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The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the membrane-fusogenic liposome surface converts its membrane-fusion performance to lysosome-dependent endocytosis, causing poorer delivery efficiency in biological conditions. Herein, we develop an antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Leveraging specific lipid composition at an optimized ratio, such antifouling membrane-fusogenic liposome facilitates fusion capacity even in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups for protein-adsorption resistance. Consequently, the antifouling membrane-fusogenic liposome demonstrates robust membranefusion-mediated delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional membrane-fusogenic liposomes effective at 4% and 6% concentrations. When injected into mice, antifouling membrane-fusogenic liposomes can keep their membrane-fusion-transportation behaviors, thereby achieving efficient luciferase transfection and enhancing gene-editingmediated viral inhibition. This study provides a promising tool for effective intracellular delivery under complex physiological environments, enlightening future nanomedicine design. [ABSTRACT FROM AUTHOR]

The emerging field of liquid biopsy has garnered significant interest in precision diagnostics, offering a non-invasive and repetitive method for analyzing bodily fluids to procure real-time diagnostic data. The precision and accuracy offered by the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas) technology have advanced and broadened the applications of liquid biopsy. Significantly, when combined with swiftly advancing nanotechnology, CRISPR/Cas-mediated nanodevices show vast potential in precise liquid biopsy applications. However, persistent challenges are still associated with off-target effects, and the current platforms also constrain the performance of the assays. In this review, we highlight the merits of CRISPR/Cas systems in liquid biopsy, tracing the development of CRISPR/Cas systems and their current applications in disease diagnosis particularly in liquid biopsies. We also outline ongoing efforts to design nanoscale devices with improved sensing and readout capabilities, aiming to enhance the performance of CRISPR/Cas detectors in liquid biopsy. Finally, we identify the critical obstacles hindering the widespread adoption of CRISPR/Cas liquid biopsy and explore potential solutions. This feature article presents a comprehensive overview of CRISPR/Cas-mediated liquid biopsies, emphasizing the progress in integrating nanodevices to improve specificity and sensitivity. It also sheds light on future research directions in employing nanodevices for CRISPR/Cas-based liquid biopsies in the realm of precision medicine. [ABSTRACT FROM AUTHOR]

As a currently common strategy to treat cancer, surgical resection may cause tumor recurrence and metastasis due to residual postoperative tumors. Herein, an implantable sandwich‐structured dual‐drug depot is developed to trigger a self‐intensified starvation therapy and hypoxia‐induced chemotherapy sequentially. The two outer layers are 3D‐printed using a calcium‐crosslinked mixture ink containing soy protein isolate, polyvinyl alcohol, sodium alginate, and combretastatin A4 phosphate (CA4P). The inner layer is one patch of poly (lactic‐co‐glycolic acid)‐based electrospun fibers loaded with tirapazamine (TPZ). The preferentially released CA4P destroys the preexisting blood vessels and prevents neovascularization, which obstructs the external energy supply to cancer cells but aggravates hypoxic condition. The subsequently released TPZ is bioreduced to cytotoxic benzotriazinyl under hypoxia, further damaging DNA, generating reactive oxygen species, disrupting mitochondria, and downregulating hypoxia‐inducible factor 1α, vascular endothelial growth factor, and matrix metalloproteinase 9. Together these processes induce apoptosis, block the intracellular energy supply, counteract the disadvantage of CA4P in favoring intratumor angiogenesis, and suppress tumor metastasis. The in vivo and in vitro results and the transcriptome analysis demonstrate that the postsurgical adjuvant treatment with the dual‐drug‐loaded sandwich‐like implants efficiently inhibits tumor recurrence and metastasis, showing great potential for clinical translation. [ABSTRACT FROM AUTHOR]

For patients carrying BRCA1 mutations, at least one‐third develop triple negative breast cancer (TNBC). Not only is TNBC difficult to treat due to the lack of molecular target receptors, but BRCA1 mutations (BRCA1m) also result in chemotherapeutic resistance, making disease recurrence more likely. Although BRCA1m are highly heterogeneous and therefore difficult to target, BRCA1 gene's synthetic lethal pair, PARP1, is conserved in BRCA1m cancer cells. Therefore, we hypothesize that targeting PARP1 might be a fruitful direction to sensitize BRCA1m cancer cells to chemotherapy. We used CRISPR/Cas9 technology to generate PARP1 deficiency in two TNBC cell lines, MDA‐MB‐231 (BRCA1 wild‐type) and MDA‐MB‐436 (BRCA1m). We explored whether this PARP1 disruption (PARP1m) could significantly lower the chemotherapeutic dose necessary to achieve therapeutic efficacy in both a 2D and 3D tumor‐on‐a‐chip model. With both BRCA1m and PARP1m, the TNBC cells were more sensitive to three representative chemotherapeutic breast cancer drugs, doxorubicin, gemcitabine and docetaxel, compared with the PARP1 wild‐type counterpart in the 2D culture environment. However, PARP1m did not result in this synergy in the 3D tumor‐on‐a‐chip model, suggesting that drug dosing in the tumor microenvironment may influence the synergy. Taken together, our results highlight a discrepancy in the efficacy of the combination of PARP1 inhibition and chemotherapy for TNBC treatment, which should be clarified to justify further clinical testing. [ABSTRACT FROM AUTHOR]

