Yi Liu

Tumor Small Extracellular Vesicle‐Transmitted LncRNA CATED Promotes Platinum‐Resistance in High‐Grade Serous Ovarian Cancer

AbstractHigh‐grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum‐resistance is a serious challenge in its treatment. Long non‐coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor‐derived sEVs in platinum‐resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED‐overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1‐mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum‐resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum‐resistance in sEV‐transmitted mouse models via the DHX36‐RAP1A‐MAPK pathway. This study newly identifies a sEV‐transmitted lncRNA CATED in driving HGSOC platinum‐resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED.

Engineering Nano‐Pills to Inhibit Ovarian Cancer Proliferation and Migration through a Combination of Chemical/Nucleic Acid Therapy

Abstract Ovarian cancer (OC) is the most fatal of all gynecological malignancies, presenting a significant threat to women's health. Its treatment is complicated by severe dose‐dependent chemotherapy toxicity, drug resistance, and tumor migration. Herein, an intelligent combination strategy of chemotherapy and nucleic acid therapy, named ApMEmiR&D is developed. This integrated system consists of three parts: the nano‐pill, the protective membrane, and the navigation element. Nano‐pills are nanospheres assembled from miRNA and doxorubicin (DOX) with the help of ferrous ions (Fe 2+ ). The protective membrane is derived from tumor‐associated macrophages (TAMs membrane) originating from the primary tumor microenvironment (TME). The navigation element is the cholesterol‐conjugated AS1411 aptamer. The resulting ApMEmiR&D nanoparticles exhibit uniform size, a well‐defined nanosphere structure, robust serum stability, and ultra‐high drug loading efficiency and capacity. The system can efficiently accumulate in the tumor, allowing for the synergistic inhibition of tumor growth and metastasis without apparent systemic toxicity. The results demonstrate the homing effect of tumor microenvironment‐derived macrophage cell membrane and the targeting effect of aptamer, leading to precise drug targeting and immune compatibility, thereby enhancing therapeutic efficacy. The success of this strategy paves the way for metastasis inhibition and targeted cancer therapy.

Split crRNA with CRISPR-Cas12a enabling highly sensitive and multiplexed detection of RNA and DNA

The CRISPR-Cas12a system has revolutionized nucleic acid testing (NAT) with its rapid and precise capabilities, yet it traditionally required RNA pre-amplification. Here we develop rapid fluorescence and lateral flow NAT assays utilizing a split Cas12a system (SCas12a), consisting of a Cas12a enzyme and a split crRNA. The SCas12a assay enables highly sensitive, amplification-free, and multiplexed detection of miRNAs and long RNAs without complex secondary structures. It can differentiate between mature miRNA and its precursor (pre-miRNA), a critical distinction for precise biomarker identification and cancer progression monitoring. The system's specificity is further highlighted by its ability to detect DNA and miRNA point mutations. Notably, the SCas12a system can quantify the miR-21 biomarker in plasma from cervical cancer patients and, when combined with RPA, detect HPV at attomole levels in clinical samples. Together, our work presents a simple and cost-effective SCas12a-based NAT platform for various diagnostic settings.

Analytical evaluation of the automated genotyping system (GenPlex) compared to a traditional real‐time PCR assay for the detection of high‐risk human papillomaviruses

AbstractThe detection of high‐risk human papillomaviruses (HPVs) is crucial for early screening and preventing cervical cancer. However, the substantial workload in high‐level hospitals or the limited resources in primary‐level hospitals hinder widespread testing. To address this issue, we explored a sample‐to‐answer genotyping system and assessed its performance by comparing it with the traditional real‐time polymerase chain reaction (PCR) method conducted manually. Samples randomly selected from those undergoing routine real‐time PCR detection were re‐analyzed using the fully automatic GenPlex® system. This system identifies 24 types of HPV through a combination of ordinary PCR and microarray‐based reverse hybridization. Inconsistent results were confirmed by repeated testing with both methods, and the κ concordance test was employed to evaluate differences between the two methods. A total of 365 samples were randomly selected from 7259 women. According to real‐time PCR results, 76 were high‐risk HPV negative, and 289 were positive. The GenPlex® system achieved a κ value greater than 0.9 (ranging from 0.920 to 1.000, p < 0.0001) for 14 types of high‐risk HPV, except HPV 51 (κ = 0.697, p < 0.0001). However, the inconsistent results in high‐risk HPV 51 were revealed to be false positive in real‐time PCR by other method. When counting by samples without discriminating the high‐risk HPV type, the results of both methods were entirely consistent (κ = 1.000, p < 0.0001). Notably, the GenPlex® system identified more positive cases, with 73 having an HPV type not covered by real‐time PCR, and 20 potentially due to low DNA concentration undetectable by the latter. Compared with the routinely used real‐time PCR assay, the GenPlex® system demonstrated high consistency. Importantly, the system's advantages in automatic operation and a sealed lab‐on‐chip format respectively reduce manual work and prevent aerosol pollution. For widespread use of GenPlex® system, formal clinical validation following international criteria should be warranted.

Cancer-Erythrocyte Hybrid Membrane-Camouflaged Magnetic Nanoparticles with Enhanced Photothermal-Immunotherapy for Ovarian Cancer

Cell-membrane-coated nanoparticles are widely studied due to their inherent cellular properties, such as immune escape and homologous homing. A cell membrane coating can also maintain the relative stability of nanoparticles during circulation in a complex blood environment through cell membrane encapsulation technology. In this study, we fused a murine-derived ID8 ovarian cancer cell membrane with a red blood cell (RBC) membrane to create a hybrid biomimetic coating (IRM), and hybrid IRM camouflaged indocyanine green (ICG)-loaded magnetic nanoparticles (Fe

FCGR2B + Macrophages as a Critical Node Linking Ferroptosis and Immunosuppression: A Multiomics Framework for Prognosis and Therapy in High‐Grade Serous Ovarian Cancer

Background High‐grade serous ovarian cancer (HGSOC) is characterized by a complex tumor microenvironment and poor prognosis, yet the roles of specific tumor‐associated macrophages (TAMs) subpopulations in driving disease progression remain elusive. Methods This study evaluated the prognostic relevance of FCGR2B in HGSOC. Single‐cell RNA sequencing identified FCGR2B + TAMs as a distinct macrophage subpopulation with unique transcriptional features. Integrative analyses combining single‐cell and bulk differentially expressed genes, macrophage‐associated modules, and ferroptosis‐related gene sets identified 26 candidate prognostic genes, from which a four‐gene signature ( CRYAB , PLAUR , EREG , and C5AR1 ) was derived to construct the prognostic risk model. The model was validated in an independent cohort. Immune infiltration, single‐cell trajectory, copy number variation, and drug–gene associations were analyzed to explore the molecular and therapeutic implications of risk stratification. Results HGSOC patients classified as high risk exhibited poorer survival outcomes, increased infiltration of M2‐like macrophages, elevated expression of immune checkpoints, and enrichment of immune‐ and ferroptosis‐related pathways. Trajectory and copy number variation analyses revealed stage‐specific gene expression patterns and amplification‐associated regulation. Drug–gene association analyses further suggested that high‐risk patients may be more responsive to targeted therapies and proteasome inhibitors, whereas low‐risk patients may benefit from conventional chemotherapy. Conclusion FCGR2B + TAMs are closely linked to HGSOC progression, and the proposed prognostic model based on FCGR2B + TAMs provides predictive value and potential therapeutic insights for patient stratification.