Search Medical Journals & Research Articles

[Articles] Comprehensive primary health care for cost-effective scale-up of depression screening in India: an economic modelling study

Integrating depression screening and management into the government primary healthcare system provides substantial public health and economic benefits, supporting the case for a PHC-oriented health system. Expanding coverage to individuals aged 20 years and above, along with ensuring high diagnostic accuracy through quality training and supportive supervision, will be key to sustaining and maximizing the programme's impact.

[Personal View] Towards a Latin American neuropsychiatry: challenges and opportunities

From the impact of armed conflict and political violence to the neuropsychiatric consequences of neglected tropical diseases, Latin America has a unique profile of region-specific risk factors that mean it is not always well-served by neuropsychiatric practice developed in high-income regions. Here, we review the region-specific neuropsychiatric characteristics of traumatic brain injury, stroke, epilepsy, dementia, functional neurological disorder, infectious diseases, environmental health risks, and substance use.

[Articles] The impact of large-scale release of Wolbachia mosquitoes on dengue incidence in Campo Grande, Brazil: an ecological study

Our results demonstrate successful large-scale Wolbachia establishment in Ae. aegypti populations and a substantial epidemiological impact on dengue incidence in an urban Brazilian setting. This study provides robust evidence supporting Wolbachia deployment as an effective, sustainable public health intervention and validates its implementation as a federal government-supported dengue control strategy in Brazil.

Intrinsic Photo‐Crosslinkable Semiconductive Small‐Molecule Crystals (i‐PSSCs) for Patterning Electronic Devices

A novel intrinsic photo‐crosslinkable semiconductive small molecule is designed and synthesized. The solution‐processed crystalline film can be patterned by in situ photopolymerization under UV light irradiation without external crosslinking agents, and the crystalline order and charge transport properties are preserved, demonstrating potential for high‐precision organic electronic devices. Abstract Precise patterning of small‐molecule semiconductive crystals without external chemical additives remains a significant challenge. Herein, intrinsic photo‐crosslinkable semiconductive small‐molecule crystals (i‐PSSCs) are designed and synthesized by associating [1]benzothieno[3,2‐b]benzothiophene core with diacetylene‐ended groups. The i‐PSSCs undergo self‐crosslinking directly upon UV light irradiation to yield micron‐scale patterned crystalline films through a combination of photo‐crosslinking and solvent rinsing. The molecular packing remains intact before and after patterning. Therefore, the electrical performance of the organic thin‐film transistors fabricated from both pristine and patterned i‐PSSCs films shows minimal difference, with maximum field‐effect mobilities of 0.46 and 0.25 cm2 V−1 s−1, respectively. Moreover, the i‐PSSCs in a transistor array exhibit high sensitivity and selective response to UV patterns, enabling bio‐inspired vision systems that mimic human retinal extraction of image descriptors. This work offers a valuable strategy for developing i‐PSSCs for UV‐selective artificial vision applications. A novel intrinsic photo-crosslinkable semiconductive small molecule is designed and synthesized. The solution-processed crystalline film can be patterned by in situ photopolymerization under UV light irradiation without external crosslinking agents, and the crystalline order and charge transport properties are preserved, demonstrating potential for high-precision organic electronic devices. Abstract Precise patterning of small-molecule semiconductive crystals without external chemical additives remains a significant challenge. Herein, intrinsic photo-crosslinkable semiconductive small-molecule crystals (i-PSSCs) are designed and synthesized by associating [1]benzothieno[3,2-b]benzothiophene core with diacetylene-ended groups. The i-PSSCs undergo self-crosslinking directly upon UV light irradiation to yield micron-scale patterned crystalline films through a combination of photo-crosslinking and solvent rinsing. The molecular packing remains intact before and after patterning. Therefore, the electrical performance of the organic thin-film transistors fabricated from both pristine and patterned i-PSSCs films shows minimal difference, with maximum field-effect mobilities of 0.46 and 0.25 cm 2 V −1 s −1, respectively. Moreover, the i-PSSCs in a transistor array exhibit high sensitivity and selective response to UV patterns, enabling bio-inspired vision systems that mimic human retinal extraction of image descriptors. This work offers a valuable strategy for developing i-PSSCs for UV-selective artificial vision applications. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Sympathetic Activation Promotes Kidney Fibrosis in Mice via Macrophage‐Derived N2ICD‐Enriched Extracellular Vesicles

