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[140] bioRxiv, 2024.05. 06.592543

Digital Profiling of Tumor Extracellular Vesicle-associated RNAs Directly from Unprocessed Blood Plasma

Elizabeth Maria Clarissa, Sumit Kumar, Juhee Park, Mamata Karmacharya, In-Jae Oh, Mi-Hyun Kim, Jeong-Seon Ryu, Yoon-Kyoung Cho

Tumor-derived extracellular vesicle (tEV)-associated RNAs are promising diagnostic biomarkers, but their clinical use is limited by the rarity of tEVs. EV-CLIP, a sensitive droplet-based digital method, addresses this by profiling EV RNA through fusion with charged liposomes (CLIPs) on a microfluidic chip. This method offers high sensitivity and selectivity for EV-derived miRNAs and mRNAs using minimal plasma volume (20 µL), without prior EV isolation or RNA preparation. In a study of 83 patient samples, EV-CLIP detected EGFR mutations with high accuracy, and its effectiveness in serial monitoring during chemotherapy underscores its potential for precise quantification of rare EV subpopulations, aiding in the exploration of single EV RNA content and understanding diverse EV populations in various diseases.

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[139] Small, 2311071

The Role of Extracellular Vesicles in the Treatment of Prostate Cancer

Cong Hu, Qi Chen, Tianyang Wu, Xinxing Du, Yanhao Dong, Zehong Peng, Wei Xue, Vijaya Sunkara*, Yoon‐Kyoung Cho*, Liang Dong*

Prostate cancer (PCa) is a growing public health concern among elderly men, with current treatments often failing to provide long-lasting responses, especially in advanced cases. Extracellular vesicles (EVs), which carry various biomolecules, have shown significant potential in diagnostics and therapeutics over the past decade. EV-based liquid biopsies offer non-invasive biomarkers for guiding treatment decisions and staging patients. They also play critical roles in tumor progression processes like proliferation, metastasis, and drug resistance. Furthermore, EVs are promising drug carriers, with both natural and engineered EVs facilitating new treatment modalities. This review highlights recent advancements in EV therapies and their potential as innovative interventions for PCa.

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[138] Cancer Science, 115, 5, 1602-1610 (2024)

Alix‐normalized exosomal programmed death‐ligand 1 analysis in urine enables precision monitoring of urothelial cancer

Hyun‐Kyung Woo, Juhee Park, Kyung Hwan Kim, Ja Yoon Ku, Hong Koo Ha, Yoon‐Kyoung Cho

Anti-PD-L1 antibody therapies are effective for metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers, but urine variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio for normalization, as Alix is less affected by heterogeneity. EVs were isolated with ExoDisc and analyzed using ExoView and on-disc ELISA. In 15 urothelial cancer patients, the Alix signal was consistent, while tetraspanin intensity varied. On-disc ELISA outperformed standard plate ELISA in detecting exosomal PD-L1. Normalizing PD-L1 with Alix offers a reliable method for monitoring patient status and detecting exosomal PD-L1 in urine samples.

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[137] Lab Chip, 24, 1541-1541 (2024)

The evolution of miniaturization, automation, and integration – a new scope for Lab on a Chip

Aaron Wheeler, Jean-Christophe Baret, Yoon-Kyoung Cho, Amy Herr, Xingyu Jiang, Séverine Le Gac, Hang Lu, Manabu Tokeshi, Hongkai Wu, Rebecca Garton, Alice Smallwood, David Lake, Harpal Minhas

... Today, Lab on a Chip has transformed into a unique forum for multidisciplinary work where miniaturization, automation and integration demonstrate a profound impact across diverse fields and has become the journal to publish work in this area relating to biology, medicine, materials science, environmental monitoring, energy, and so much more. Microfluidic, nanofluidic and miniaturized systems now span a long list of disciplines, and our community encompasses more researchers than ever before, including engineers, chemists, biologists, biomedical scientists, physicists, materials scientists, and many others across academia, industry, and clinical practices....

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[136] Journal of extracellular vesicles 13 (2), e12404

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year‐on‐year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non‐vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’,...

