在休息和激活的T细胞中系统优化siRNA的生产性吸收ex vivo
A Kremer1, T Ryaykenen1, R A Haraszti1
1Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Germany; Gene and RNA Therapy Center (GRTC), Faculty of Medicine, University Tuebingen, Germany.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
|February 21, 2024
概括
脂类结合物输送有效地将小干扰RNA (siRNA) 输送给T细胞,即使是静止细胞,也优于增强细胞疗法的纳米粒子方法.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 生物技术是生物技术.
背景情况:
- RNA干扰 (RNAi) 疗法,特别是小干扰RNA (siRNA),为癌症免疫疗法和自身免疫性疾病治疗提供了对T细胞功能的精确控制.
- 有效和有针对性地将siRNA传递给T细胞仍然是一个重大障碍,限制了基于RNA的药物的治疗潜力.
- 当前的研究经常使用未经修改或未披露的化学修改siRNAs,需要系统的方法来优化传递途径.
研究的目的:
- 系统地比较结合物介导与纳米粒子介导的化学修饰siRNAs向T细胞的输送.
- 调查siRNA传递到激活和休息T细胞,以进行ex vivo免疫调节.
- 在各种T细胞群体中确定增强siRNA吸收和沉默活性的最佳策略.
主要方法:
- 脂类结合物,脂类纳米粒子和细胞外囊介导的完全化学修饰siRNAs的输送的比较.
- 在活化和休息初级人类T细胞中评估siRNA传递和沉默功效.
- 在多种单核免疫细胞类型 (淋巴细胞和骨髓细胞) 中评估脂质结合物输送.
主要成果:
- 在激活的T细胞中,脂类结合物介导的siRNA输送显著超过了脂类纳米粒子和细胞外膀输送.
- 首次使用脂质结合物输送实现了生产性siRNA吸收到静止T细胞中.
- 静止活动在休息的T细胞显示强烈依赖脂质结合体的身份,与激活的T细胞不同.
- 脂类结合物证明有效地将siRNA传递给所有单核免疫细胞类型,包括淋巴细胞和骨髓细胞系.
结论:
- 脂类结合物介导的输送代表了对T细胞的ex vivosiRNA输送的优越策略,包括具有挑战性的静止种群.
- 这些发现为推进基于T细胞的疗法,如CAR-T和TCR-T细胞的ex vivo调制提供了一个强大的平台.
- 了解siRNA向静止T细胞传递的特定要求,为各种临床应用中的免疫调节开辟了新的途径.
相关概念视频
02:30siRNA - Small Interfering RNAs
Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
02:15Experimental RNAi
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
02:30Small interfering RNAs (siRNA)
Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...