Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes...Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.展开更多
Underwater target detection is extensively applied in domains such as underwater search and rescue,environmental monitoring,and marine resource surveys.It is crucial in enabling autonomous underwater robot operations ...Underwater target detection is extensively applied in domains such as underwater search and rescue,environmental monitoring,and marine resource surveys.It is crucial in enabling autonomous underwater robot operations and promoting ocean exploration.Nevertheless,low imaging quality,harsh underwater environments,and obscured objects considerably increase the difficulty of detecting underwater targets,making it difficult for current detection methods to achieve optimal performance.In order to enhance underwater object perception and improve target detection precision,we propose a lightweight underwater target detection method using You Only Look Once(YOLO)v8 with multi-scale cross-channel attention(MSCCA),named YOLOv8-UOD.In the proposed multiscale cross-channel attention module,multi-scale attention(MSA)augments the variety of attentional perception by extracting information from innately diverse sensory fields.The cross-channel strategy utilizes RepVGGbased channel shuffling(RCS)and one-shot aggregation(OSA)to rearrange feature map channels according to specific rules.It aggregates all features only once in the final feature mapping,resulting in the extraction of more comprehensive and valuable feature information.The experimental results show that the proposed YOLOv8-UOD achieves a mAP50 of 95.67%and FLOPs of 23.8 G on the Underwater Robot Picking Contest 2017(URPC2017)dataset,outperforming other methods in terms of detection precision and computational cost-efficiency.展开更多
This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by ...This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.展开更多
Nanotechnology in cancer therapy has significantly advanced treatment precision,effectiveness,and safety,improving patient outcomes and personalized care.Engineered smart nanoparticles and cell-based therapies are des...Nanotechnology in cancer therapy has significantly advanced treatment precision,effectiveness,and safety,improving patient outcomes and personalized care.Engineered smart nanoparticles and cell-based therapies are designed to target tumor cells,precisely sensing the tumor microenvironment(TME)and sparing normal cells.These nanoparticles enhance drug accumulation in tumors by solubilizing insoluble compounds or preventing their degradation,and they can also overcome therapy resistance and deliver multiple drugs simultaneously.Despite these benefits,challenges remain in patient-specific responses and regulatory approvals for cell-based or nanoparticle therapies.Cell-based drug delivery systems(DDSs)that primarily utilize the immune-recognition principle between ligands and receptors have shown promise in selectively targeting and destroying cancer cells.This review aims to provide a comprehensive overview of various nanoparticle and cell-based drug delivery system types used in cancer research.It covers approved and experimental nanoparticle therapies,including liposomes,micelles,protein-based and polymeric nanoparticles,as well as cell-based DDSs like macrophages,T-lymphocytes,dendritic cells,viruses,bacterial ghosts,minicells,SimCells,and outer membrane vesicles(OMVs).The review also explains the role of TME and its impact on developing smart DDSs in combination therapies and integrating nanoparticles with cell-based systems for targeting cancer cells.By detailing DDSs at different stages of development,from laboratory research to clinical trials and approved treatments,this review provides the latest insights and a collection of valuable citations of the innovative strategies that can be improved for the precise treatment of cancer.展开更多
Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonuc...Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonucleoprotein C(HNRNPC),a member belonging to the heterogeneous nuclear ribonucleoprotein(hnRNP)family,plays a pivotal role in nucleic acid metabolism.Previous studies have underscored the significance of HNRNPC in tumorigenesis;however,its specific role in malignant tumor progression remains inadequately characterized.Methods:We leveraged publicly available databases,including The Cancer Genome Atlas(TCGA),to explore the potential involvement of HNRNPC across various cancers.Additionally,we performed experimental validation studies focused on liver cancer.Results:Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies,including liver and lung cancers,and is strongly linked to unfavorable outcomes.Furthermore,HNRNPC was observed to be closely linked to tumor immunity.Through immune checkpoint analysis and immune cell infiltration assessment,HNRNPC emerged as a potential target for modulating tumor immunotherapy.Notably,silencing of HNRNPC markedly inhibited the proliferation,metastasis,and infiltration of liver cancer cells.Conclusion:In summary,our findings highlight HNRNPC as a prognostic marker in various cancers,including liver cancer,and suggest its involvement in shaping the tumor immune microenvironment.These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression,particularly through immunotherapeutic strategies.