Simultaneous Targeting of Tumor Cells and Tumor-Associated Macrophages To Reprogram Glioblastoma Using Trypsinized Extracellular Vesicles Carrying Tumor Suppressive MicroRNA.

in Nano letters by Grace H Nguyen, MinHye Noh, Jin Muk Kang, Alexandra A Miller, Minxin Huang, Jiyeon Kim, Jeong-Yeon Lee, Sangwoon Chung, Hongyu Wang, George A Calin, Cynthia Ju, Holger K Eltzschig, Yeshavanth Banasavadi-Siddegowda, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee

TLDR

  • The study demonstrates the therapeutic potential of miRNA-loaded trypsinized EVs for glioblastoma treatment, offering a novel and more effective approach by selectively targeting tumor cells and tumor-associated macrophages.

Abstract

Glioblastoma (GBM) remains difficult to treat due to poor drug delivery across the blood-brain barrier and an immunosuppressive tumor microenvironment (TME). Tumor-suppressive microRNAs (miRNAs) offer a promising strategy to reprogram both tumor cells and the TME, but inefficient delivery systems limit their clinical application. We previously reported that tumor-suppressive miR-138 regresses tumor growth in preclinical GBM models. Here, we demonstrate that trypsin digestion of extracellular vesicles (EVs) enhances labeling efficiency with folate (FA), enhancing selective targeting of folate receptor (FR)-positive GBM cells and enabling simultaneous targeting of tumor-associated macrophages (TAMs). FA-labeled trypsinized EVs (tEVs) loaded with miR-138 inhibit tumor growth, depolarize TAMs, and enhance antitumor immunity. This study represents the first preclinical attempt to modulate tumor cells and innate immunity via miRNA-loaded tEVs, offering a novel and more effective therapeutic approach to GBM treatment.

Overview

  • The study aimed to develop a novel therapeutic approach for glioblastoma (GBM) by using tumor-suppressive microRNAs (miRNAs) loaded into extracellular vesicles (EVs) and enhancing their selective targeting of tumor cells.
  • The researchers used trypsin digestion to enhance the labeling efficiency of EVs with folate (FA), allowing for selective targeting of folate receptor (FR)-positive GBM cells and tumor-associated macrophages (TAMs).
  • The primary objective of the study was to investigate the therapeutic potential of miRNA-loaded trypsinized EVs (tEVs) in preclinical GBM models, with a focus on inhibition of tumor growth, reprogramming of TAMs, and enhancement of antitumor immunity.

Comparative Analysis & Findings

  • The study found that FA-labeled tEVs loaded with miR-138 efficiently targeted FR-positive GBM cells and TAMs, leading to inhibition of tumor growth and reprogramming of TAMs.
  • In comparison to non-trypsinized EVs, trypsinized EVs showed enhanced labeling efficiency and selective targeting of tumor cells and TAMs.
  • The study demonstrated that miR-138-loaded tEVs depolarized TAMs, enhanced antitumor immunity, and inhibited tumor growth in preclinical GBM models, suggesting a promising therapeutic approach for GBM treatment.

Implications and Future Directions

  • The study provides a novel approach to modulate tumor cells and innate immunity in GBM treatment, offering a potential revolutionary therapeutic option.
  • Future studies should investigate the scalability and translational potential of this approach in human clinical trials, as well as the optimal miRNA cargo and EV composition for efficient delivery and targeting.
  • The enhanced labeling efficiency and selective targeting of tumor cells and TAMs achieved by trypsinized EVs could be applied to other cancer types, potentially opening up new avenues for cancer treatment and research.
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