Tuber sinoaestivum-derived nanovesicles protect against cisplatin-induced acute liver and kidney injury in mice

Cisplatin (CP) is a highly effective chemotherapy agent, but its clinical utility is severely hampered by dose-dependent organ toxicities, particularly acute liver injury (ALI) and acute kidney injury (AKI). These toxicities often necessitate dose reductions or treatment interruptions, compromising therapeutic efficacy. Current supportive care strategies are often insufficient to fully mitigate these severe side effects, highlighting an urgent need for novel protective agents. Research into natural products and nanovesicles, such as exosome-like nanovesicles, offers a promising avenue for developing adjuvant therapies that can enhance the safety profile of CP-based chemotherapy by targeting underlying mechanisms like inflammation and oxidative stress.

This preclinical study investigated the protective effects of Tuber sinoaestivum-derived exosome-like nanovesicles (TELNs) against cisplatin-induced organ damage. Researchers established a CP-induced acute toxicity model in mice. They evaluated hepatic and renal function by measuring serum alanine aminotransferase, creatinine, and urea nitrogen levels. Histopathological examination was performed to assess tissue damage. Inflammatory cytokine levels, oxidative stress markers, and gut microbiota profiles were also analyzed using techniques like ELISA for cytokines and 16S rRNA gene sequencing for microbiota. The study aimed to identify the mechanisms by which TELNs might confer protection.

TELNs remarkably attenuated CP-induced tissue damage and dysfunction in both the liver and kidneys. Specifically, TELNs significantly reduced serum markers of organ injury, including alanine aminotransferase, creatinine, and urea nitrogen levels, and improved histopathological findings in affected tissues. Mechanistic analysis revealed that TELNs exerted their protective effects through multiple pathways. They reduced key pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, which are central mediators of inflammation in ALI and AKI. Furthermore, TELNs enhanced the antioxidant capacity of the mice, evidenced by elevated levels of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), increased GSH (glutathione), and decreased MDA (malondialdehyde), a marker of lipid peroxidation. TELNs also restored gut microbiota diversity, modulating the abundances of both beneficial and harmful bacterial species. This restoration of gut microbiota is crucial, given the established gut-liver and gut-kidney axes in toxicity.

PICRUSt analysis further indicated that TELNs influenced critical metabolic pathways, including glutathione metabolism and DNA repair, suggesting a broad impact on cellular resilience and detoxification processes.