展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms...Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms, requiring histopathology for diagnosis. Surgery remains the standard of care for localized disease, serving both diagnostic and therapeutic purposes, though adjuvant chemotherapy has shown limited efficacy. In metastatic CDC, the gemcitabine-cisplatin regimen is commonly used due to its resemblance to urothelial cancer and supportive data from prospective studies. Newer therapies offer promise in advanced cases. Immune checkpoint inhibitors, such as nivolumab alone or with ipilimumab, have shown benefits in patients with high PD-L1 expression. Targeted therapies like cabozantinib demonstrated efficacy and safety as first-line treatments in phase II trials, while sunitinib and sorafenib have shown responses in various case reports and cohorts. However, combining chemotherapy with bevacizumab did not improve outcomes in phase II trials. Despite therapeutic advances in urothelial cancers and clear cell renal tumors, the CDC entity remains a challenging malignancy, emphasizing the need for continued research to understand the true efficacy of treatment and to prolong survival in advanced disease.展开更多
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–b...Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.展开更多
The application of deep learning for target detection in aerial images captured by Unmanned Aerial Vehicles(UAV)has emerged as a prominent research focus.Due to the considerable distance between UAVs and the photograp...The application of deep learning for target detection in aerial images captured by Unmanned Aerial Vehicles(UAV)has emerged as a prominent research focus.Due to the considerable distance between UAVs and the photographed objects,coupled with complex shooting environments,existing models often struggle to achieve accurate real-time target detection.In this paper,a You Only Look Once v8(YOLOv8)model is modified from four aspects:the detection head,the up-sampling module,the feature extraction module,and the parameter optimization of positive sample screening,and the YOLO-S3DT model is proposed to improve the performance of the model for detecting small targets in aerial images.Experimental results show that all detection indexes of the proposed model are significantly improved without increasing the number of model parameters and with the limited growth of computation.Moreover,this model also has the best performance compared to other detecting models,demonstrating its advancement within this category of tasks.展开更多
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central ...Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.展开更多
A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,...A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,enabling the acquisition of full-process data of the fragment scattering process.However,mismatches between camera frame rates and target velocities can lead to long motion blur tails of high-speed fragment targets,resulting in low signal-to-noise ratios and rendering conventional detection algorithms ineffective in dynamic strong interference testing environments.In this study,we propose a detection framework centered on dynamic strong interference disturbance signal separation and suppression.We introduce a mixture Gaussian model constrained under a joint spatialtemporal-transform domain Dirichlet process,combined with total variation regularization to achieve disturbance signal suppression.Experimental results demonstrate that the proposed disturbance suppression method can be integrated with certain conventional motion target detection tasks,enabling adaptation to real-world data to a certain extent.Moreover,we provide a specific implementation of this process,which achieves a detection rate close to 100%with an approximate 0%false alarm rate in multiple sets of real target field test data.This research effectively advances the development of the field of damage parameter testing.展开更多
Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton h...Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton has further exacerbated its pest status and amplified the need for more sustainable methods of control.RNA interference(RNAi)-based pest management strategies,such as root soaking and transgenic plants that express dsRNAs,have proven to be reliable,eco-friendly pest control strategies.To identify new RNAi targets for potential A.suturalis population control,we investigated the target of rapamycin(TOR)signaling pathway.A critical role for this pathway in A.suturalis reproductive regulation was suggested by pharmacological analyses.Subsequent RNAi-mediated knockdown of the A.suturalis TOR pathway genes TOR,Ras homolog enriched in the brain(Rheb),and ribosomal S6 kinase(S6K)reduced fertility.Moreover,a spray-induced and nanocarrier-delivered gene silencing(SI-NDGS)system targeting TOR successfully suppressed ovarian development,which demonstrates its effectiveness as a pest control target.These results provide a critical foundation for understanding reproductive regulation in A.suturalis and introduce new candidates for RNAi-based A.suturalis management.展开更多
