NanoBio (United States)

Cancer is one of the leading causes of deaths worldwide. Once cancer cells acquire therapy resistance, they become the main driver of cancer lethality in patients. Thus, mechanisms of therapy resistance must be investigated to improve patient outcomes. Mitochondria are critical organelles in the cellular stress responses, undergoing dynamic morphological and functional changes in response to external stimuli. We and others have identified a chemotherapy-resistant cancer cell state where cells that survive treatment exhibit a dramatic increase in cell size and remain non-proliferative for weeks. In this study, we demonstrate that cancer cells that enter this resistant cell state in response to cisplatin increase OMA1 activity and decrease mitochondrial fusion and function to combat oxidative stress. These findings contribute to further understanding the role of the mitochondrial stress responses in therapy resistance in cancer and provide a potential therapeutic avenue to targeting cancer cells that enter this chemotherapy-resistant cell state.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-33677-1.

This study advances bioelectronic platforms and cellular behavior analysis by enhancing the precision and scalability of nanopatterned membranes integrated with electrode arrays for real-time, high-throughput monitoring. By employing self-assembled monolayers (SAMs) and optimizing imprinting parameters, uniform large-area nanopatterns are successfully fabricated, overcoming challenges such as the "rabbit ears" effect and inconsistent pattern fidelity. The nanopatterned substrates, integrated within 96-well plates with electrode arrays, enable real-time impedance spectroscopy, providing a dynamic assessment of cellular behavior under chemotherapeutic drug exposure. The developed NanoIEA platform facilitates comprehensive investigations into cellular growth and drug interactions. RNA sequencing of MCF-7 cells cultured on nanopatterned substrates reveals significant differential gene expression, suggesting that traditional flat-surface cultures may induce artificial gene regulation, potentially biasing drug screening results. Patterned cell cultures that mimic physiological conditions yield more accurate and predictive outcomes for anticancer drug screening. This research underscores the critical role of nanopatterning in recapitulating in vivo-like gene expression and highlights the profound impact of microenvironmental cues on cellular behavior. By integrating advanced nanofabrication with precise real-time monitoring, this approach addresses technical limitations in bioelectronic sensing while providing deeper insights into dynamic cellular responses, reinforcing the importance of substrate design in tissue engineering and drug development.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.

Immune checkpoint blockade involving inhibition of the PD-1/PD-L1 interaction has provided unprecedented clinical benefits in treating a variety of tumors. To date, a total of six antibodies that bind to either PD-1 or PD-L1 protein and in turn inhibit the PD-1/PD-L1 interaction have received clinical approvals. Despite being highly effective, these expensive large biotherapeutics possess several inherent pharmacokinetic limitations that can be successfully overcome through the use of low-molecular-weight inhibitors. One such promising approach involves small-molecule induced dimerization and sequestration of PD-L1, leading to effective PD-1/PD-L1 inhibition. Herein, we present discovery of such potential bioactive PD-L1 dimerizers through a structure- and ligand-based screening of a focused library of approved and investigational drugs worldwide. The most promising compound Pyrvinium, an FDA-approved anthelmintic drug, showed IC50 value of ~29.66 µM. It is noteworthy that Pyrvinium, being an approved drug, may prove especially suitable as a good starting point for further medicinal chemistry efforts, leading to design and development of even more potent structural analogs as selective PD-1/PD-L1 inhibitors. Furthermore, the adopted integrated virtual screening protocol may prove useful in screening other larger databases of lead- and drug-like molecules for hit identification in the domain of small-molecule PD-1/PD-L1 inhibitors.

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.

Liquid cellular compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.

Nano-dagger coated gauze was bactericidal against both Gram-positive and Gram-negative bacteria, with log reduction >7 for Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Compared with the commercially available Ag gauze, the ZIF-L nano-dagger coated gauze was more biocompatible with a lower haemolytic activity, less cytotoxicity and improved wound healing performance. Animal studies showed that the ZIF-L coated gauze can effectively kill bacteria in a S. aureus wound infection model in mice. This novel nano-dagger coated gauze offers an effective and safe alternative for patients to protect against wound infections. This study demonstrates the first application of a MOF coating as an antibiotic-free wound dressing with potent antimicrobial activity and improved biocompatibility.