The
lack of safe and effective delivery across the blood-brain
barrier and the profound immune suppressive microenvironment are two
main hurdles to glioblastoma (GBM) therapies. Extracellular vesicles
(EVs) have been used as therapeutic delivery vehicles to GBM but with
limited efficacy. We hypothesized that EV delivery to GBM can be enhanced
by (i) modifying the EV surface with a brain-tumor-targeting cyclic
RGDyK peptide (RGD-EV) and (ii) using bursts of radiation for enhanced
accumulation. In addition, EVs were loaded with small interfering
RNA (siRNA) against programmed cell death ligand-1 (PD-L1) for immune
checkpoint blockade. We show that this EV-based strategy dramatically
enhanced the targeting efficiency of RGD-EV to murine GBM, while the
loaded siRNA reversed radiation-stimulated PD-L1 expression on tumor
cells and recruited tumor-associated myeloid cells, offering a synergistic
effect. The combined therapy significantly increased CD8+ cytotoxic T cells activity, halting tumor growth and prolonging
animal survival. The selected cell source for EVs isolation and the
presented functionalization strategy are suitable for large-scale
production. These results provide an EV-based therapeutic strategy
for GBM immune checkpoint therapy which can be translated to clinical
applications.
In recent years, mesenchymal stem cells (MSCs)–derived extracellular vesicles (EVs) are emerging as a potential therapeutic agent for pulmonary hypertension (PH). However, the full realization of MSCs–derived EVs therapy has been hampered by the absence of standardization in MSCs culture and the challenges of industrial scale–up. The study was to exploit an alternative replacement for MSCs using currently commercialized stem cell lines for effective targeted PH therapy. ReNcell VM—a human neural stem cell line—has been utilized here as a reliable and easily adoptable source of EVs. We first demonstrated that ReNcell-derived EVs (ReNcell-EVs) pretreatment effectively prevented Su/Hx (SU5416/hypoxia)–induced PH in mice. Then for targeted therapy, we conjugated ReNcell-EVs with CAR (CARSKNKDC) peptide (CAR-EVs)—a peptide identified to specifically target hypertensive pulmonary arteries, by bio-orthogonal chemistry. Intravenous administration of CAR-EVs selectively targeted hypertensive pulmonary artery lesions especially pulmonary artery smooth muscle cells. Moreover, compared with unmodified ReNcell-EVs, CAR-EVs treatment significantly improved therapeutic effect in reversing Su/Hx-induced PH in mice. Mechanistically, ReNcell-EVs inhibited hypoxia-induced proliferation, migration, and phenotype switch of pulmonary artery smooth muscle cells, at least in part, via the delivery of its endogenous highly expressed miRNAs, let-7b-5p, miR-92b-3p, and miR-100-5p. In addition, we also found that ReNcell-EVs inhibited hypoxia-induced cell apoptosis and endothelial-mesenchymal transition in human microvascular endothelial cells. Taken together, our results provide an alternative to MSCs-derived EVs–based PH therapy via using ReNcell as a reliable source of EVs. Particularly, our CAR-conjugated EVs may serve as a novel drug carrier that enhances the specificity and efficiency of drug delivery for effective PH-targeted therapy.
Shuttling various bioactive substances across the blood−brain barrier (BBB) bidirectionally, extracellular vesicles (EVs) have been opening new frontiers for the diagnosis and therapy of central nervous system (CNS) diseases. However, clinical translation of EV-based theranostics remains challenging due to difficulties in effective EV engineering for superior imaging/ therapeutic potential, ultrasensitive EV detection for small sample volume, as well as scale-up and standardized EV production. In the past decade, continuous advancement in nanotechnology provided extensive concepts and strategies for EV engineering and analysis, which inspired the application of EVs for CNS diseases. Here we will review the existing types of EV−nanomaterial hybrid systems with improved diagnostic and therapeutic efficacy for CNS diseases. A summary of recent progress in the incorporation of nanomaterials and nanostructures in EV production, separation, and analysis will also be provided. Moreover, the convergence between nanotechnology and microfluidics for integrated EV engineering and liquid biopsy of CNS diseases will be discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.