LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2024-01-25 DOI:10.1038/s41467-024-45094-5

Yonger Xue, Yuebao Zhang, Yichen Zhong, Shi Du, Xucheng Hou, Wenqing Li, Haoyuan Li, Siyu Wang, Chang Wang, Jingyue Yan, Diana D. Kang, Binbin Deng, David W. McComb, Darrell J. Irvine, Ron Weiss, Yizhou Dong

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Abstract

Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies.

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用于加速糖尿病伤口愈合的 LNP-RNA 工程脂肪干细胞

脂肪干细胞（ASCs）具有促进组织再生的能力，因此作为潜在的治疗药物备受关注。然而，它们有限的组织修复能力给实现最佳治疗效果带来了挑战。在此，我们构想了一系列脂质纳米颗粒，用于对具有持久蛋白质分泌能力的 ASCs 进行重编程，以增强组织工程和再生能力。体外研究发现，异芒硝衍生脂质纳米颗粒（DIM1T LNP）能有效地将 RNA 运送到 ASCs。使用 DIM1T LNP 共同递送自扩增 RNA（saRNA）和 E3 mRNA 复合物（saRNA 和 E3 mRNA 的组合被命名为 SEC）可调节宿主对 saRNA 的免疫反应，并促进 ASCs 中相关蛋白质的持久生成。DIM1T LNP-SEC 工程 ASCs（DS-ASCs）延长了肝细胞生长因子（HGF）和 C-X-C motif 趋化因子配体 12（CXCL12）的表达，在糖尿病皮肤伤口模型中，其伤口愈合效果优于野生型和 DIM1T LNP-mRNA 对应物。总之，这项工作表明 LNPs 是一种有效的平台，可用于设计具有更强蛋白质生成能力的 ASCs，从而加快开发基于 ASCs 的细胞疗法。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.