Exosomal nanovesicles derived from Atractylodes macrocephala delivering exogenous miRNA-146a-5p for treatment of sepsis-induced acute kidney injury.

Sepsis-associated acute kidney injury (SA-AKI) is a critical complication in intensive care units (ICUs) with a high mortality rate, and current treatments lack precision. Its pathogenesis involves interconnected mechanisms such as systemic inflammation, renal microcirculatory disturbances, mitochondrial dysfunction, and metabolic reprogramming. In this study, we designed an innovative synergistic delivery system combining a natural vector with gene regulation-Atractylodes macrocephala exosome-like nanoparticles loaded with miR-146a-5p (AMEVLP@miR). The system was prepared via electroporation and evaluated in LPS-induced HK2 cells and mouse models. Results showed that the nanocomplex exhibited uniform particle size (~ 90 nm), favorable stability, and high renal-targeted accumulation. Compared with AMEVLP alone, AMEVLP@miR significantly decreased the release of IL-6, IL-1β, and TNF-α, decreased ROS levels, remedied mitochondrial membrane potential, attenuated apoptosis, and promoted macrophage polarization from an M1 to an M2 phenotype. Transcriptomic analysis revealed that AMEVLP@miR precisely regulated key targets by specifically inhibiting the NF-κB/IL-6 inflammatory axis and oxidative stress pathways, while also ameliorating intestinal microbiota imbalance. In summary, AMEVLP@miR effectively alleviates pathological damage in SA-AKI through multi-target synergistic effects, including anti-inflammatory effects being one aspect, antioxidant, and anti-apoptotic actions, as well as intestinal flora regulation. This work advances a new theoretical architecture and experimental substantiation of developing precise organ-protective strategies based on plant-derived nanocarriers combined with miRNAs.