Tea leaf-derived exosome-like nanotherapeutics retard breast tumor growth by pro-apoptosis and microbiota modulation

Abstract

While several artificial nanodrugs have been approved for clinical treatment of breast tumor, their long-term applications are restricted by unsatisfactory therapeutic outcomes, side reactions and high costs. Conversely, edible plant-derived natural nanotherapeutics (NTs) are source-widespread and cost-effective, which have been shown remarkably effective in disease treatment. Herein, we extracted and purified exosome-like NTs from tea leaves (TLNTs), which had an average diameter of 166.9 nm and a negative-charged surface of − 28.8 mV. These TLNTs contained an adequate slew of functional components such as lipids, proteins and pharmacologically active molecules. In vitro studies indicated that TLNTs were effectively internalized by breast tumor cells (4T1 cells) and caused a 2.5-fold increase in the amount of intracellular reactive oxygen species (ROS) after incubation for 8 h. The high levels of ROS triggered mitochondrial damages and arrested cell cycles, resulting in the apoptosis of tumor cells. The mouse experiments revealed that TLNTs achieved good therapeutic effects against breast tumors regardless of intravenous injection and oral administration through direct pro-apoptosis and microbiota modulation. Strikingly, the intravenous injection of TLNTs, not oral administration, yielded obvious hepatorenal toxicity and immune activation. These findings collectively demonstrate that TLNTs can be developed as a promising oral therapeutic platform for the treatment of breast cancer. Graphic Abstract

Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles

“…Betker et al [ 29 ] and Samuel et al [ 28 ] also show that orally ingested sEVs can migrate and accumulate in xenograft tumors in vivo. Other sources of sEVs studied in similar investigations are those obtained from yeast [ 28 ], beer [ 28 ], grape [ 34 ], acerola [ 33 ], ginger [ 32 ], garlic [ 35 ], tea leaves [ 36 ], and mulberry bark [ 37 ]. Yeast-, grape-, acerola-, ginger-, garlic-, tea leaves- and mulberry bark-derived sEVs showed a biodistribution pattern like that previously described for cow’s milk-derived sEVs, but beer-derived sEVs in the mouse’s organs could not be detected [ 28 ].…”

“…In global terms, the biological effect reported for FDVs is highly associated with the source of identification. However, comparing articles is challenging since different isolation methods are employed, the doses administrated are different, and several routes of administration are tested [ 36 , 64 ].…”

Engineered Exosomes as Theranostic Platforms for Cancer Treatment

“…225 Furthermore, the authors also manifested that the intravenous injection administration of TFENs induced evident hepatorenal toxicity and immune activation compared with oral administration, which showed the great potential of TFENs as oral therapeutic platforms for the treatment of breast cancer. 226 To reduce the clearance rate by the mononuclear phagocytic system, mPEG2000-TK-CP05 decorated exosomes that contain RB (photosensitizer Rose Bengal) and Dox (Doxorubicin) were constructed by Wan et al for enhanced chemo/photodynamic therapy by prolonging exosomal blood circulation and accumulation in the tumor region. These engineered exosomes were called Stealth Exo, which not only improved the accessibility and efficiency of drug delivery but also minimized the side effects of Dox and enhanced antitumor immune responses in cancer treatment.…”

“…Chen et al reported that natural exosome-like nanoplatform from tea flowers (TFENs) could promote ROS amplification to trigger mitochondrial damage in cancer cells, which are mainly responsible for the inhibition of the growth and metastasis of breast cancer . Furthermore, the authors also manifested that the intravenous injection administration of TFENs induced evident hepatorenal toxicity and immune activation compared with oral administration, which showed the great potential of TFENs as oral therapeutic platforms for the treatment of breast cancer …”

Plant-derived extracellular vesicles (PDEVs) in nanomedicine for human disease and therapeutic modalities

“…The engineered KPEVs were stably absorbed into the gastric adenocarcinoma (AGS) cells, leading to the suppression of cell viability in a dose-dependent manner [ 60 ]. Other interesting findings were the identification of exosome-like nanotherapeutics from tea flowers [ 61 ] and tea leaves [ 62 ]. The cellular experiments indicated strong cytotoxicity effects of these exosome-like nanotherapeutics against breast cancer cells in vivo and in vitro.…”