HCP Network – Latest Medical Journals, Research Articles & Clinical Updates

Bisphenol B Exposure Induces Miscarriage by Suppressing Migration/Invasion and Migrasome Formation

BPB (Bisphenol B) exposure up‐regulates ER (estrogen receptor) levels, enhances its interactions with the lnc‐HZ04 promoter region, and thus promotes ER‐mediated lnc‐HZ04 transcription. Subsequently, lnc‐HZ04 suppresses TCF4 (transcription factor 4)‐mediated PKCA (protein kinase C alpha) transcription and subsequently suppresses migration/invasion and migrasome formation. Abstract Unexplained miscarriage (UM) remains challenge due to unclear pathogenesis and biological mechanisms. BPB (Bisphenol B), an extensively used endocrine disrupting chemical, has been widely detected out in human. Migrasomes are newly identified cellular organelles with a large number of unknown functions. However, whether and how BPB exposure may suppress migrasome formation (MF) to induce miscarriage are completely unknown. In this study, it is found that higher urinary BPB levels are associated with the suppressed MF in villous tissues and unexplained miscarriage. It is further confirmed that BPB exposure suppresses MF in the mouse placenta and thus induces miscarriage. Supplement with Pkca or Tspan4, two essential proteins for migration/invasion (MI) and MF, can efficiently treat against BPB‐induced miscarriage. In biological mechanisms, BPB up‐regulates ER levels, enhances its interactions with the lnc‐HZ04 promoter region, and thus promotes ER‐mediated lnc‐HZ04 transcription. Subsequently, lnc‐HZ04 suppresses TCF4‐mediated PKCA transcription and subsequently suppresses MI and MF. Collectively, this study not only identifies BPB as a novel risk factor for unexplained miscarriage, discovers novel pathogenesis and biological mechanisms in BPB‐induced miscarriage, but also provides potential targets for treatment against unexplained miscarriage. BPB (Bisphenol B) exposure up-regulates ER (estrogen receptor) levels, enhances its interactions with the lnc-HZ04 promoter region, and thus promotes ER-mediated lnc-HZ04 transcription. Subsequently, lnc-HZ04 suppresses TCF4 (transcription factor 4)-mediated PKCA (protein kinase C alpha) transcription and subsequently suppresses migration/invasion and migrasome formation. Abstract Unexplained miscarriage (UM) remains challenge due to unclear pathogenesis and biological mechanisms. BPB (Bisphenol B), an extensively used endocrine disrupting chemical, has been widely detected out in human. Migrasomes are newly identified cellular organelles with a large number of unknown functions. However, whether and how BPB exposure may suppress migrasome formation (MF) to induce miscarriage are completely unknown. In this study, it is found that higher urinary BPB levels are associated with the suppressed MF in villous tissues and unexplained miscarriage. It is further confirmed that BPB exposure suppresses MF in the mouse placenta and thus induces miscarriage. Supplement with Pkca or Tspan4, two essential proteins for migration/invasion (MI) and MF, can efficiently treat against BPB-induced miscarriage. In biological mechanisms, BPB up-regulates ER levels, enhances its interactions with the lnc-HZ04 promoter region, and thus promotes ER-mediated lnc-HZ04 transcription. Subsequently, lnc-HZ04 suppresses TCF4-mediated PKCA transcription and subsequently suppresses MI and MF. Collectively, this study not only identifies BPB as a novel risk factor for unexplained miscarriage, discovers novel pathogenesis and biological mechanisms in BPB-induced miscarriage, but also provides potential targets for treatment against unexplained miscarriage. Advanced Science, EarlyView.

