic and tissue-specific delivery vehicles. Herein, we report that bioresponsive chimaeric polymersomes (BCP) with short poly(ethylenimine) as inner shell mediate highly efficacious, sustained, and liver-specific transfection . BCP exhibited remarkable encapsulation efficiencies of (95-100%) at feeding contents of 15-25 wt %, to afford stable, small-sized (55-64 nm), and neutral-charged BCP-. -Loaded BCP (BCP-) outperformed lipofectamine counterparts and silenced 93% of mRNA in HepG2 cells at 50 nM without inducing cytotoxicity. Intriguingly, the studies using wild-type C57BL/6 mice revealed that BCP- preferentially accumulated in the liver, and a single dose of 4.5 mg/kg achieved over 90% downregulation of mRNA for at least 10 days. The systemic administration of BCP- at 4.5 mg/kg every 2 weeks or 1.5 mg/kg weekly in diet-induced obese mice could also achieve up to 80% silencing of mRNA. The liver specificity and silencing efficacy of BCP- could further be improved by decorating it with the trivalent -acetylgalactosamine (TriGalNAc) ligand. These bioresponsive and liver-specific chimaeric polymersomes provide an enabling technology for therapy of various liver-related diseases.
用小干扰RNA（siRNA）沉默致病基因，为不同疾病提供了一种特别有效的治疗策略；然而，其临床疗效依赖于无毒且组织特异性递送载体的开发。在此，我们报道以短聚乙二胺为内壳的生物响应性嵌合聚合物囊泡（BCP）介导高效、持续且肝脏特异性的siRNA转染。在15 - 25 wt%的进料含量下，BCP表现出显著的包封效率（95 - 100%），以提供稳定、小尺寸（55 - 64 nm）且带中性电荷的BCP-siRNA。负载siRNA的BCP（BCP-siRNA）优于脂质体转染试剂，在50 nM siRNA时可使HepG2细胞中93%的HNF4α mRNA沉默，且不诱导细胞毒性。有趣的是，使用野生型C57BL/6小鼠的研究表明，BCP-siRNA优先在肝脏中积累，4.5 mg/kg的单剂量可使HNF4α mRNA下调超过90%，至少持续10天。在饮食诱导肥胖的小鼠中，每2周以4.5 mg/kg或每周以1.5 mg/kg的剂量全身给药BCP-siRNA，也可使HNF4α mRNA沉默高达80%。通过用三价N-乙酰半乳糖胺（TriGalNAc）配体修饰BCP-siRNA，可进一步提高其肝脏特异性和沉默效率。这些生物响应性和肝脏特异性的嵌合聚合物囊泡为各种肝脏相关疾病的RNAi治疗提供了一项 enabling 技术。 （注：“enabling”此处暂未找到完全准确对应的简洁中文表述，保留英文）
