Wedelactone-loaded exosomes for sepsis-induced liver injury: a novel therapeutic strategy.
Yin Yanping, Zhang Lulu, Yin Yanli, Zhao Jinyi, Gong Rui, Zhou Xuan, Zhang Haiyue, Mu Fei, Wang Jingwen
Abstract
Sepsis-induced liver injury (SILI) is an important cause of death in intensive care patients, which seriously affects clinical prognosis. Wedelolactone (WEL) exhibits hepatoprotective properties, however, its clinical application is constrained by its poor solubility and insufficient targeting ability. Therefore, in this study, an innovative exosome (Exo)-based drug delivery system loaded with WEL (Exo@WEL) was constructed. The aim was to enhance the liver-targeting efficacy and therapeutic performance of WEL. Exo were extracted from the mice macrophages cell line RAW264.7 by differential centrifugation, and WEL was successfully loaded using ultrasonic incubation. Exo@WEL was characterized by TEM, particle size analysis, and NTA, confirming its structural suitability as an exogenous agent. DiR labeling revealed that Exo@WEL had a significantly enhanced liver-targeting ability compared to WEL. Safety was confirmed by HE staining test. In the SILI models, Exo@WEL showed better hepatoprotection over WEL. Beyond entinfinmtory actvity menifested y decreased ro infammatory rokines, Exo@WEL reinforced antioxidant function and efectively restained feroptosis. Importantly, pharmacological inhibition of ML385, a selective Nrf2 inhibitor, confirmed the critical regulatory role of the Nrf2 pathway in mediating these multifaceted liver protective effects. This study pioneered the development of a targeted Exo-based nanoplatform (Exo@WEL) for SILI therapy. The mechanism study has revealed a potential therapeutic strategy for inhibiting oxidative stress and ferroptosis by regulating the Nrf2/SLC7A11/GPX4 axis. This preparation provides a novel nanotherapeutic strategy that combines high efficiency and safety for the treatment of SILI. These findings also lay a theoretical foundation for the clinical translation of Exo drug delivery systems.
Key Findings
- Wedelolactone-loaded exosomes (Exo@WEL) enhance liver-targeting efficacy and therapeutic performance in sepsis-induced liver injury (SILI).
- Exo@WEL reduces inflammatory cytokines, reinforces antioxidant function, and effectively restrains ferroptosis in liver tissue.
- The Nrf2 pathway plays a critical regulatory role in mediating the liver protective effects of Exo@WEL via the Nrf2/SLC7A11/GPX4 axis.
Clinical Significance
This study introduces a novel exosome-based nanotherapeutic strategy that targets oxidative stress and ferroptosis through Nrf2 pathway modulation, offering a promising and safe treatment approach for sepsis-induced liver injury with potential for clinical translation.
Citation
Yin Yanping, Zhang Lulu, Yin Yanliet al.. Wedelactone-loaded exosomes for sepsis-induced liver injury: a novel therapeutic strategy. Drug delivery. 2026-Dec-31.