Norepinephrine/α2B‐adrenoceptor axis promotes the secretion of Notch2 intracellular domain (N2ICD)‐enriched extracellular vesicles (EVs) from macrophages. These EVs deliver N2ICD into fibroblasts, thereby inducing their activation. Deletion of Notch2 or α2B‐AR in macrophages disrupts N2ICD‐enriched EV formation and alleviates kidney fibrosis in mice. Mechanistically, N2ICD stabilizes Smad3 by preventing its ubiquitin‐mediated degradation, enhancing TGF‐β signaling, and promoting fibroblast activation. Abstract Persistent overactivation of the renal sympathetic nervous system drives kidney inflammation and fibrosis. Macrophages contribute to fibrogenesis by secreting various pro‐fibrogenic mediators. However, whether the sympathetic nervous system regulates renal fibrosis by modulating macrophage‐fibroblast interaction remains unclear. Here, it is demonstrated that norepinephrine (NE)‐treated macrophages promoted renal fibroblast activation through the transfer of Notch2 intracellular domain (N2ICD)‐enriched extracellular vesicles (EVs) to fibroblasts. Depletion of macrophage mitigated kidney fibrosis in mice subjected to unilateral nephrectomy plus contralateral ischemia‐reperfusion injury (Npx‐IRI) or repeated low‐dose cisplatin (RLDC) regimen. Macrophage‐specific deletion of Notch2 or α2B‐adrenoceptor disrupted N2ICD‐EV formation and protected mice from kidney fibrosis. Mechanistically, N2ICD stabilized Smad3 by preventing its ubiquitin‐dependent degradation, thereby enhancing TGF‐β signaling to promote fibroblast activation. These findings establish a sympathetic nerve‐macrophage‐fibroblast axis in renal fibrosis and highlight macrophage‐specific Notch2 inhibition as a potential therapeutic strategy. Norepinephrine/α2B-adrenoceptor axis promotes the secretion of Notch2 intracellular domain (N2ICD)-enriched extracellular vesicles (EVs) from macrophages. These EVs deliver N2ICD into fibroblasts, thereby inducing their activation. Deletion of Notch2 or α2B-AR in macrophages disrupts N2ICD-enriched EV formation and alleviates kidney fibrosis in mice. Mechanistically, N2ICD stabilizes Smad3 by preventing its ubiquitin-mediated degradation, enhancing TGF-β signaling, and promoting fibroblast activation. Abstract Persistent overactivation of the renal sympathetic nervous system drives kidney inflammation and fibrosis. Macrophages contribute to fibrogenesis by secreting various pro-fibrogenic mediators. However, whether the sympathetic nervous system regulates renal fibrosis by modulating macrophage-fibroblast interaction remains unclear. Here, it is demonstrated that norepinephrine (NE)-treated macrophages promoted renal fibroblast activation through the transfer of Notch2 intracellular domain (N2ICD)-enriched extracellular vesicles (EVs) to fibroblasts. Depletion of macrophage mitigated kidney fibrosis in mice subjected to unilateral nephrectomy plus contralateral ischemia-reperfusion injury (Npx-IRI) or repeated low-dose cisplatin (RLDC) regimen. Macrophage-specific deletion of Notch2 or α2B-adrenoceptor disrupted N2ICD-EV formation and protected mice from kidney fibrosis. Mechanistically, N2ICD stabilized Smad3 by preventing its ubiquitin-dependent degradation, thereby enhancing TGF-β signaling to promote fibroblast activation. These findings establish a sympathetic nerve-macrophage-fibroblast axis in renal fibrosis and highlight macrophage-specific Notch2 inhibition as a potential therapeutic strategy. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Advanced Biomaterial Delivery of Hypoxia‐Conditioned Extracellular Vesicles (EVs) as a Therapeutic Platform for Traumatic Brain Injury

This research introduces a novel approach to enhance neuroregeneration following Traumatic Brain Injury (TBI). Extracellular Vesicles (EVs) are isolated from human neural progenitor cells under hypoxic conditions, leading to enhanced expression of neurogenic and angiogenic factors. Substantial reversal of injury pathology is observed, including increased neurogenesis, angiogenesis, NSC differentiation into neurons, and reduced inflammation. Abstract Traumatic Brain Injury (TBI) is a common and debilitating injury, causing long‐lasting neurological deficits. Current therapeies for recovery remain inadequate, undersing the urgent need for innovative interventions. In this study, a novel therapeutic approach is introduced that delivers extracellular vesicles (EVs) derived from human‐induced pluripotent stem cell‐derived neural progenitor cells (hiPSC‐NPCs) with a gelatin‐based injectable bioorthogonal hydrogel (BIOGEL). The hiPSC‐NPCs are conditioned with deferoxamine (DFO) to simulate hypoxia, resulting in EVs enriched with neurotrophic and angiogenic factors critical for neural repair. The biomimetic mechanical properties of BIOGEL, similar to those of native brain tissue, contribute to sustained EV delivery and promote neural regeneration. BIOGEL with hypoxia‐conditioned EVs showed significant tissue regeneration in vivo using a rat model of TBI. Our nanomaterial platform reduced cortical lesions, improved neurological and motor recovery, enhanced hippocampal neurogenesis and myelination, and reduced neuroinflammation, demonstrating strong therapeutic potential for neural repair. In summary, this study demonstrated proof‐of‐concept for a multifaceted therapeutic platform that simultaneously targets key pathological features of TBI, providing a scalable and clinically translatable approach to effective neural tissue regeneration. The synergistic combination of hypoxia‐conditioned EVs and biomaterial delivery offers a promising strategy for advancing regenerative medicine techniques for neural repair. This research introduces a novel approach to enhance neuroregeneration following Traumatic Brain Injury (TBI). Extracellular Vesicles (EVs) are isolated from human neural progenitor cells under hypoxic conditions, leading to enhanced expression of neurogenic and angiogenic factors. Substantial reversal of injury pathology is observed, including increased neurogenesis, angiogenesis, NSC differentiation into neurons, and reduced inflammation. Abstract Traumatic Brain Injury (TBI) is a common and debilitating injury, causing long-lasting neurological deficits. Current therapeies for recovery remain inadequate, undersing the urgent need for innovative interventions. In this study, a novel therapeutic approach is introduced that delivers extracellular vesicles (EVs) derived from human-induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) with a gelatin-based injectable bioorthogonal hydrogel (BIOGEL). The hiPSC-NPCs are conditioned with deferoxamine (DFO) to simulate hypoxia, resulting in EVs enriched with neurotrophic and angiogenic factors critical for neural repair. The biomimetic mechanical properties of BIOGEL, similar to those of native brain tissue, contribute to sustained EV delivery and promote neural regeneration. BIOGEL with hypoxia-conditioned EVs showed significant tissue regeneration in vivo using a rat model of TBI. Our nanomaterial platform reduced cortical lesions, improved neurological and motor recovery, enhanced hippocampal neurogenesis and myelination, and reduced neuroinflammation, demonstrating strong therapeutic potential for neural repair. In summary, this study demonstrated proof-of-concept for a multifaceted therapeutic platform that simultaneously targets key pathological features of TBI, providing a scalable and clinically translatable approach to effective neural tissue regeneration. The synergistic combination of hypoxia-conditioned EVs and biomaterial delivery offers a promising strategy for advancing regenerative medicine techniques for neural repair. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Vitiligo Signature‐Based Drug Screening Identifies Fulvestrant as a Novel Immunotherapy Combination Strategy

