Abstract

Pancreatic ductal adenocarcinoma (PDAC) often metastasizes to the peritoneum and is highly resistant to treatments due to its immunosuppressive microenvironment. In this study, we evaluate the safety and efficacy of a novel therapeutic strategy that combines KRAS-targeting antisense oligonucleotides (ASOs) with immunomodulatory RNA (immRNA), a RIG-I agonist, both delivered by extracellular vesicles (EVs), in preclinical models using PDAC patient-derived organoids and mice bearing PDAC peritoneal metastasis. Our data demonstrate that the combination of KRAS ASO and immRNA synergistically activates anti-tumor immune responses. EV-mediated co-delivery of both agents significantly inhibits tumor growth, reduces peritoneal metastasis, and markedly prolongs overall survival through the induction of immunologic cancer cell death. Importantly, this combination therapy is well-tolerated in non-human primates, with no observable changes in physical condition or behavior, blood parameters, or organ histology. These findings suggest that EV-delivered KRAS ASO and immRNA is a safe and potent therapeutic approach for treating PDAC and its peritoneal metastasis, positioning it as a promising strategy for future clinical advancement.

Full Article:https://www.sciencedirect.com/science/article/pii/S016836592500851X?via%3Dihub

ABSTRACT

N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmis­sion in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetra­meric assemblies of two GluN1 and two GluN2 subunits encoded by five genes (GRIN1 and GRIN2A–GRIN2D), which produce GluN1 and GluN2A–GluN2D subunits. NMDA receptors that contain the GluN2B subunit have unique pharmacological properties, being inhibited by multiple structurally distinct series of biaryl compounds with high po­tency and selectivity. These agents are of considerable therapeutic interest, given the numerous roles that GluN2B-containing NMDA receptors play in normal brain function and pathological situations.
Among GluN2B-selective negative allosteric modulators, radiprodil inhibits NMDA receptors that contain GluN2B with high potency and selectivity and appears to be safe in humans. Here, we evaluate the structural determinants of radiprodil binding to the heterodimeric GluN1–GluN2B amino terminal domain by X-ray crystallography and ex­plore the molecular mechanism of inhibition. A large number of de novo variants have been identified in the GRIN gene family in patients with various neurological and neuropsychiatric conditions, including autism, intellectual dis­ability, epilepsy, language disorders and movement disorders. We show that radiprodil is an effective antagonist at >80% of human disease-associated GRIN1 and GRIN2B missense variants tested in vitro (22/27, equally or more effect­ive as wild-type receptors), including variants in the pore-forming region, linker regions and elsewhere that uniform­ly increase NMDA receptor-mediated charge transfer. We show that radiprodil blocks synaptic GluN2B receptors in brain slices acutely isolated from a knock-in mouse line harbouring the gain-of-function variant GluN2B-Ser810Arg associated with early-onset epileptic encephalopathy and intractable seizures in patients. In addition, radiprodil de­lays the onset of seizures (458 ± 90 s, versus 207 ± 23 s in the vehicle group) in response to in vivo administration of the chemoconvulsant pentylenetetrazole.
These data support the potential utility of GluN2B-selective antagonists, such as radiprodil, for clinical treatments of neurological conditions where clinical aetiologies might involve increased current mediated by GluN2B-containing NMDA receptors.

Full Article: https://doi.org/10.1093/brain/awaf355

ABSTRACT

Autophagy, a conserved lysosomal degradation pathway, is increasingly recognized as a central regulator of metabolic health. Its impairment contributes directly to obesity and type 2 diabetes by disrupting nutrient sensing, stress adaptation, and organelle quality control. Hyperactivation of MTORC1 with insufficient AMPK and SIRT1 signaling suppresses autophagic flux, driving lipid accumulation, insulin resistance, and mitochondrial dysfunction. Clinically relevant consequences include adipose inflammation and hypertrophy, hepatic steatosis with impaired β-oxidation, pancreatic β-cell failure from unresolved ER stress, and skeletal muscle atrophy due to loss of proteostasis. Moreover, defective autophagy across the gut – liver – brain axis exacerbates intestinal barrier dysfunction, endotoxemia, and neuroendocrine imbalance, amplifying systemic metabolic deterioration. Emerging interventions that restore autophagic capacity, including exercise-induced AMPK activation, dietary modulation of unsaturated fatty acids, pharmacological inducers, and nanotechnology-based lysosomal re-acidification show promise in preclinical models. However, the tissue-specific duality of autophagy, where suppression may be beneficial in some contexts but harmful in others, highlights the complexity of therapeutic targeting. This review highlights current mechanistic and translational insights to position autophagy as a therapeutic linchpin in obesity-associated metabolic disease. By aligning molecular pathways with clinical outcomes, we herein highlight opportunities to develop precision strategies that harness autophagy to combat the global burden of obesity and metabolic disorders.