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[135] Lab Chip, 24, 2069-2079 (2024)

Tonicity-induced cargo loading into extracellular vesicles

Chaeeun Lee‡, Sumit Kumar‡, Juhee Park, Yongjun Choi, Elizabeth Maria Clarissa, and Yoon-Kyoung Cho*

A key challenge in using extracellular vesicles (EVs) for drug delivery is controlling membrane permeability without compromising their integrity. A new method, utilizing tonicity control (TC) on a lab-on-a-disc platform, addresses this by using a hypotonic solution to temporarily permeabilize the EV membrane for cargo loading, followed by isotonic washing to reseal it. This technique effectively loads various cargos, such as doxorubicin, ssDNA, and miRNA, with significantly higher yields than traditional methods like sonication or extrusion. Intracellular assessments of miRNA-497 and doxorubicin-loaded EVs confirmed the superior performance of TC-prepared EVs, highlighting their potential for developing novel exosome-based therapeutic systems for clinical applications.

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[134] ACS Applied Materials & Interfaces, 2024

Exosome Precipitation by Ionic Strength Modulation: ExoPRISM

Vijaya Sunkara, Juhee Park, Jiyun Han, Jonathan Sabaté Del Río, Hyun-Ju Cho, In-Jae Oh, Yoon-Kyoung Cho*

Here, we present EV precipitation by ionic strength modulation (ExoPRISM), a simple, low-cost, user-friendly, and readily adaptable approach for separating EVs in high yields without compromising their biological functions. Adding an electrolyte solution to blood plasma in small increments generates the sequential precipitation of proteins and EVs, allowing for fractional separation of EVs using low-speed centrifugation. The coprecipitated electrolytes are easily washed away, and the entire EV separation and washing process takes less than an hour. This approach successfully separates EVs from a broad range of volumes and types of biological fluids, including culture medium, urine, plasma, and serum, showing promise as a robust tool for next-generation liquid biopsies and regenerative medicine.

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[133] Advanced Healthcare Materials, 2023,

Platelet Membrane-Enclosed Bioorthogonal Catalysis for Combating Dental Caries

Mamata Karmacharya, Sumit Kumar,* Yoon Jeong Choi, Yoon-Kyoung Cho*

"bind and kill" strategy utilizing a biologically interfaced nanoreactor with platelet membrane-coated surfaces is introduced for synthesizing an antimicrobial drug through biorthogonal chemistry. The nanoreactor exploits the diverse functional proteins found in human platelets, enabling selective binding to a broad range of bacteria and effectively eliminate pathogenic biofilms formed on human teeth while maintaining excellent biocompatibility.

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[132] Neoplasia, 42, 100906, 2023

Nuclear morphology predicts cell survival to cisplatin chemotherapy

Chi-Ju Kim*, Anna LK Gonye, Kevin Truskowski, Cheng-Fan Lee, Yoon-Kyoung Cho, Robert H Austin, Kenneth J Pienta, Sarah R Amend*

Chemotherapy resistance is a major factor contributing to cancer-related deaths. While researchers have studied the molecular mechanisms of resistance, less is known about the cell biology of cancer cells surviving chemotherapy. Here, we focus on prostate cancer cells treated with cisplatin and found that surviving cells grew larger, had larger nuclei, and employed efficient DNA damage repair. These cells also exhibited distinct nucleolar features and increased ribosomal RNA levels. This suggests that after chemotherapy, most cells with severe DNA damage die, while a minority adapt to a pro-survival state known as the polyaneuploid cancer cell (PACC) state. Understanding these characteristics is crucial for combating cancer resistance and recurrence.

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[131] Front. Immunol., 14 (2023)

A machine learning approach to discover migration modes and transition dynamics of heterogeneous dendritic cells

Taegeun Song, Yongjun Choi, Jae-Hyung Jeon* and Yoon-Kyoung Cho*

Dendritic cells (DCs) are responsible for initiating and controlling immune responses and exhibit a heterogeneous and dynamic migratory behavior that is important for their function. We used unsupervised machine learning to analyze long-term cell migration trajectories and identified three distinct migratory modes: slow-diffusive, slow-persistent, and fast-persistent. We found that the distribution and dynamic transitions of these modes are related to the maturation status of the DCs, with immature DCs exhibiting more frequent mode changes than mature DCs. Additionally, we observed that immature DCs follow a unicyclic transition from diffusive to persistent motility, while mature DCs show no directionality in their transitions. The study highlights the complexity of biological motility and the potential of machine learning to provide new insights into this process.

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[130] J. Funct. Biomater. 14(2), 117 (2023)

Tuning the Extracellular Vesicles Membrane through Fusion for Biomedical Applications

Mamata Karmacharya, Sumit Kumar*, Yoon-Kyoung Cho*

EVs have a high loading capacity, bio-compatibility, and stability, making them ideal for producing effective drugs and diagnostics. The unique properties of fused EVs and the crucial design and development procedures that are necessary to realize their potential as drug carriers and diagnostic tools are examined. The promise of EVs in various stages of disease management highlights their potential role in future healthcare.

