Hyperbranched poly(β-amino ester)s-mediated delivery of engineered Klotho mRNA rescues senescence and restores cellular homeostasis in aged and Klotho deficient iMSCs.

Syed Aqib Ali Zaidi, Haiyang Yong, Arshad Ahmed Padhiar, Abdullah Faqeer, Jingwei Song, Liangge He, Syed Saqib Ali Zaidi, Nawaz Khan, Dezhong Zhou, Guangqian Zhou

Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Medical School, Shenzhen University, Shenzhen, 518060, China.Guangdong Key Laboratory of Genomic Stability and Disease Prevention, Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen Engineering Laboratory of Regenerative Technologies for Orthopedic Diseases, Department of Medical Cell Biology and Genetics, Health Science Center, Medical School, Shenzhen University, Shenzhen, 518060, China. · pubmed

Paper

Abstract

A decline in Klotho expression is a defining feature of aging and contributes to cellular dysfunctions. Here, we developed an engineered IVT Klotho mRNA incorporating ARCA capping. Ψ-modification and poly(A) tailing, delivered using a hyperbranched poly(β-amino ester) (HPAE)-based platform to enhance intracellular delivery and translation. Using CRISPR edited KL (-/-) iPSCs and derived iMSCs, we show that loss of KL induces a robust senescent phenotype characterized by activation of p53-p21-p16 pathways, mitochondrial depolarization, elevated ROS, and altered Ca

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Research summary

The paper claims that delivering engineered Klotho mRNA can rescue senescence and restore cellular homeostasis in aged and Klotho deficient iMSCs. This research addresses a root cause of aging by targeting Klotho expression, which is linked to cellular dysfunctions associated with aging.

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