Full Article: https://www.tandfonline.com/doi/full/10.1080/15548627.2026.2636096

Abstract

Abstract

Abstract

Rationale: Vascular dementia (VaD), driven by chronic cerebral hypoperfusion (CCH), leads to synaptic degeneration and cognitive decline, yet mechanisms linking vascular dysfunction to synaptic loss remain unclear. Intermittent fasting (IF) has emerged as a potential intervention, but its effects on synaptic integrity in VaD are unknown. This study aims to investigate the effects of IF against synaptic degeneration and cognitive impairment induced by CCH.

Methods: Bilateral common carotid artery stenosis (BCAS) was employed to induce chronic CCH by placing 0.18 mm micro-coils around each common carotid artery in mice. To assess temporal differences, the coils remained in place for 1, 7, 14, or 30 days. IF was implemented for 16 hours daily over three months prior to BCAS induction. Cognitive impairment was evaluated using the Barnes maze test. White matter lesions (WMLs) and neuronal loss were assessed using Luxol fast blue and cresyl violet staining, respectively. Immunoblotting and immunohistochemistry were performed to quantify synaptic protein levels. Synaptic integrity was examined using transmission electron microscopy. Proteomic analysis of the hippocampus was conducted to investigate molecular adaptations to IF following CCH.

Results: We demonstrate that a 16-hour IF regimen preserves cognitive function and synaptic density despite persistent hypoperfusion. Behavioral assays revealed that IF prevented spatial memory deficits in BCAS mice, while electron microscopy confirmed synaptic preservation without altering baseline architecture. Surprisingly, key synaptic protein levels remained unchanged, suggesting IF protects synaptic function rather than abundance. Proteomic profiling revealed dynamic hippocampal adaptations under IF, including upregulation of synaptic stabilizers, enhanced GABAergic signaling, and suppression of neuroinflammatory mediators. CCH induced microglial engulfment of synapses, suggesting a role in complement-mediated synaptic pruning. Temporal pathway analysis revealed IF’s multi-phase neuroprotection: early synaptic reinforcement, mid-phase metabolic optimization, and late-phase suppression of chronic neuroinflammation.

Conclusion: These findings establish IF as a potent modulator of synaptic resilience in VaD, acting through coordinated preservation of synaptic structure, inhibition of inflammatory synapse loss, and metabolic reprogramming. Our results highlight IF’s potential as a non-pharmacological strategy to combat vascular cognitive impairment by targeting the synaptic vulnerability underlying dementia progression.

Full Article: https://www.thno.org/v15p8429

Abstract

A pervasive dilemma in brain-wide association studies¹ (BWAS) is whether to prioritize functional magnetic resonance imaging (fMRI) scan time or sample size. We derive a theoretical model showing that individual-level phenotypic prediction accuracy increases with sample size and total scan duration (sample size × scan time per participant). The model explains empirical prediction accuracies well across 76 phenotypes from nine resting-fMRI and task-fMRI datasets (R² = 0.89), spanning diverse scanners, acquisitions, racial groups, disorders and ages. For scans of ≤20 min, accuracy increases linearly with the logarithm of the total scan duration, suggesting that sample size and scan time are initially interchangeable. However, sample size is ultimately more important. Nevertheless, when accounting for the overhead costs of each participant (such as recruitment), longer scans can be substantially cheaper than larger sample size for improving prediction performance. To achieve high prediction performance, 10 min scans are cost inefficient. In most scenarios, the optimal scan time is at least 20 min. On average, 30 min scans are the most cost-effective, yielding 22% savings over 10 min scans. Overshooting the optimal scan time is cheaper than undershooting it, so we recommend a scan time of at least 30 min. Compared with resting-state whole-brain BWAS, the most cost-effective scan time is shorter for task-fMRI and longer for subcortical-to-whole-brain BWAS. In contrast to standard power calculations, our results suggest that jointly optimizing sample size and scan time can boost prediction accuracy while cutting costs. Our empirical reference is available online for future study design.