Multimaterial 3D Printing of Soft and Stretchable Electronics

A multimaterial resin for two‐photon polymerization integrates PEDOT:PSS and carbon nanotubes to enable direct 3D printing of conductive, insulating, and electroactive microstructures. The hybrid exhibits high conductivity, optical transparency, and stability under strain and pH variation, advancing scalable fabrication of flexible soft electronics and bioelectronic microsystems. Abstract The development of soft and stretchable microelectronics is critical for next‐generation flexible devices, biointerfaces, and microscale energy systems due to their unique electrical and mechanical properties. However, current 3D printing methods, particularly two‐photon polymerization (2PP), remain limited by low electrical conductivity, filler aggregation, and loss of optical transparency. Here, we present a multimaterial 2PP‐compatible resin that integrates the conducting polymer PEDOT:PSS and multi‐walled carbon nanotubes within a hydrogel PEGDA matrix to overcome these challenges. The optimized composite achieves a conductivity of 1.4 × 10⁵ S m−1 (≈10⁴‐fold improvement over pristine PEGDA), > 80% optical transmittance, and stable high‐resolution patterning. Directly printed microresistors and microcapacitors exhibit a specific capacitance of ≈667 F g−1, combining electric‐double‐layer and pseudocapacitive charge storage. The printed structures maintain ≈65% of their conductivity under 50% tensile strain and remain conductive after 3000 stretching cycles at 10% strain, with no delamination from PDMS. The composite also preserves geometry and adhesion across pH 3–10, confirming chemical robustness. This sequential multimaterial 2PP approach enables monolithic integration of conductive, insulating, and electroactive domains for flexible, stretchable, and chemically stable soft microelectronics, advancing scalable fabrication of biointerfaces, wearable devices, and microscale energy‐storage systems. A multimaterial resin for two-photon polymerization integrates PEDOT:PSS and carbon nanotubes to enable direct 3D printing of conductive, insulating, and electroactive microstructures. The hybrid exhibits high conductivity, optical transparency, and stability under strain and pH variation, advancing scalable fabrication of flexible soft electronics and bioelectronic microsystems. Abstract The development of soft and stretchable microelectronics is critical for next-generation flexible devices, biointerfaces, and microscale energy systems due to their unique electrical and mechanical properties. However, current 3D printing methods, particularly two-photon polymerization (2PP), remain limited by low electrical conductivity, filler aggregation, and loss of optical transparency. Here, we present a multimaterial 2PP-compatible resin that integrates the conducting polymer PEDOT:PSS and multi-walled carbon nanotubes within a hydrogel PEGDA matrix to overcome these challenges. The optimized composite achieves a conductivity of 1.4 × 10⁵ S m −1 (≈10⁴-fold improvement over pristine PEGDA), > 80% optical transmittance, and stable high-resolution patterning. Directly printed microresistors and microcapacitors exhibit a specific capacitance of ≈667 F g −1, combining electric-double-layer and pseudocapacitive charge storage. The printed structures maintain ≈65% of their conductivity under 50% tensile strain and remain conductive after 3000 stretching cycles at 10% strain, with no delamination from PDMS. The composite also preserves geometry and adhesion across pH 3–10, confirming chemical robustness. This sequential multimaterial 2PP approach enables monolithic integration of conductive, insulating, and electroactive domains for flexible, stretchable, and chemically stable soft microelectronics, advancing scalable fabrication of biointerfaces, wearable devices, and microscale energy-storage systems. Advanced Science, EarlyView.

Cinnamic‐Hydroxamic‐Acid Derivatives Exhibit Antibiotic, Anti‐Biofilm, and Supercoiling Relaxation Properties by Targeting Bacterial Nucleoid‐Associated Protein HU