A vitiligo‐derived gene signature predicts response to immune checkpoint blockade across multiple cancer cohorts, providing a framework for patient stratification. Building on this, Fulvestrant—a clinically approved estrogen receptor degrader—further enhances antitumor immunity by reprogramming tumor‐associated macrophages and promoting CD8⁺ T cell infiltration, suggesting a potential combination strategy to improve immunotherapy efficacy. Abstract Immunotherapy has revolutionized cancer treatment; however, only 10–30% of patients experience durable survival benefits, while most malignancies remain resistant. In melanoma, vitiligo‐like depigmentation is a frequent and generally mild immune‐related adverse event, whose presence correlates positively with enhanced antitumor immune responses and prolonged patient survival. By performing comparative analyses between vitiligo and melanoma, we established a biomarker panel—designated the vitiligo signature (VGS)—that differentiates “cold” from “hot” tumors with high accuracy. Leveraging a deep learning–based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti–programmed cell death ligand 1 (PD L1) therapy in preclinical models. Single cell RNA sequencing revealed that Fulvestrant expanded cytotoxic T cell populations, while immunofluorescence and flow cytometry confirmed markedly increased CD8⁺ T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C─C motif chemokine 5 (CCL5), major histocompatibility complex class I (MHC I), and type II interferon (IFN II) signaling pathways, thereby potentiating antitumor immunity. Collectively, our study introduces a precision approach for patient stratification in immunotherapy and highlights Fulvestrant as a promising component of immunotherapy based combination strategies warranting clinical evaluation. A vitiligo-derived gene signature predicts response to immune checkpoint blockade across multiple cancer cohorts, providing a framework for patient stratification. Building on this, Fulvestrant—a clinically approved estrogen receptor degrader—further enhances antitumor immunity by reprogramming tumor-associated macrophages and promoting CD8⁺ T cell infiltration, suggesting a potential combination strategy to improve immunotherapy efficacy. Abstract Immunotherapy has revolutionized cancer treatment; however, only 10–30% of patients experience durable survival benefits, while most malignancies remain resistant. In melanoma, vitiligo-like depigmentation is a frequent and generally mild immune-related adverse event, whose presence correlates positively with enhanced antitumor immune responses and prolonged patient survival. By performing comparative analyses between vitiligo and melanoma, we established a biomarker panel—designated the vitiligo signature (VGS)—that differentiates “cold” from “hot” tumors with high accuracy. Leveraging a deep learning–based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti–programmed cell death ligand 1 (PD L1) therapy in preclinical models. Single cell RNA sequencing revealed that Fulvestrant expanded cytotoxic T cell populations, while immunofluorescence and flow cytometry confirmed markedly increased CD8⁺ T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C─C motif chemokine 5 (CCL5), major histocompatibility complex class I (MHC I), and type II interferon (IFN II) signaling pathways, thereby potentiating antitumor immunity. Collectively, our study introduces a precision approach for patient stratification in immunotherapy and highlights Fulvestrant as a promising component of immunotherapy based combination strategies warranting clinical evaluation. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Histone Lactylation‐Driven Upregulation of VRK1 Expression Promotes Stemness and Proliferation of Glioma Stem Cells

