ATP-responsive mitochondrial probes for monitoring metabolic processes of glioma stem cells in a 3D model.

The metastatic cascade of cancer stem cells (CSCs) is always accompanied by elevated levels of adenosine triphosphate (ATP) as well as the alterntion of energy metabolism to support their differentiation and migration. Here we propose a 3D microfluidic tumor model coupled with an ATP-responsive mitochondrial probe (AMP) for investigation of metabolic processes of glioma stem cells (GSCs). The 3D tumor model has a middle matrix gel microchannel mimicking the extracellular matrix (ECM), which is sandwiched between a GSC culture chamber and a stimulation chamber. The AMPs consist of structure-switching ATP aptamers and triphenylphosphonium (TPP)-conjugated peptide nucleic acids (PNAs). Under TGF-ß stimulation, invasive migration of GSCs accompanied by a high ATP level and spindle mesenchymal morphologies is observed due to the epithelial-to-mesenchymal transition (EMT). Moreover, acidic stress can keep GSCs in a low-energy state, while long-term low pH stimulation screens out more malignant glioma cells. This AMP-assisted 3D microfluidic tumor model provides a tremendous opportunity for studying the biological properties of CSCs.

Microfluidic Sonication To Assemble Exosome Membrane-Coated Nanoparticles for Immune Evasion-Mediated Targeting.

Using natural membranes to coat nanoparticles (NPs) provides an efficient means to reduce the immune clearance of NPs and improve their tumor-specific targeting. However, fabrication of these drug-loaded biomimetic NPs, such as exosome membrane (EM)- or cancer cell membrane (CCM)-coated poly(lactic-co-glycolic acid) (PLGA) NPs, remains a challenging task owing to the heterogeneous nature of biomembranes and labor-intensive procedures. Herein, we report a microfluidic sonication approach to produce EM-, CCM-, and lipid-coated PLGA NPs encapsulated with imaging agents in a one-step and straightforward manner. Tumor cell-derived EM-coated PLGA NPs consisting of both endosomal and plasma membrane proteins show superior homotypic targeting as compared to CCM-PLGA NPs of similar sizes and core-shell structures in both in vitro and in vivo models. The underlying mechanism is associated with a significantly reduced uptake of EM-PLGA NPs by macrophages and peripheral blood monocytes, revealing an immune evasion-mediated targeting of EM-PLGA NPs to homologous tumors. Overall, this work illustrates the promise of using microfluidic sonication approach to fabricate biomimetic NPs for better biocompatibility and targeting efficacy.