Cinnamic‐hydroxamic‐acid derivatives (CHADs) are identified as novel inhibitors of the bacterial nucleoid‐associated protein HU, exhibiting potent antibacterial, anti‐biofilm (both inhibition and eradication), and DNA relaxation (anti‐supercoiling) activities. Moreover, CHADs demonstrate strong synergistic effects with multiple antibiotics. Abstract Finding novel compounds and drug targets is crucial for antibiotic development. The nucleoid‐associated protein HU plays a significant role in bacterial DNA metabolism, supercoiling, and biofilm formation, making it a promising new target. In this work, structure‐based screening and identified cinnamic‐hydroxamic‐acid derivatives (CHADs) are conducted as HU inhibitors, with a minimum inhibitory concentration (MIC) of as low as 12 µg mL−1 against a range of pathogenic bacteria. CHADs induce nucleoid deformation, preventing bacterial division and inhibiting growth. They exhibit low toxicity in mice and effectively treat infections in mouse models. Additionally, CHADs possess anti‐biofilm activity and supercoiling relaxation properties, countering bacterial stress responses to antibiotics. They suppress changes in gene expression required for optimal stress responses, resulting in synergistic effects with other antibiotics. Thus, CHADs represent a new class of antibiotics that inhibit bacterial stress responses by co‐targeting biofilm formation and DNA supercoiling. Cinnamic-hydroxamic-acid derivatives (CHADs) are identified as novel inhibitors of the bacterial nucleoid-associated protein HU, exhibiting potent antibacterial, anti-biofilm (both inhibition and eradication), and DNA relaxation (anti-supercoiling) activities. Moreover, CHADs demonstrate strong synergistic effects with multiple antibiotics. Abstract Finding novel compounds and drug targets is crucial for antibiotic development. The nucleoid-associated protein HU plays a significant role in bacterial DNA metabolism, supercoiling, and biofilm formation, making it a promising new target. In this work, structure-based screening and identified cinnamic-hydroxamic-acid derivatives (CHADs) are conducted as HU inhibitors, with a minimum inhibitory concentration (MIC) of as low as 12 µg mL −1 against a range of pathogenic bacteria. CHADs induce nucleoid deformation, preventing bacterial division and inhibiting growth. They exhibit low toxicity in mice and effectively treat infections in mouse models. Additionally, CHADs possess anti-biofilm activity and supercoiling relaxation properties, countering bacterial stress responses to antibiotics. They suppress changes in gene expression required for optimal stress responses, resulting in synergistic effects with other antibiotics. Thus, CHADs represent a new class of antibiotics that inhibit bacterial stress responses by co-targeting biofilm formation and DNA supercoiling. Advanced Science, EarlyView.

Advanced Therapeutic Approach Based on LDHs–Mimetic Oxidoreductase

Overview of Sructure, Multienzyme‐mimicking Activity and Advanced Therapeutic Approach Based on LDHs–Mimetic Oxidoreductase. Abstract Redox dysregulation is recognized as a key driver in the pathophysiology of numerous refractory diseases, contributing significantly to the progression and poor prognosis. The precise targeting and sophisticated modulation of redox processes within pathological microenvironments thus offer a promising avenue for innovative therapeutic strategies. Layered double hydroxides (LDHs)−based nanozyme lies in the programmable multi−active site architecture, which enables unprecedented functional integration for precise pathological microenvironment remodeling. In this review, the redox modulating mechanisms of LDHs−based nanozyme in these critical disease contexts are systematically explored, with special emphasis on intrinsic enzyme−like activities and structure−activity relationships. At the same time, it highlights how designing LDHs−based nanozyme can manipulate redox homeostasis to precisely reprogram the pathological microenvironment for stimulating effective, context−dependent pro− and anti−inflammatory therapeutic outcomes, which is a crucial requirement in conditions such as tumors and tissue injury. Finally, building upon recent advances, a forward−looking perspective is provided on the current challenges and future research directions in this rapidly progressing field. Overview of Sructure, Multienzyme-mimicking Activity and Advanced Therapeutic Approach Based on LDHs–Mimetic Oxidoreductase. Abstract Redox dysregulation is recognized as a key driver in the pathophysiology of numerous refractory diseases, contributing significantly to the progression and poor prognosis. The precise targeting and sophisticated modulation of redox processes within pathological microenvironments thus offer a promising avenue for innovative therapeutic strategies. Layered double hydroxides (LDHs)−based nanozyme lies in the programmable multi−active site architecture, which enables unprecedented functional integration for precise pathological microenvironment remodeling. In this review, the redox modulating mechanisms of LDHs−based nanozyme in these critical disease contexts are systematically explored, with special emphasis on intrinsic enzyme−like activities and structure−activity relationships. At the same time, it highlights how designing LDHs−based nanozyme can manipulate redox homeostasis to precisely reprogram the pathological microenvironment for stimulating effective, context−dependent pro− and anti−inflammatory therapeutic outcomes, which is a crucial requirement in conditions such as tumors and tissue injury. Finally, building upon recent advances, a forward−looking perspective is provided on the current challenges and future research directions in this rapidly progressing field. Advanced Science, EarlyView.