Glioblastoma (GBM) is the most aggressive primary brain tumor, with glioma stem cells (GSCs) driving treatment resistance. This study reveals that lactate promotes histone lactylation (H3K18la) at the VRK1 promoter, regulating GSC stemness and proliferation via the H3K18la/VRK1/YBX1/SOX2 pathway. The VRK1‐targeted nanoliposome A/TMZ‐siVRK1 demonstrates therapeutic potential in GBM. These findings underscore the role of histone lactylation in stem cell regulation. Abstract Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with glioma stem cells (GSCs) as a subpopulation contributing to treatment resistance and recurrence. This study investigates the role of lactate and its regulatory gene, vaccinia‐related kinase 1 (VRK1), in the regulation of GSC stemness. Utilizing multiple glioma‐related databases and patient‐derived GSCs, it is discovered that lactate enhances the stemness and proliferation of GSCs via VRK1. Mechanistically, lactate promotes histone lactylation (H3K18la) at the VRK1 promoter in GSCs, thereby upregulating VRK1 expression. VRK1 enhances Y‐box binding protein 1 (YBX1) protein stability by inhibiting its ubiquitination and degradation, and phosphorylates YBX1 to promote its nuclear translocation, thereby regulating GSC stemness and proliferation via the YBX1/SOX2 pathway. Additionally, the VRK1‐targeted nanoliposome A/TMZ‐siVRK1 effectively suppresses the stemness and proliferation of GSCs, demonstrating its therapeutic potential. In conclusion, lactate regulates the stemness and proliferation of GSCs via the H3K18la/VRK1/YBX1/SOX2 pathway. This study elucidates the role of histone lactylation in stem cell regulation and suggests that VRK1 is a potential therapeutic target for GBM. Glioblastoma (GBM) is the most aggressive primary brain tumor, with glioma stem cells (GSCs) driving treatment resistance. This study reveals that lactate promotes histone lactylation (H3K18la) at the VRK1 promoter, regulating GSC stemness and proliferation via the H3K18la/VRK1/YBX1/SOX2 pathway. The VRK1-targeted nanoliposome A/TMZ-siVRK1 demonstrates therapeutic potential in GBM. These findings underscore the role of histone lactylation in stem cell regulation. Abstract Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with glioma stem cells (GSCs) as a subpopulation contributing to treatment resistance and recurrence. This study investigates the role of lactate and its regulatory gene, vaccinia-related kinase 1 ( VRK1 ), in the regulation of GSC stemness. Utilizing multiple glioma-related databases and patient-derived GSCs, it is discovered that lactate enhances the stemness and proliferation of GSCs via VRK1. Mechanistically, lactate promotes histone lactylation (H3K18la) at the VRK1 promoter in GSCs, thereby upregulating VRK1 expression. VRK1 enhances Y-box binding protein 1 (YBX1) protein stability by inhibiting its ubiquitination and degradation, and phosphorylates YBX1 to promote its nuclear translocation, thereby regulating GSC stemness and proliferation via the YBX1/SOX2 pathway. Additionally, the VRK1-targeted nanoliposome A/TMZ-siVRK1 effectively suppresses the stemness and proliferation of GSCs, demonstrating its therapeutic potential. In conclusion, lactate regulates the stemness and proliferation of GSCs via the H3K18la/VRK1/YBX1/SOX2 pathway. This study elucidates the role of histone lactylation in stem cell regulation and suggests that VRK1 is a potential therapeutic target for GBM. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Closed‐Loop Bioelectronic Artificial Pancreas Patch for Continuous Monitoring and Regulation of Blood Glucose in Diabetic Rats and Pigs

A closed‐loop bioelectronic artificial pancreas patch is presented for glucose monitoring and regulation. Utilizing transiently dissolvable microneedle arrays integrated with microtube arrays, the patch efficiently delivers insulin into interstitial fluid, eliminating the need for external long needles. In diabetic pigs, it demonstrates excellent blood glucose control comparable to commercial closed‐loop systems, while offering advantages such as miniaturization, low cost, and low power consumption. Abstract Integrated artificial pancreas devices with continuous glucose monitoring (CGM) and closed‐loop insulin delivery are crucial for diabetes management. However, design challenges remain, including miniaturization, low cost, stability, and low power consumption. Current commercial products are expensive ($3,000 to $8,000 USD), and bulky, typically exceeding 100 cm3. Here, a closed‐loop bioelectronic artificial pancreas patch is presented for continuous blood glucose regulation in diabetic rats and pigs. By designing transiently dissolvable microneedle arrays incorporated with microtube arrays, insulin is efficiently delivered into interstitial fluid, eliminating the need for an external long needle. Leveraging multi‐layer sensing electrodes, Ag/Ag2O glass‐fiber pumping electrodes, and a polyethylene‐glycol (PEG) functionalized polycarbonate membrane, the closed‐loop artificial pancreas patch demonstrates highly stable sensing and pumping with low power consumption (only 0.422 mW), enabling long‐term continuous operation to regulate blood glucose. In particular, diabetic pigs are operated on for 3 consecutive days, showing steady blood glucose control with a time in range (3.9–10.0 mm) of ≈67.98%, comparable to a commercial closed‐loop system at ≈74.95%. The total volume of the entire system is ≈2 cm3, and the cost is ≈$10. This method opens up promising avenues for the development and application of wearable devices to manage diabetes. A closed-loop bioelectronic artificial pancreas patch is presented for glucose monitoring and regulation. Utilizing transiently dissolvable microneedle arrays integrated with microtube arrays, the patch efficiently delivers insulin into interstitial fluid, eliminating the need for external long needles. In diabetic pigs, it demonstrates excellent blood glucose control comparable to commercial closed-loop systems, while offering advantages such as miniaturization, low cost, and low power consumption. Abstract Integrated artificial pancreas devices with continuous glucose monitoring (CGM) and closed-loop insulin delivery are crucial for diabetes management. However, design challenges remain, including miniaturization, low cost, stability, and low power consumption. Current commercial products are expensive ($3,000 to $8,000 USD), and bulky, typically exceeding 100 cm 3. Here, a closed-loop bioelectronic artificial pancreas patch is presented for continuous blood glucose regulation in diabetic rats and pigs. By designing transiently dissolvable microneedle arrays incorporated with microtube arrays, insulin is efficiently delivered into interstitial fluid, eliminating the need for an external long needle. Leveraging multi-layer sensing electrodes, Ag/Ag 2 O glass-fiber pumping electrodes, and a polyethylene-glycol (PEG) functionalized polycarbonate membrane, the closed-loop artificial pancreas patch demonstrates highly stable sensing and pumping with low power consumption (only 0.422 mW), enabling long-term continuous operation to regulate blood glucose. In particular, diabetic pigs are operated on for 3 consecutive days, showing steady blood glucose control with a time in range (3.9–10.0 m m ) of ≈67.98%, comparable to a commercial closed-loop system at ≈74.95%. The total volume of the entire system is ≈2 cm 3, and the cost is ≈$10. This method opens up promising avenues for the development and application of wearable devices to manage diabetes. Advanced Science, Volume 12, Issue 44, November 27, 2025.

