Abstract: TH-PO0654
Endogenous Extracellular Vesicle Engineering Delivers HNF4α mRNA to Attenuate Cisplatin-Induced Acute Kidney and Liver Injury
Session Information
- AKI: Mechanisms - Inflammation and Repair
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Author
- Yang, Hong-bin, Southeast University Zhongda Hospital, Nanjing, Jiangsu, China
Background
Acute kidney injury (AKI), particularly when accompanied by hepatic injury, remains a major clinical challenge due to limited tissue-directed gene delivery strategies. Hepatocyte nuclear factor 4α (HNF4α), a key regulator of metabolic homeostasis and epithelial integrity, has shown protective potential in both renal and hepatic injury. However, efficient and organ-directed delivery of HNF4α mRNA remains challenging. In this study, we developed an in vivo extracellular vesicle (EV) engineering strategy to generate endogenous HNF4α mRNA-loaded EVs for hepato–renal protection.
Methods
C/D box–modified Hnf4α mRNA and an engineered EV scaffold protein, EN-144, containing an L7Ae RNA-binding domain, were co-delivered into hepatocytes to promote selective incorporation of Hnf4α mRNA into newly generated EVs in vivo. In a C57BL/6 mouse model of cisplatin-induced AKI with hepatic injury, endogenous EVs were isolated and evaluated for uptake efficiency in HK-2 cells. Therapeutic efficacy was assessed by evaluating renal and hepatic injury through histological analysis, serum biochemical markers, inflammatory mediators, tubular injury markers, and apoptosis-related assays.
Results
The engineered system efficiently loaded Hnf4α mRNA into endogenous EVs and enabled systemic delivery of functional EV-Hnf4α mRNA. In cellular uptake assays, engineered EVs showed 3.67-fold greater uptake by renal tubular epithelial cells than unmodified EVs (P < 0.05). EV-Hnf4α mRNA significantly increased HNF4α expression by 1.43-fold in kidney tissue and 2.08-fold in liver tissue, respectively (P < 0.05). It also improved survival by 20% in C57BL/6 mice (n = 5) and attenuated cisplatin-induced renal and hepatic injury. Compared with cisplatin-treated controls, EV-Hnf4α mRNA significantly reduced serum creatinine, blood urea nitrogen, and AST levels by 9.87%, 24.48%, and 17.23%, respectively (all P < 0.05). These effects were accompanied by suppression of TNF-α–associated inflammatory signaling, with KIM-1 and NGAL expression levels reduced by 50.2% and 39.4%, respectively (P < 0.05).
Conclusion
In vivo EV engineering enables endogenous generation of HNF4α mRNA-loaded EVs and promotes hepato–renal protection in cisplatin-induced AKI with hepatic injury. This platform provides a biocompatible and organ-directed strategy for mRNA therapy in AKI complicated by systemic organ injury.
Acknowledgment
The authors thank all members of the research team for their technical support and constructive discussions.
Funding
- Government Support – Non-U.S.