Novel Antifungal Scaffold Targeting Tubulin Overcomes Sclerotinia Sclerotiorum Resistance

Addressing pesticide resistance, novel chromone‐acylhydrazone hybrids targeting fungal tubulin are synthesized. Compound G24 potently inhibited S. sclerotiorum (EC50 = 0.21µg mL−1) and demonstrated enhanced field performance via microencapsulation, offering a sustainable strategy against resistance and for global food security. Abstract The increasing prevalence of pesticide resistance in pathogenic bacteria, particularly among broad‐host‐range fungal pathogens such as S. sclerotiorum, poses a significant threat to global crop production and food security. Addressing this challenge requires the development of targeted compounds with novel mechanisms of action. Herein, a novel chromone‐acylhydrazone hybrid scaffold is designed and synthesized to specifically target fungal tubulin. Bioassay results identified compound G24 as a highly potent inhibitor of S. sclerotiorum (EC50 = 0.21 µg mL−1), exhibiting superior efficacy compared to conventional fungicides. Mechanistic investigations, including molecular docking, molecular dynamics, and immunofluorescence staining, revealed that G24 effectively disrupts tubulin polymerization by forming hydrogen bonds with key tubulin residues. Notably, G24 exhibits selective antifungal activity while maintaining mammalian safety, addressing critical toxicity concerns. To enhance field performance, polyurethane microcapsules loaded with G24 (G24‐Loaded PU‐MCs) are developed with an encapsulation efficiency of 89.41%, facilitating slow‐release kinetics, improved foliar adhesion, and prolonged pathogen suppression. This integrated approach, combining targeted compound design with microencapsulation, offers a promising and sustainable strategy for combating pesticide resistance and promoting global food security. Addressing pesticide resistance, novel chromone-acylhydrazone hybrids targeting fungal tubulin are synthesized. Compound G24 potently inhibited S. sclerotiorum (EC 50 = 0.21µg mL −1 ) and demonstrated enhanced field performance via microencapsulation, offering a sustainable strategy against resistance and for global food security. Abstract The increasing prevalence of pesticide resistance in pathogenic bacteria, particularly among broad-host-range fungal pathogens such as S. sclerotiorum, poses a significant threat to global crop production and food security. Addressing this challenge requires the development of targeted compounds with novel mechanisms of action. Herein, a novel chromone-acylhydrazone hybrid scaffold is designed and synthesized to specifically target fungal tubulin. Bioassay results identified compound G24 as a highly potent inhibitor of S. sclerotiorum (EC 50 = 0.21 µg mL −1 ), exhibiting superior efficacy compared to conventional fungicides. Mechanistic investigations, including molecular docking, molecular dynamics, and immunofluorescence staining, revealed that G24 effectively disrupts tubulin polymerization by forming hydrogen bonds with key tubulin residues. Notably, G24 exhibits selective antifungal activity while maintaining mammalian safety, addressing critical toxicity concerns. To enhance field performance, polyurethane microcapsules loaded with G24 (G24-Loaded PU-MCs) are developed with an encapsulation efficiency of 89.41%, facilitating slow-release kinetics, improved foliar adhesion, and prolonged pathogen suppression. This integrated approach, combining targeted compound design with microencapsulation, offers a promising and sustainable strategy for combating pesticide resistance and promoting global food security. Advanced Science, EarlyView.

