新型纳米聚合物 RNA 疗法可使人类糖尿病性角膜伤口愈合和上皮干细胞正常化。
Novel nanopolymer RNA therapeutics normalize human diabetic corneal wound healing and epithelial stem cells.
机构信息
Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
出版信息
Nanomedicine. 2021 Feb;32:102332. doi: 10.1016/j.nano.2020.102332. Epub 2020 Nov 10.
Human diabetic corneas develop delayed wound healing, epithelial stem cell dysfunction, recurrent erosions, and keratitis. Adenoviral gene therapy modulating c-Met, cathepsin F and MMP-10 normalized wound healing and epithelial stem cells in organ-cultured diabetic corneas but showed toxicity in stem cell-enriched cultured limbal epithelial cells (LECs). For a safer treatment, we engineered a novel nanobiopolymer (NBC) that carried antisense oligonucleotide (AON) RNA therapeutics suppressing cathepsin F or MMP-10, and miR-409-3p that inhibits c-Met. NBC was internalized by LECs through transferrin receptor (TfR)-mediated endocytosis, inhibited cathepsin F or MMP-10 and upregulated c-Met. Non-toxic NBC modulating c-Met and cathepsin F accelerated wound healing in diabetic LECs and organ-cultured corneas vs. control NBC. NBC treatment normalized levels of stem cell markers (keratins 15 and 17, ABCG2, and ΔNp63), and signaling mediators (p-EGFR, p-Akt and p-p38). Non-toxic nano RNA therapeutics thus present a safe alternative to viral gene therapy for normalizing diabetic corneal cells.
人糖尿病角膜发展延迟伤口愈合，上皮干细胞功能障碍，反复糜烂和角膜炎。腺病毒基因治疗调节 c-Met、组织蛋白酶 F 和 MMP-10 可使器官培养的糖尿病角膜中的伤口愈合和上皮干细胞正常化，但在富含干细胞的培养的角膜缘上皮细胞 (LEC) 中显示出毒性。为了更安全的治疗，我们设计了一种新型纳米生物聚合物 (NBC)，它携带抑制组织蛋白酶 F 或 MMP-10 的反义寡核苷酸 (AON) RNA 治疗药物和抑制 c-Met 的 miR-409-3p。NBC 通过转铁蛋白受体 (TfR) 介导的内吞作用被 LEC 内化，抑制组织蛋白酶 F 或 MMP-10 并上调 c-Met。无毒的 NBC 调节 c-Met 和组织蛋白酶 F 可加速糖尿病 LEC 和器官培养角膜中的伤口愈合，与对照 NBC 相比。NBC 治疗可使干细胞标志物（角蛋白 15 和 17、ABCG2 和 ΔNp63）和信号转导介质（p-EGFR、p-Akt 和 p-p38）的水平正常化。因此，无毒纳米 RNA 治疗为正常化糖尿病角膜细胞提供了一种替代病毒基因治疗的安全方法。
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