Full Article: https://www.nature.com/articles/s41586-025-09250-1

Abstract

Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, etc.) are caused by the progressive loss of neurons, which affects many people worldwide. Therefore, many efforts have focused on neurodegenerative disease mechanisms and therapeutic strategies. Moreover, amyloid precursor proteins and their cleaving products, including APP-C31, may play important roles in neurodegeneration. This review provides a comprehensive introduction to the structure, neurotoxicity, regulatory mechanism, and relevance of APP-C31 to clinical diseases and its therapeutic potential as a drug target. This work will bridge the gap in our understanding of the function of APP-C31, which provides an experimental basis for neurodegenerative disease therapeutics. Meanwhile, a hypothesis is postulated that the APP-C31 functions not merely as a byproduct of caspase cleavage, but as the critical “central executioner” bridging upstream triggers and downstream neurodegeneration. Diverse upstream stressors, initiate the cascade to generate APP-C31. Once generated, C31 acts as a multi-functional signalling hub driving four distinct pathogenic pathways. Consequently, APP-C31 is hypothesized to be the essential mediator that amplifies these molecular damages into macroscopic failures.

Full Article: https://link.springer.com/article/10.1186/s12929-026-01216-3

Abstract

Background

Nanoparticles (NPs) have emerged as highly efficient drug delivery vehicles. NPs are characterised by their ability to safeguard drugs, enhance stability, prolong durability, and facilitate targeted tissue delivery. Moreover, NPs can be customised to either stimulate or suppress immune responses while evading immune detection.

Main body

An increasing body of research demonstrated the therapeutic advantages of delivering various substances via surface-engineered NPs particularly in targeting immune cells. A broad spectrum of nanomaterials has been recognised for their superior ability to elicit immune responses, thereby enhancing disease prevention and therapeutic outcomes in vivo. In this comprehensive review, we discuss the impact of bioresponsive NPs on immunostimulation, immunomodulation, and immunosuppression. Particular focus is placed on how the physiochemical properties of these NPs influence the interaction between immune cells and host tissues, thereby achieving the desired immune regulation to combat various human diseases while reducing immunotoxicity. Additionally, we examined immune-inspired and immune-mediated strategies for the targeted delivery of NPs to specific sites within the body. Finally, we highlight the importance of understanding and focusing on immune cell trafficking mechanisms, as deeper insights into these processes may guide the rational design and fabrication of NPs capable of specifically targeting altered immune pathways under pathological conditions. This review offers an in-depth understanding of the diverse roles of bioresponsive NPs in immune regulation and targeted drug delivery, aiming to advance therapeutic strategies for a wide range of human diseases.

Conclusion

Nanomaterials possess significant immunomodulatory capabilities, enhancing both disease prevention and therapeutic efficacy in vivo, yet their clinical translation is hindered by complex fabrication methods and high production costs. Future efforts must focus on simplifying synthesis and improving cost-efficiency to facilitate their adoption in clinical practice.

Full Article: https://link.springer.com/article/10.1186/s12916-025-04305-6

Abstract

Cancer therapy has been revolutionised by the emergence of RNA-based therapeutics, providing several strategies and mechanisms to regulate gene expression via messenger RNA (mRNA), small interfering RNA (siRNA), microRNAs (miRNA), antisense oligonucleotides (ASOs), and RNA aptamers. The present review highlights the recent advances in the preclinical development and clinical applications of RNA-based therapeutics, focusing on the delivery strategies, biological targets, and pharmacological optimisation, together with key clinical data. mRNA therapeutics, especially those adapted from vaccine platforms are being developed for the cancer immunotherapy and protein replacement, while siRNAs and ASOs enable highly specific gene silencing and splice correction. miRNA therapies show potential for diverse oncogenic pathway control, despite ongoing challenges in the delivery and specificity. RNA aptamers are obtaining attention as tumor-targeting agents in the drug delivery systems. Progress in lipid nanoparticles, chemical modifications, and tissue-specific delivery has improved the stability and efficacy of these agents. Early-phase clinical trials report encouraging outcomes in both solid tumours and haematologic malignancies, particularly in overcoming resistance and modulating the tumor microenvironment (TME). Although challenges remain in scalability, immune activation, and deep-tumour penetration, RNA-based strategies are advancing towards integration into clinical oncology. Continued refinement of delivery technologies and targeted trial designs will be critical for translating these therapies into effective, personalized cancer treatments.

Full Article: https://link.springer.com/article/10.1186/s12943-025-02463-y