PVC Nanoplastics Exposure Exacerbates Asthma through R‐Loop Accumulation and Subsequent STING Activation in Macrophages

Polyvinyl chloride (PVC) nanoplastics (NPs) are shown to aggravate allergic airway inflammation in asthma by triggering R‐loop accumulation and activating the cGAS‐STING pathway in macrophages. This study reveals a novel immunotoxic mechanism linking environmental plastic exposure to asthma pathogenesis and highlights potential molecular targets for mitigating nanoplastic‐induced respiratory inflammation. Abstract Asthma is a chronic inflammatory respiratory disease influenced by genetic and environmental factors. Emerging evidence suggests that microplastics and nanoplastics (NPs) pose significant health risks. When inhaled, these tiny particles can accumulate in the lungs, triggering inflammation, oxidative stress, and other disruptions in pulmonary function. This study investigates the role of polyvinyl chloride (PVC) NPs, which are extensively used in products such as packaging, medical devices, and construction materials, in asthma pathogenesis. Using an ovalbumin (OVA)‐induced murine asthma model, it is demonstrated that PVC NPs exposure exacerbates airway hyperresponsiveness, increases inflammatory cell infiltration, and elevates inflammatory cytokine levels in the lungs. Further mechanistic studies reveal that PVC NPs suppress Ribonuclease H1 (RNASEH1), leading to RNA–DNA hybrid loop (R‐loop) accumulation and activation of the Cyclic GMP‐AMP Synthase (cGAS)‐Stimulator of Interferon Genes (STING) inflammatory pathway. The critical involvement of this pathway is confirmed using STING‐deficient mice, where pathway inhibition alleviates the inflammation exacerbated by PVC NPs exposure. These findings provide new insights into the potential role of NPs pollutants in modulating immune responses through R‐loop formation, linking PVC NPs to asthma pathogenesis. This study highlights the importance of addressing environmental exposure to NPs in asthma prevention and management and identifies potential molecular targets for therapeutic intervention. Polyvinyl chloride (PVC) nanoplastics (NPs) are shown to aggravate allergic airway inflammation in asthma by triggering R-loop accumulation and activating the cGAS-STING pathway in macrophages. This study reveals a novel immunotoxic mechanism linking environmental plastic exposure to asthma pathogenesis and highlights potential molecular targets for mitigating nanoplastic-induced respiratory inflammation. Abstract Asthma is a chronic inflammatory respiratory disease influenced by genetic and environmental factors. Emerging evidence suggests that microplastics and nanoplastics (NPs) pose significant health risks. When inhaled, these tiny particles can accumulate in the lungs, triggering inflammation, oxidative stress, and other disruptions in pulmonary function. This study investigates the role of polyvinyl chloride (PVC) NPs, which are extensively used in products such as packaging, medical devices, and construction materials, in asthma pathogenesis. Using an ovalbumin (OVA)-induced murine asthma model, it is demonstrated that PVC NPs exposure exacerbates airway hyperresponsiveness, increases inflammatory cell infiltration, and elevates inflammatory cytokine levels in the lungs. Further mechanistic studies reveal that PVC NPs suppress Ribonuclease H1 (RNASEH1), leading to RNA–DNA hybrid loop (R-loop) accumulation and activation of the Cyclic GMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) inflammatory pathway. The critical involvement of this pathway is confirmed using STING-deficient mice, where pathway inhibition alleviates the inflammation exacerbated by PVC NPs exposure. These findings provide new insights into the potential role of NPs pollutants in modulating immune responses through R-loop formation, linking PVC NPs to asthma pathogenesis. This study highlights the importance of addressing environmental exposure to NPs in asthma prevention and management and identifies potential molecular targets for therapeutic intervention. Advanced Science, Volume 12, Issue 44, November 27, 2025.

XBP1s Mediates Cross‐resistance to Combination Treatment of CDK4/6 Inhibitors plus Endocrine Therapy in Breast Cancer

