光感受器靶向细胞外囊泡介导的 Cul7 siRNA 输送用于视网膜变性治疗

IF 12.4 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Theranostics Pub Date : 2024-08-12 DOI:10.7150/thno.99484

Dong Guo, Yuntong Sun, Junqi Wu, Linchao Ding, Yiwen Jiang, Yadong Xue, Yongjun Ma, Fengtian Sun

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引用次数: 0

摘要

理由光感受器缺失是视网膜变性（RD）的主要病理特征，但治疗策略有限。RNA 干扰（RNAi）已成为再生医学中一种前景广阔的基因治疗方法。然而，将RNAi疗法转移到感光细胞以及缺乏有效的治疗靶点仍然是治疗RD的主要挑战：本研究利用锚定肽CP05制备了与光感受器结合肽MH42（PEVsMH42）共轭的光感受器源性细胞外囊泡（PEVs）。转录组测序被用于研究 RD 的潜在治疗靶点。然后，我们通过电穿孔将 PEVsMH42 与特异性小干扰 RNAs（siRNAs）结合，并评估了它们在 N-甲基-N-亚硝基脲（MNU）诱导的 RD 小鼠和 Pde6βrd1/rd1 突变小鼠中的疗效：静脉注射后，PEVsMH42在光感受器中选择性蓄积。Cullin-7（Cul7）被确定为 RD 的新型治疗靶点。利用已建立的 PEVsMH42 的优势，靶向 Cul7 的 siRNAs（siCul7）被有效地传递到光感受器，从而阻断了 Cul7 的表达。此外，在MNU诱导的小鼠模型和Pde6βrd1/rd1突变小鼠模型中，抑制Cul7能有效保护光感受器，缓解RD。从机理上讲，PEVsMH42加载siCul7（PEVsMH42-siCul7）诱导的Cul7下调是阻止Cul7介导的谷胱甘肽过氧化物酶4（Gpx4）泛素化和降解，从而抑制光感受器铁突变的原因：综上所述，PEVsMH42-siCul7通过抑制Cul7诱导的Gpx4泛素化，减轻了感光细胞的铁突变，从而治疗RD。我们的研究开发了一个基于PEVs的光感受器靶向递送平台，并强调了PEVsMH42-siCul7作为RD有效治疗药物的潜力。

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Photoreceptor-targeted extracellular vesicles-mediated delivery of Cul7 siRNA for retinal degeneration therapy

Rationale: Photoreceptor loss is a primary pathological feature of retinal degeneration (RD) with limited treatment strategies. RNA interference (RNAi) has emerged as a promising method of gene therapy in regenerative medicine. However, the transfer of RNAi therapeutics to photoreceptors and the deficiency of effective therapeutic targets are still major challenges in the treatment of RD./nMethods: In this study, photoreceptor-derived extracellular vesicles (PEVs) conjugated with photoreceptor-binding peptide MH42 (PEVs^MH42) were prepared using the anchoring peptide CP05. Transcriptome sequencing was applied to investigate the potential therapeutic target of RD. We then engineered PEVs^MH42 with specific small-interfering RNAs (siRNAs) through electroporation and evaluated their therapeutic efficacy in N-methyl-N-nitrosourea (MNU)-induced RD mice and Pde6β^rd1/rd1 mutant mice./nResults: PEVs^MH42 were selectively accumulated in photoreceptors after intravitreal injection. Cullin-7 (Cul7) was identified as a novel therapeutic target of RD. Taking advantage of the established PEVs^MH42, siRNAs targeting Cul7 (siCul7) were efficiently delivered to photoreceptors and consequently blocked the expression of Cul7. Moreover, suppression of Cul7 effectively protected photoreceptors to alleviate RD both in MNU-induced mouse model and Pde6β^rd1/rd1 mutant mouse model. Mechanistically, PEVs^MH42 loaded with siCul7 (PEVs^MH42-siCul7)-induced Cul7 downregulation was responsible for preventing Cul7-mediated glutathione peroxidase 4 (Gpx4) ubiquitination and degradation, resulting in the inhibition of photoreceptor ferroptosis./nConclusions: In summary, PEVs^MH42-siCul7 attenuate photoreceptor ferroptosis to treat RD by inhibiting Cul7-induced ubiquitination of Gpx4. Our study develops a PEVs-based platform for photoreceptor-targeted delivery and highlights the potential of PEVs^MH42-siCul7 as effective therapeutics for RD.

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来源期刊

Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

25.40

自引率

1.60%

发文量

433

审稿时长

1 months

期刊介绍： Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.