Cathode Electrolyte Interphase Engineering by Quaternized Chitosan for Stabilized Li–SPAN Batteries

In this work, quaternized chitosan (QCS) is reported as an additive optimizing the sulfurized polyacrylonitrile (SPAN) cathode/electrolyte interphase (CEI). Its high positive charge density adsorbs PF6− anions, enriching the Helmholtz layer with aggregates. This promotes rapid anion desolvation, forming an anion‐derived CEI enriched in LiF. The resulting robust, ion‐conductive CEI significantly enhances Li‐SPAN cell electrochemical performance. Abstract Sulfurized polyacrylonitrile (SPAN) represents a highly promising cathode material for lithium–sulfur (Li–S) batteries, leveraging a solid‐solid sulfur conversion mechanism. However, persistent interfacial side reactions and sluggish redox kinetics in SPAN cathodes compromise the electrochemical performance. Here, quaternized chitosan (QCS) is employed as a functional agent to stabilize the SPAN cathode electrolyte interphase (CEI). The positively charged quaternary ammonium groups selectively adsorb PF6– anions, modifying the Helmholtz layer structure and facilitating the formation of an anion‐derived CEI enriched with LiF. Consequently, the SPAN@QCS‐1.0% cathode delivers a high discharge capacity of 1499 mAh g−1 at 0.2 C, an outstanding rate capability of 902 mAh g−1 at 10 C, and a prolonged cycle life exceeding 1500 cycles at 1 C. Under practical conditions of high sulfur loading (12.0 mg cm−2) and lean electrolyte (E/S ratio = 5 µL mg−1), the SPAN cell achieves a high areal capacity of 17.1 mAh cm−2, surpassing that of conventional lithium–ion batteries (≈4 mAh cm−2) by more than fourfold. Furthermore, a 0.9 Ah pouch‐cell prototype demonstrates stable cycling for over 30 cycles. The interface strategy provides a facile and effective approach to developing high‐performance SPAN‐based Li–S batteries. In this work, quaternized chitosan (QCS) is reported as an additive optimizing the sulfurized polyacrylonitrile (SPAN) cathode/electrolyte interphase (CEI). Its high positive charge density adsorbs PF 6 − anions, enriching the Helmholtz layer with aggregates. This promotes rapid anion desolvation, forming an anion-derived CEI enriched in LiF. The resulting robust, ion-conductive CEI significantly enhances Li-SPAN cell electrochemical performance. Abstract Sulfurized polyacrylonitrile (SPAN) represents a highly promising cathode material for lithium–sulfur (Li–S) batteries, leveraging a solid-solid sulfur conversion mechanism. However, persistent interfacial side reactions and sluggish redox kinetics in SPAN cathodes compromise the electrochemical performance. Here, quaternized chitosan (QCS) is employed as a functional agent to stabilize the SPAN cathode electrolyte interphase (CEI). The positively charged quaternary ammonium groups selectively adsorb PF 6 – anions, modifying the Helmholtz layer structure and facilitating the formation of an anion-derived CEI enriched with LiF. Consequently, the SPAN@QCS-1.0% cathode delivers a high discharge capacity of 1499 mAh g −1 at 0.2 C, an outstanding rate capability of 902 mAh g −1 at 10 C, and a prolonged cycle life exceeding 1500 cycles at 1 C. Under practical conditions of high sulfur loading (12.0 mg cm −2 ) and lean electrolyte (E/S ratio = 5 µL mg −1 ), the SPAN cell achieves a high areal capacity of 17.1 mAh cm −2, surpassing that of conventional lithium–ion batteries (≈4 mAh cm −2 ) by more than fourfold. Furthermore, a 0.9 Ah pouch-cell prototype demonstrates stable cycling for over 30 cycles. The interface strategy provides a facile and effective approach to developing high-performance SPAN-based Li–S batteries. Advanced Science, EarlyView.