Elevated spliced form of X‐box–binding protein 1 (XBP1) correlates with unfavorable responses to endocrine therapy plus CDK4/6 inhibitors in HR+/HER2− advanced breast cancer. XBP1s facilitates cell proliferation and G1/S transition by transcriptionally activating SND1, thereby activating the E2F1 pathway. By blocking XBP1 splicing, 4µ8C sensitizes cells and exhibits a synergistic effect with fulvestrant and palbociclib, providing a novel therapeutic strategy. Abstract CDK4/6 inhibitors combined with endocrine therapy is the standard treatment for patients with hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2‐negative (HER2−) metastatic breast cancer (MBC). However, the inevitable development of treatment resistance and lack of approved biomarkers for predicting therapeutic efficacy remain urgent concerns. This study indicates that XBP1 is prominently and specifically expressed in HR+/HER2− breast cancer, and correlated with unfavorable response and poor progression‐free survival in patients with MBC receiving the combined therapy. XBP1s, a transcriptionally active spliced form of XBP1, accelerates tumor progression by facilitating cell proliferation and G1/S transition, and attenuates the efficacy of palbociclib and fulvestrant. Conversely, it can be reversed through epigenetic and pharmacological inhibition of XBP1s expression. Mechanistically, XBP1s activates the E2F1 pathway and upregulates downstream targets by transcriptionally activating SND1. Using patient‐derived organoids, it is confirmed that XBP1s plays a pro‐survival role and counteracts E2F1 pathway inhibition caused by the combined therapy, whereas 4µ8C sensitizes cells and exerts a synergistic effect with both fulvestrant and palbociclib. In conclusion, the findings indicate that XBP1s may serve as a potential marker for identifying patients who may not benefit from the medication, and offer a novel therapeutic strategy for patients with HR+/HER2− MBC. Elevated spliced form of X-box–binding protein 1 (XBP1) correlates with unfavorable responses to endocrine therapy plus CDK4/6 inhibitors in HR+/HER2− advanced breast cancer. XBP1s facilitates cell proliferation and G1/S transition by transcriptionally activating SND1, thereby activating the E2F1 pathway. By blocking XBP1 splicing, 4µ8C sensitizes cells and exhibits a synergistic effect with fulvestrant and palbociclib, providing a novel therapeutic strategy. Abstract CDK4/6 inhibitors combined with endocrine therapy is the standard treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). However, the inevitable development of treatment resistance and lack of approved biomarkers for predicting therapeutic efficacy remain urgent concerns. This study indicates that XBP1 is prominently and specifically expressed in HR+/HER2− breast cancer, and correlated with unfavorable response and poor progression-free survival in patients with MBC receiving the combined therapy. XBP1s, a transcriptionally active spliced form of XBP1, accelerates tumor progression by facilitating cell proliferation and G1/S transition, and attenuates the efficacy of palbociclib and fulvestrant. Conversely, it can be reversed through epigenetic and pharmacological inhibition of XBP1s expression. Mechanistically, XBP1s activates the E2F1 pathway and upregulates downstream targets by transcriptionally activating SND1. Using patient-derived organoids, it is confirmed that XBP1s plays a pro-survival role and counteracts E2F1 pathway inhibition caused by the combined therapy, whereas 4µ8C sensitizes cells and exerts a synergistic effect with both fulvestrant and palbociclib. In conclusion, the findings indicate that XBP1s may serve as a potential marker for identifying patients who may not benefit from the medication, and offer a novel therapeutic strategy for patients with HR+/HER2− MBC. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Rational Grain Boundary Segregation Enables Long‐Term Thermally Stable, Catalytically Active, and CO‐Tolerant Nanograined Metals

Grain boundaries endow nanocrystalline metals with unique functions but suffer thermal instability. In boron‐segregated platinum, stability depends critically on segregation level—sub‐equilibrium concentrations strengthen boundaries, whereas oversaturation induces decohesion. A three‐step design framework enables fabrication of thermally stable, catalytically active Pt nanograins with enhanced CO tolerance, offering a blueprint for robust nanocrystalline materials. Abstract Grain boundaries (GBs) impart nanocrystalline metals with unique functional properties but are often plagued by poor thermal stability. While solute segregation is commonly used to stabilize GBs, stability alone is insufficient—effective strategies must also preserve, or ideally enhance, functional activity, a critical aspect largely overlooked. Here, it is shown that GB segregation is not universally beneficial: the same segregant can either stabilize or destabilize GBs depending on its local concentration and spatial distribution. Using boron‐segregated platinum as an example, a concentration‐dependent duality is uncovered: at sub‐equilibrium levels, boron strengthens GB cohesion and preserves structure during prolonged annealing; when oversaturated, boron clusters near GBs, generating repulsive interactions that trigger decohesion. In extreme cases, segregation can render GBs less stable than those without segregants. To address this, a three‐step framework is established for rational GB design: 1) theoretical selection of segregants with strong GB affinity and minimal impact on catalytic energetics, 2) thermodynamic determination of segregation limits, and 3) kinetic trapping during nanoparticle attachment for targeted GB incorporation. Guided by this approach, thermally stable, GB‐rich platinum nanograins that retain high catalytic activity and exhibit enhanced carbon monoxide tolerance are fabricated. This work provides a blueprint for engineering robust, high‐performance nanocrystalline materials. Grain boundaries endow nanocrystalline metals with unique functions but suffer thermal instability. In boron-segregated platinum, stability depends critically on segregation level—sub-equilibrium concentrations strengthen boundaries, whereas oversaturation induces decohesion. A three-step design framework enables fabrication of thermally stable, catalytically active Pt nanograins with enhanced CO tolerance, offering a blueprint for robust nanocrystalline materials. Abstract Grain boundaries (GBs) impart nanocrystalline metals with unique functional properties but are often plagued by poor thermal stability. While solute segregation is commonly used to stabilize GBs, stability alone is insufficient—effective strategies must also preserve, or ideally enhance, functional activity, a critical aspect largely overlooked. Here, it is shown that GB segregation is not universally beneficial: the same segregant can either stabilize or destabilize GBs depending on its local concentration and spatial distribution. Using boron-segregated platinum as an example, a concentration-dependent duality is uncovered: at sub-equilibrium levels, boron strengthens GB cohesion and preserves structure during prolonged annealing; when oversaturated, boron clusters near GBs, generating repulsive interactions that trigger decohesion. In extreme cases, segregation can render GBs less stable than those without segregants. To address this, a three-step framework is established for rational GB design: 1) theoretical selection of segregants with strong GB affinity and minimal impact on catalytic energetics, 2) thermodynamic determination of segregation limits, and 3) kinetic trapping during nanoparticle attachment for targeted GB incorporation. Guided by this approach, thermally stable, GB-rich platinum nanograins that retain high catalytic activity and exhibit enhanced carbon monoxide tolerance are fabricated. This work provides a blueprint for engineering robust, high-performance nanocrystalline materials. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Dissecting the Molecular Determinants of α‐synuclein Phase Separation and Condensate Aging: The Pivotal Role of β‐Sheet‐Rich Motifs