Invited review
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[129] Biosensors and Bioelectronics, 224, 115057, (2023)

Integrated technologies for continuous monitoring of organs-on-chips: Current challenges and potential solutions

Jonathan Sabaté del Río, Jooyoung Ro , Heejeong Yoon, Tae-Eun Park*, Yoon-Kyoung Cho*

Organs-on-chips (OoCs) are biomimetic in vitro systems based on microfluidic cell cultures that recapitulate the in vivo physicochemical microenvironments and the physiologies and key functional units of specific human organs. Continuous monitoring of important quality parameters of OoCs via a label-free, non-destructive, reliable, high-throughput, and multiplex method is critical for assessing the conditions of these systems and generating relevant analytical data; moreover, elaboration of quality predictive models is required for clinical trials of OoCs. In this review, we describe recent efforts to integrate biosensing technologies into OoCs for monitoring the physiologies, functions, and physicochemical microenvironments of OoCs. Furthermore, we present potential alternative solutions to current challenges and future directions for the application of artificial intelligence in the development of OoCs and cyber-physical systems.

Invited review
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[128] Small, 19, 2202962 [2023]

Bridging the Gap between Nonliving Matter and Cellular Life

Sumit Kumar,Mamata Karmacharya,Yoon-Kyoung Cho*

Though synthetic micro or nanoreactors have been used to mimic life-like functions and to learn about the fundamental biology of natural cells, constructing a life-like structure out of non-living building blocks remains a considerable challenge. In this review, we focus on hybrid approaches that use both natural and synthetic materials to mimic and interface with biological systems. Using hybrid vesicle micro or nanoreactors, bioinspired life-like functions such as chemical compartments, cascade signaling, energy generation, growth, replication, and environmental adaptation are demonstrated. Here, we discuss the strategies for constructing cell membrane-engineered hybrid synthetic vesicles and their biomedical applications, as well as the remaining challenges and future research opportunities.

invited review
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[127] Lab Chip, 22, 2726-274, (2022)

Prediction of tumor metastasis via extracellular vesicles-treated platelet adhesion on a blood vessel chip

Junyoung Kim, Vijaya Sunkara, Jungmin Kim, Jooyoung Ro, Chi-Ju Kim, Elizabeth Maria Clarissa, Sung Wook Jung, Hee Jin Lee, and Yoon-Kyoung Cho*

Here, we found that interleukin-8 (IL-8) in cancer-derived EVs contributed to platelet activation by increasing P-selectin expression and ligand affinity, resulting in increased platelet adhesion on the human vessel-mimicking microfluidic system. Furthermore, platelet adhesion levels on vessels treated with human plasma-derived EVs demonstrated good discrimination between breast cancer patients with metastasis and those without, with the area under the curve (AUC) value of 0.88. While EpCAM expression on EVs could detect the existence of a tumor (AUC = 0.89), it performed poorly in predicting metastasis (AUC = 0.42). We believe that these findings shed light on the role of the interaction between cancer-derived EVs and platelets in pre-metastatic niche formation and tumor metastasis, potentially leading to the development of platelet–tumor interaction-based novel diagnostic and therapeutic strategies.

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[126] Advance Materials, 34, 2200981 (2022)

SEEDING to Enable Sensitive Electrochemical Detection of Biomarkers in Undiluted Biological Samples

Jonathan Sabaté del Río,Hyun-Kyung Woo,Juhee Park,Hong Koo Ha,Jae-Ryong Kim,Yoon-Kyoung Cho*

Electrochemical biosensors forf complex biological fluids such as plasma has been limited by the loss of sensitivity caused by biofouling. Herein, we demonstrate the preferential etching of chloride and surfactant-assisted anisotropic gold reduction to create homogeneous, nanostructured, and nanoporous gold electrodes, yielding 190 ± 20 times larger surface area within a minute without using templates. We named this process Surfactant-based Electrochemical Etch-Deposit Interplay for Nanostructure/Nanopore Growth (SEEDING). SEEDING on electrodes enhanced the sensitivity and anti-biofouling capabilities of amperometric biosensors, enabling direct analysis of tumor-derived extracellular vesicles (tEVs) in complex biofluids with a limit of detection of 300 tEVs/μL from undiluted plasma and good discrimination between patients with prostate cancer from healthy ones with an area under the curve (AUC) of 0.91 in urine and 0.90 in plasma samples.

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