Delayformer: Spatiotemporal Transformation for Predicting High‐Dimensional Dynamics

Delayformer introduces a multivariate spatiotemporal transformation (mvSTI) that converts observed variables into delay‐embedded states and cross‐learns their dynamics using a shared Vision Transformer encoder. This approach, grounded in dynamical systems theory, simultaneously predicts all variables in high‐dimensional systems, outperforming state‐of‐the‐art methods on synthetic and real‐world benchmarks and demonstrating strong potential as a foundational time‐series model. Abstract Predicting time series is of great importance in various scientific and engineering fields. However, in the context of limited and noisy data, accurately predicting the dynamics of all variables in a high‐dimensional system is a challenging task due to their nonlinearity and complex interactions. This study introduces the Delayformer framework for simultaneously predicting the dynamics of all variables by developing a novel multivariate spatiotemporal information (mvSTI) transformation that makes each observed variable into a delay‐embedded state (vector) and further cross‐learns those states from different variables. From a dynamical systems viewpoint, Delayformer predicts system states rather than individual variables, thus theoretically and computationally overcoming such nonlinearity and cross‐interaction problems. Specifically, it first utilizes a single shared Visual Transformer (ViT) encoder to cross‐represent dynamical states from observed variables in a delay‐embedded form and then employs distinct linear decoders for predicting next states, i.e., equivalently predicting all original variables in parallel. By leveraging the theoretical foundations of delay embedding theory and the representational capabilities of Transformers, Delayformer outperforms current state‐of‐the‐art methods in forecasting tasks on both synthetic and real‐world datasets. Furthermore, the potential of Delayformer as a foundational time‐series model is demonstrated through cross‐domain forecasting tasks, highlighting its broad applicability across various scenarios. Delayformer introduces a multivariate spatiotemporal transformation (mvSTI) that converts observed variables into delay-embedded states and cross-learns their dynamics using a shared Vision Transformer encoder. This approach, grounded in dynamical systems theory, simultaneously predicts all variables in high-dimensional systems, outperforming state-of-the-art methods on synthetic and real-world benchmarks and demonstrating strong potential as a foundational time-series model. Abstract Predicting time series is of great importance in various scientific and engineering fields. However, in the context of limited and noisy data, accurately predicting the dynamics of all variables in a high-dimensional system is a challenging task due to their nonlinearity and complex interactions. This study introduces the Delayformer framework for simultaneously predicting the dynamics of all variables by developing a novel multivariate spatiotemporal information (mvSTI) transformation that makes each observed variable into a delay-embedded state (vector) and further cross-learns those states from different variables. From a dynamical systems viewpoint, Delayformer predicts system states rather than individual variables, thus theoretically and computationally overcoming such nonlinearity and cross-interaction problems. Specifically, it first utilizes a single shared Visual Transformer (ViT) encoder to cross-represent dynamical states from observed variables in a delay-embedded form and then employs distinct linear decoders for predicting next states, i.e., equivalently predicting all original variables in parallel. By leveraging the theoretical foundations of delay embedding theory and the representational capabilities of Transformers, Delayformer outperforms current state-of-the-art methods in forecasting tasks on both synthetic and real-world datasets. Furthermore, the potential of Delayformer as a foundational time-series model is demonstrated through cross-domain forecasting tasks, highlighting its broad applicability across various scenarios. Advanced Science, EarlyView.

A Rationally Engineered Spleen‐Tropic One‐Component Lipid‐mRNA Complex (OncoLRC) for Cancer Vaccines