Breast cancer is a highly heterogenous family of malignant neoplasms with significant interpatient variations. CRISPR technology offers a toolkit to diagnose, model, and treat the disease in a more precise manner. In article number 1800132, Kam W. Leong and co‐workers analyze the potential application of CRISPR technology in these three aspects and provide insights on developing a precision medicine‐based approach against breast cancer. [ABSTRACT FROM AUTHOR]

Molecularly, breast cancer represents a highly heterogenous family of neoplastic disorders, with substantial interpatient variations regarding genetic mutations, cell composition, transcriptional profiles, and treatment response. Consequently, there is an increasing demand for alternative diagnostic approaches aimed at the molecular annotation of the disease on a patient‐by‐patient basis and the design of more personalized treatments. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) technology enables the development of such novel approaches. For instance, in diagnostics, the use of the RNA‐specific C2c2 system allows ultrasensitive nucleic acid detection and could be used to characterize the mutational repertoire and transcriptional breast cancer signatures. In disease modeling, CRISPR/Cas9 technology can be applied to selectively engineer oncogenes and tumor‐suppressor genes involved in disease pathogenesis. In treatment, CRISPR/Cas9 can be used to develop gene‐therapy, while its catalytically‐dead variant (dCas9) can be applied to reprogram the epigenetic landscape of malignant cells. As immunotherapy becomes increasingly prominent in cancer treatment, CRISPR/Cas9 can engineer the immune cells to redirect them against cancer cells and potentiate antitumor immune responses. In this review, CRISPR strategies for the advancement of breast cancer diagnostics, modeling, and treatment are highlighted, culminating in a perspective on developing a precision medicine‐based approach against breast cancer. The limitations of current breast cancer diagnostics, modeling, and treatment methods are recounted followed by approaches in which clustered regularly interspaced short palindromic repeats (CRISPR) variants can be exploited for more precise outcomes. The review concludes by analyzing the present barriers for CRISPR delivery and translation, highlighting the engineering innovations to overcome them. [ABSTRACT FROM AUTHOR]

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7 + ) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7 + IgG + plasmablasts in circulation, as well as IgG + plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Spatially resolved gene expression profiling provides insight into tissue organization and cell-cell crosstalk; however, sequencing-based spatial transcriptomics (ST) lacks single-cell resolution. Current ST analysis methods require single-cell RNA sequencing data as a reference for rigorous interpretation of cell states, mostly do not use associated histology images and are not capable of inferring shared neighborhoods across multiple tissues. Here we present Starfysh, a computational toolbox using a deep generative model that incorporates archetypal analysis and any known cell type markers to characterize known or new tissue-specific cell states without a single-cell reference. Starfysh improves the characterization of spatial dynamics in complex tissues using histology images and enables the comparison of niches as spatial hubs across tissues. Integrative analysis of primary estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer (TNBC) and metaplastic breast cancer (MBC) tissues led to the identification of spatial hubs with patient- and disease-specific cell type compositions and revealed metabolic reprogramming shaping immunosuppressive hubs in aggressive MBC., (© 2024. The Author(s).)

Mesenchymal stem cell (MSC) has been increasingly applied to cancer therapy because of its tumor-tropic capability. However, short retention at target tissue and limited payload option hinder the progress of MSC-based cancer therapy. Herein, we proposed a hybrid spheroid/nanomedicine system, comprising MSC spheroid entrapping drug-loaded nanocomposite, to address these limitations. Spheroid formulation enhanced MSC's tumor tropism and facilitated loading of different types of therapeutic payloads. This system acted as an active drug delivery platform seeking and specifically targeting glioblastoma cells. It enabled effective delivery of combinational protein and chemotherapeutic drugs by engineered MSC and nanocomposite, respectively. In an in vivo migration model, the hybrid spheroid showed higher nanocomposite retention in the tumor tissue compared with the single MSC approach, leading to enhanced tumor inhibition in a heterotopic glioblastoma murine model. Taken together, this system integrates the merits of cell- and nanoparticle- mediated drug delivery with the tumor-homing characteristics of MSC to advance targeted combinational cancer therapy.