Through multiscale simulations and experimental approaches, the molecular determinants of α‐synuclein phase separation and condensate aging, which are linked to Parkinson's disease, are uncovered. Seven motifs are identified with high β‐sheet propensity in monomeric α‐synuclein and increasing β‐sheet tendencies during condensation and pre‐solidification. Persistent and transient interactions among them drive the fibrilization and phase separation of α‐synuclein. Abstract Emerging evidence indicates that liquid‐liquid phase separation of α‐synuclein occurs during the nucleation step of its aggregation, a pivotal step in the onset of Parkinson's disease. Elucidating the molecular determinants governing this process is essential for understanding the pathological mechanisms of diseases and developing therapeutic strategies that target early‐stage aggregation. While previous studies have identified residues critical for α‐synuclein amyloid formation, the key residues and molecular drivers of its phase separation remain largely unexplored. Herein, multiscale simulations and experimental approaches are employed to uncover the molecular determinants dictating α‐synuclein phase separation and the pre‐solidification of its condensates. Seven motifs are identified that exhibit high β‐sheet propensity in the monomeric state of α‐synuclein and progressively increase in β‐sheet content during condensation. Notably, two C‐terminal motifs engage in a percolated network of intermolecular interactions through transient hydrogen bonds, contributing to the phase boundary properties. Deletion of these motifs reduces the phase separation ability of α‐synuclein, underscoring their essential roles in this process. Together, the findings reveal crucial phase separation hotspots and shed light on the molecular mechanism underlying α‐synuclein phase separation, offering significant insights and novel potential therapeutic targets for Parkinson's disease. Through multiscale simulations and experimental approaches, the molecular determinants of α-synuclein phase separation and condensate aging, which are linked to Parkinson's disease, are uncovered. Seven motifs are identified with high β-sheet propensity in monomeric α-synuclein and increasing β-sheet tendencies during condensation and pre-solidification. Persistent and transient interactions among them drive the fibrilization and phase separation of α-synuclein. Abstract Emerging evidence indicates that liquid-liquid phase separation of α-synuclein occurs during the nucleation step of its aggregation, a pivotal step in the onset of Parkinson's disease. Elucidating the molecular determinants governing this process is essential for understanding the pathological mechanisms of diseases and developing therapeutic strategies that target early-stage aggregation. While previous studies have identified residues critical for α-synuclein amyloid formation, the key residues and molecular drivers of its phase separation remain largely unexplored. Herein, multiscale simulations and experimental approaches are employed to uncover the molecular determinants dictating α-synuclein phase separation and the pre-solidification of its condensates. Seven motifs are identified that exhibit high β-sheet propensity in the monomeric state of α-synuclein and progressively increase in β-sheet content during condensation. Notably, two C-terminal motifs engage in a percolated network of intermolecular interactions through transient hydrogen bonds, contributing to the phase boundary properties. Deletion of these motifs reduces the phase separation ability of α-synuclein, underscoring their essential roles in this process. Together, the findings reveal crucial phase separation hotspots and shed light on the molecular mechanism underlying α-synuclein phase separation, offering significant insights and novel potential therapeutic targets for Parkinson's disease. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Constructing Stable Sub/Surface Structure to Boost Superior Cyclabilities of Single‐Crystalline Ni‐Rich Cathode

