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

Authors

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

Publication Date

5-21-2025

Journal

Nano Letters

DOI

10.1021/acs.nanolett.5c01897

PMID

40357748

PMCID

PMC12398074

PubMedCentral® Posted Date

8-31-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Glioblastoma, MicroRNAs, Extracellular Vesicles, Humans, Tumor Microenvironment, Animals, Mice, Tumor-Associated Macrophages, Cell Line, Tumor, Brain Neoplasms, Folic Acid, Glioblastoma (GBM), Tumor-associated macrophages (TAMs), Extracellular vesicle (EV), microRNA-138 (miR-138), Trypsin, Tumor microenvironment (TME)

Published Open-Access

yes

Recommended Citation

Nguyen, Grace H; Noh, MinHye; Kang, Jin Muk; et al., "Simultaneous Targeting of Tumor Cells and Tumor-Associated Macrophages To Reprogram Glioblastoma Using Trypsinized Extracellular Vesicles Carrying Tumor Suppressive MicroRNA" (2025). Faculty, Staff and Student Publications. 5099.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5099