OncoLRC, a one‐component lipid‐mRNA complex, enables efficient spleen‐targeted delivery at an exceptionally low lipid‐to‐mRNA mass ratio (1.5:1), robustly activates immune responses, inhibits tumor growth, and synergizes with checkpoint blockade, presenting a next‐generation platform for mRNA vaccines. Abstract mRNA vaccines offer great potential for cancer immunotherapy, yet efficient delivery of antigen‐encoding mRNA to antigen‐presenting cells (APCs) in lymphoid organs remains a significant challenge. Here, OncoLRC is introduced, a rationally engineered, spleen‐tropic, one‐component lipid‐mRNA complex that selectively delivers mRNA to splenic APCs following systemic administration. Through a systemic screening and optimization process, a dimethylamino (DMA)‐lipidoid‐based OncoLRC formulation that achieves nearly exclusive spleen‐targeting mRNA delivery, outperforming its conventional four‐component lipid nanoparticle (LNP) formulation counterpart has been developed. Notably, OncoLRC requires a reduced lipid‐to‐mRNA weight ratio of 1.5:1 compared to the typical 10:1 ratio in standard LNPs. OncoLRC formulated with ovalbumin (OVA) mRNA (OncoLRCOVA) promotes dendritic cell (DC) maturation and activation, eliciting robust antigen‐specific immune responses. Mechanistic studies suggest that splenic delivery is mediated primarily via macropinocytosis. Moreover, OncoLRCOVA enhances the secretion of endogenous cytokines such as IL‐12, further stimulating T cell activation and cytotoxic activity. In the B16F10‐OVA cold tumor model, OncoLRCOVA demonstrates strong prophylactic antitumor efficacy and exhibits a profound synergistic effect when combined with immune checkpoint blockade therapy, leading to significant tumor growth inhibition. Collectively, our findings establish OncoLRC as a simple yet effective APC‐targeted mRNA delivery platform, highlighting its potential as a next‐generation mRNA cancer vaccine system. OncoLRC, a one-component lipid-mRNA complex, enables efficient spleen-targeted delivery at an exceptionally low lipid-to-mRNA mass ratio (1.5:1), robustly activates immune responses, inhibits tumor growth, and synergizes with checkpoint blockade, presenting a next-generation platform for mRNA vaccines. Abstract mRNA vaccines offer great potential for cancer immunotherapy, yet efficient delivery of antigen-encoding mRNA to antigen-presenting cells (APCs) in lymphoid organs remains a significant challenge. Here, OncoLRC is introduced, a rationally engineered, spleen-tropic, one-component lipid-mRNA complex that selectively delivers mRNA to splenic APCs following systemic administration. Through a systemic screening and optimization process, a dimethylamino (DMA)-lipidoid-based OncoLRC formulation that achieves nearly exclusive spleen-targeting mRNA delivery, outperforming its conventional four-component lipid nanoparticle (LNP) formulation counterpart has been developed. Notably, OncoLRC requires a reduced lipid-to-mRNA weight ratio of 1.5:1 compared to the typical 10:1 ratio in standard LNPs. OncoLRC formulated with ovalbumin (OVA) mRNA (OncoLRC OVA ) promotes dendritic cell (DC) maturation and activation, eliciting robust antigen-specific immune responses. Mechanistic studies suggest that splenic delivery is mediated primarily via macropinocytosis. Moreover, OncoLRC OVA enhances the secretion of endogenous cytokines such as IL-12, further stimulating T cell activation and cytotoxic activity. In the B16F10-OVA cold tumor model, OncoLRC OVA demonstrates strong prophylactic antitumor efficacy and exhibits a profound synergistic effect when combined with immune checkpoint blockade therapy, leading to significant tumor growth inhibition. Collectively, our findings establish OncoLRC as a simple yet effective APC-targeted mRNA delivery platform, highlighting its potential as a next-generation mRNA cancer vaccine system. Advanced Science, EarlyView.

Single‐Cell Insights Into Macrophage Subtypes in Pulmonary Infections

This review highlights the dynamic plasticity of macrophages during pulmonary infections and proposes an integrative framework defining six functional subtypes: Inflam‐Ms, Hub‐Ms, Reg‐Ms, Prolif‐Ms, Memory‐Ms, and Senesc‐Ms. Single‐cell omics delineate their distinct roles in homeostasis and infection, refining our understanding of macrophage heterogeneity and its implications for infection biology and therapeutic exploration. Abstract Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single‐cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single‐cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections. This review highlights the dynamic plasticity of macrophages during pulmonary infections and proposes an integrative framework defining six functional subtypes: Inflam-Ms, Hub-Ms, Reg-Ms, Prolif-Ms, Memory-Ms, and Senesc-Ms. Single-cell omics delineate their distinct roles in homeostasis and infection, refining our understanding of macrophage heterogeneity and its implications for infection biology and therapeutic exploration. Abstract Macrophages are pivotal innate immune cells that play essential roles in pathogen recognition, inflammation modulation, and tissue repair during pulmonary infections. Macrophages have remarkable plasticity that is shaped by diverse external stimuli to adapt to the dynamic lung microenvironment. Traditional models of macrophage polarization (M1/M2) cannot capture the full complexity of macrophage heterogeneity and diverse functions during lung infections. Recent advances in single-cell omics have provided new insights into distinct macrophage subtypes, revealing their unique transcriptional profiles across various stages of infection. This review focuses on the functional plasticity of pulmonary macrophages and how environmental cues modulate their activation and effector functions. An integrative classification framework that defines six major functional macrophage subtypes in pulmonary infections, based on single-cell omics with functional perspectives is proposed. This framework refines the understanding of macrophage heterogeneity and offers a foundation for developing targeted immunotherapeutic strategies against lung infections. Advanced Science, EarlyView.

