Bio-hybrid nanovesicles with multimodal antioxidant and immunomodulatory functions attenuate acute kidney injury

Oxidative stress, marked by a disparity between the generation of reactive oxygen species (ROS) and the body’s antioxidant defenses, is crucial in the development of acute kidney injury (AKI), where excessive ROS accumulation drives tubular epithelial cell damage and inflammatory cascades. Dysregulated inflammatory immunity further exacerbates tissue injury, highlighting the need for integrated strategies that simultaneously regulate oxidative defense and inflammatory immune activation. Given this rationale, we developed bio-hybrid nanovesicles (ES-EVs) by integrating ES NPs of epigallocatechin-3-gallate (EGCG) and selenomethionine (SeMet) into extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUMSC-EVs). In this study, ES NPs were synthesized, preserving the biological activities of EGCG and SeMet while enhancing their stability and bioavailability. Furthermore, the integration of the potent antioxidant and anti-inflammatory properties of ES NPs with the passive targeted delivery and immunomodulatory functions of hUMSC-EVs offers a promising strategy for the treatment of AKI. In vitro evaluation confirmed that ES-EVs were able to mitigate oxidative stress, protect mitochondria, inhibit apoptosis and polarize macrophages toward an anti-inflammatory phenotype, thereby preventing excessive inflammatory cascades. In vivo experiments demonstrated that ES-EVs effectively enhanced renal function, repaired damaged renal tissue and decreased apoptosis. ES-EVs aid renal function recovery by inhibiting oxidative stress, maintaining inflammatory homeostasis and reprogramming the immune microenvironment. RNA sequencing analysis demonstrated that ES-EVs can alleviate cisplatin induced oxidative stress and DNA damage, and at the same time play an anti-inflammatory role. In summary, this study has established a bionic hybrid nanovesicular with multifunctional therapeutic properties, which lays the foundation for the clinical translation of management of AKI. In this study, we engineered biohybrid nanovesicles (ES-EVs) through integration of hUMSC-EVs and EGCG-SeMet nanoparticles (ES NPs), demonstrating multimodal therapeutic efficacy against AKI via coordinated oxidative stress regulation, inflammatory homeostasis maintenance and immune microenvironment remodeling. ES-EVs offer cytoprotection by scavenging excessive intracellular ROS and support inflammatory homeostasis by regulating macrophage polarization. Notably, when compared to the individual use of ES NPs and hUMSC-EVs, the synthesized ES-EVs demonstrated a superior ability to modulate inflammation. In vivo experiments demonstrated that ES-EVs have the potential to ameliorate AKI by inhibiting the cGAS-STING signaling pathway and modulating macrophage phenotypes. To investigate the potential applications of ES-EVs, a series of flow cytometry experiments were conducted to assess their immunomodulatory effects in a murine model of AKI. The results showed that ES-EVs could not only regulate macrophage polarization, but also inhibit the transformation of DCs to a mature state and inhibit CD8 + activation. This biocompatible strategy using extracellular vesicle-natural product complexes shows promise for AKI treatment.