A dual‐modification strategy combining gradient Al/B co‐doping and a robust Al5BO9 surface coating in this work enables synergistic bulk and surface stabilization in single‐crystalline LiNi0.90Co0.05Mn0.05O2 for lithium‐ion batteries. The engineered cathode exhibits 89.6% capacity retention over 1000 cycles in pouch full cells, among the best performances reported for single‐crystalline Ni‐rich cathodes. Abstract Under prolonged high‐voltage cycling, single‐crystalline Ni‐rich cathodes are prone to severe transition metal dissolution, irreversible phase transformations, and reduced structural stability, which significantly hinder their practical application. Hence, a dual‐modification strategy is proposed and implemented for single‐crystalline LiNi0.90Co0.05Mn0.05O2 (SCNCM90) cathodes by introducing Al/B gradient co‐doping and an Al5BO9 surface coating to mitigate anisotropic structural changes. The subsurface Al/B gradient doping induces a lithium‐rich vacancy disordered structure, which effectively suppresses the H2‐H3 phase transition, while suppressing lattice strain and mechanical degradation. In parallel, the chemically stable Al5BO9 surface coating significantly mitigates harmful electrode‐electrolyte interfacial reactions, thereby enhancing both structural and electrochemical stability under high‐voltage conditions. Electrochemical tests reveal that the Al/B co‐modified SCNCM90 electrode exhibits markedly improved performance, achieving 95.83% capacity retention after 200 cycles at 4.5 V and maintaining 89.6% retention at 1C after 1000 cycles in pouch‐type full cells within 3–4.25 V. Moreover, the modified electrode demonstrates superior lithium‐ion diffusion kinetics and enhanced thermodynamic stability during cycling. This effective dual‐modification strategy offers a promising pathway to improve the structural robustness and electrochemical durability of single‐crystalline Ni‐rich cathodes, thus accelerating their adoption in next‐generation high‐energy lithium‐ion batteries. A dual-modification strategy combining gradient Al/B co-doping and a robust Al 5 BO 9 surface coating in this work enables synergistic bulk and surface stabilization in single-crystalline LiNi 0.90 Co 0.05 Mn 0.05 O 2 for lithium-ion batteries. The engineered cathode exhibits 89.6% capacity retention over 1000 cycles in pouch full cells, among the best performances reported for single-crystalline Ni-rich cathodes. Abstract Under prolonged high-voltage cycling, single-crystalline Ni-rich cathodes are prone to severe transition metal dissolution, irreversible phase transformations, and reduced structural stability, which significantly hinder their practical application. Hence, a dual-modification strategy is proposed and implemented for single-crystalline LiNi 0.90 Co 0.05 Mn 0.05 O 2 (SCNCM90) cathodes by introducing Al/B gradient co-doping and an Al 5 BO 9 surface coating to mitigate anisotropic structural changes. The subsurface Al/B gradient doping induces a lithium-rich vacancy disordered structure, which effectively suppresses the H2-H3 phase transition, while suppressing lattice strain and mechanical degradation. In parallel, the chemically stable Al 5 BO 9 surface coating significantly mitigates harmful electrode-electrolyte interfacial reactions, thereby enhancing both structural and electrochemical stability under high-voltage conditions. Electrochemical tests reveal that the Al/B co-modified SCNCM90 electrode exhibits markedly improved performance, achieving 95.83% capacity retention after 200 cycles at 4.5 V and maintaining 89.6% retention at 1C after 1000 cycles in pouch-type full cells within 3–4.25 V. Moreover, the modified electrode demonstrates superior lithium-ion diffusion kinetics and enhanced thermodynamic stability during cycling. This effective dual-modification strategy offers a promising pathway to improve the structural robustness and electrochemical durability of single-crystalline Ni-rich cathodes, thus accelerating their adoption in next-generation high-energy lithium-ion batteries. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Unveiling Thermoelectric Properties of SURMOF Nanofilms: A New Frontier in Molecular Thermoelectrics

Layer‐by‐layer engineered surface‐mounted metal‐organic framework (SURMOF) nanofilms exhibit enhanced thermoelectric performance through precise control of thickness, molecular alignment, and guest doping. Abstract Molecular thermoelectric materials, which harness molecular‐level design principles to optimize energy conversion, have emerged as a promising strategy for addressing the limitations of bulk inorganic thermoelectrics, such as brittleness and high production costs. In this study, a layer‐by‐layer (LbL) engineered HKUST‐1 surface‐mounted metal‐organic framework (SURMOF) nanofilm is proposed as a promising thermoelectric nanostructure, systematically characterized across its thickness. By employing LbL growth of HKUST‐1 on self‐assembled monolayers (SCnCOOH, n = 2, 10), nanofilms ranging from 5 to 30 nm in thickness are successfully fabricated. Thermoelectric characterization of these nanofilms revealed a significant enhancement in Seebeck coefficient (S) and power factor (PF), with PF values surpassing those of conventional organic SAMs by a factor of 103. Ultraviolet photoelectron spectroscopy (UPS) measurements further confirmed a correlation between molecular orbital alignment and thermoelectric performance, particularly in junctions doped with guest molecules such as ferrocene (Fc) and 7,7,8,8‐tetracyanoquinodimethane (TCNQ). These findings establish SURMOF nanofilms as a viable molecular thermoelectric architecture, offering enhanced carrier transport, guest‐responsive electronic properties, and precise structural control at the nanoscale. Layer-by-layer engineered surface-mounted metal-organic framework (SURMOF) nanofilms exhibit enhanced thermoelectric performance through precise control of thickness, molecular alignment, and guest doping. Abstract Molecular thermoelectric materials, which harness molecular-level design principles to optimize energy conversion, have emerged as a promising strategy for addressing the limitations of bulk inorganic thermoelectrics, such as brittleness and high production costs. In this study, a layer-by-layer (LbL) engineered HKUST-1 surface-mounted metal-organic framework (SURMOF) nanofilm is proposed as a promising thermoelectric nanostructure, systematically characterized across its thickness. By employing LbL growth of HKUST-1 on self-assembled monolayers (SC n COOH, n = 2, 10), nanofilms ranging from 5 to 30 nm in thickness are successfully fabricated. Thermoelectric characterization of these nanofilms revealed a significant enhancement in Seebeck coefficient ( S ) and power factor (PF), with PF values surpassing those of conventional organic SAMs by a factor of 10 3. Ultraviolet photoelectron spectroscopy (UPS) measurements further confirmed a correlation between molecular orbital alignment and thermoelectric performance, particularly in junctions doped with guest molecules such as ferrocene (Fc) and 7,7,8,8-tetracyanoquinodimethane (TCNQ). These findings establish SURMOF nanofilms as a viable molecular thermoelectric architecture, offering enhanced carrier transport, guest-responsive electronic properties, and precise structural control at the nanoscale. Advanced Science, Volume 12, Issue 44, November 27, 2025.