Tissue‐Resident Macrophage‐Derived E3 Ligase SMURF2 Restricts Autoimmune Inflammation by Mediating the Degradation of p‐TBK1

Dysregulated Tissue resident macrophage (TRMs) link to autoimmune inflammation. SMURF2 mediates Lys‐27 (K27)‐linked ubiquitination of p‐TBK1 and its degradation, which inhibits CSF1R signaling‐triggered TRM proliferation, thereby restraining the autoimmune inflammation. Impaired expression of SMURF2 in TRM correlates with the progression of autoimmune disease in humans and mice. Abstract Dysregulated tissue‐resident macrophages (TRMs) contribute to the pathogenesis of inflammatory bowel disease (IBD) and multiple sclerosis (MS). Uncovering molecular regulators of the divergent role of TRMs in inflammation can advance therapeutic strategies for autoimmune disorders. Here, a significant downregulation of SMAD‐specific E3 ubiquitin protein ligase 2 (SMURF2) is reported in TRMs within inflamed intestinal tissues from both IBD patients and mouse models. Notably, TRM‐specific deficiency of Smurf2 significantly exacerbates TRM proliferation in dextran sulfate sodium (DSS)‐induced colitis and experimental autoimmune encephalomyelitis (EAE), leading to augmented autoimmune inflammation. Mechanistically, SMURF2 interacts with phosphorylated TBK1 (p‐TBK1), mediating its Lys‐27‐linked ubiquitination and its subsequent lysosomal degradation, thereby suppressing TRM proliferation and autoimmune inflammation. Collectively, these findings establish SMURF2 as a pivotal mediator of TRM proliferation and autoimmune inflammation via p‐TBK1 modulation. Given that impaired SMURF2 expression correlates with the progression of autoimmune inflammation, SMURF2 represents a potential target for autoimmune disease treatment. Dysregulated Tissue resident macrophage (TRMs) link to autoimmune inflammation. SMURF2 mediates Lys-27 (K27)-linked ubiquitination of p-TBK1 and its degradation, which inhibits CSF1R signaling-triggered TRM proliferation, thereby restraining the autoimmune inflammation. Impaired expression of SMURF2 in TRM correlates with the progression of autoimmune disease in humans and mice. Abstract Dysregulated tissue-resident macrophages (TRMs) contribute to the pathogenesis of inflammatory bowel disease (IBD) and multiple sclerosis (MS). Uncovering molecular regulators of the divergent role of TRMs in inflammation can advance therapeutic strategies for autoimmune disorders. Here, a significant downregulation of SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) is reported in TRMs within inflamed intestinal tissues from both IBD patients and mouse models. Notably, TRM-specific deficiency of Smurf2 significantly exacerbates TRM proliferation in dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE), leading to augmented autoimmune inflammation. Mechanistically, SMURF2 interacts with phosphorylated TBK1 (p-TBK1), mediating its Lys-27-linked ubiquitination and its subsequent lysosomal degradation, thereby suppressing TRM proliferation and autoimmune inflammation. Collectively, these findings establish SMURF2 as a pivotal mediator of TRM proliferation and autoimmune inflammation via p-TBK1 modulation. Given that impaired SMURF2 expression correlates with the progression of autoimmune inflammation, SMURF2 represents a potential target for autoimmune disease treatment. Advanced Science, EarlyView.