The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to s...The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects.Herein,we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions.mRNA and its carriers are first described in detail.Then,mechanisms of passive targeting,endogenous targeting,and active targeting are outlined,with a focus on various biological barriers that mRNA may encounter during in vivo delivery.Next,emphasis is placed on summarizing mRNA-based organtargeting strategies.Lastly,the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned.This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.展开更多
Objective:To develop and demonstrate a comprehensive methodological framework for target trial emulation(TTE)implementation via post-laparoscopic septic shock fluid management as a clinical case study.Methods:We desig...Objective:To develop and demonstrate a comprehensive methodological framework for target trial emulation(TTE)implementation via post-laparoscopic septic shock fluid management as a clinical case study.Methods:We designed a simulated study of 10,000 patients in which colloid resuscitation was compared with crystalloid resuscitation.The framework incorporated precise eligibility criteria,standardized intervention protocols,and balanced treatment allocation with temporal anchoring.The primary analyses focused on 28-day mortality and were evaluated through survival analysis and comparative statistics.Results:The methodological framework successfully demonstrated the systematic implementation of TTE principles,providing reproducible protocols for eligibility determination,intervention standardization,and outcome assessment in observational studies.Conclusion:This work bridges the gap between TTE theory and practice by providing a detailed technical roadmap that enhances methodological transparency and reproducibility in comparative effectiveness research.展开更多
Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly...Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly accepted that disruption of SS18-SSX function represents a therapeutic means of treating synovial sarcoma,but emerging evidence suggests that upon depletion of SS18-SSX,an anti-apoptotic signal surprisingly arises to protect synovial sarcoma cell survival.In this article,we discuss the controversial roles of SS18-SSX’s transcriptional activity in synovial sarcoma biology and outline a synergistic strategy for overcoming the resistance of synovial sarcoma cells to SS18-SSX targeted therapeutics.展开更多
Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through ...Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.展开更多
Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the...Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.展开更多
Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-c...Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.展开更多
Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxyge...Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.展开更多
Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic...Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic clearance;and short tumor retention.Therefore;developing advanced radiopharmaceuticals with great tumor specificity and prolonged retention time is highly desirable for efficient tumor treatment.Herein;we report a tumor-targeted covalently anchoring strategy that selectively crosslinks the radiopharmaceuticals to intratumoral macromolecules for prolonged tumor theranostics.A covalent multi-targeted radiopharmaceutical(CMTR)d-IR-2(^(125)IRGD)that includes a sulfenic acid-reactive 1;3-cyclohexanedione group was developed.We demonstrated this probe could specifically accumulate at the tumor site and bind to the sulfenated proteins that are overexpressed within tumors;which greatly prevents the efflux of probes in tumor tissues while having faster clearance in healthy tissues resulting in 12 h longer tumor retention than conventional probes for sensitive NIR and SPECT/CT detection of tumors in vivo.More notably;the 131I-labeled probe could significantly suppress the growth of lung tumor A549.We thus envision that this work may offer a promising approach to developing effective radiopharmaceuticals for precise diagnosis and treatment of various tumors.展开更多
基金supported by grants from the Natural Science Foundation of Tianjin(General Program),Nos.23JCYBJC01390(to RL),22JCYBJC00220(to XC),and 22JCYBJC00210(to QL).
文摘Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities.Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites,neglecting multilevel pathological analysis of the overall nervous system and target organs.This has led to restrictions on current therapeutic approaches.In this paper,we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective,covering the central nervous system,peripheral nervous system,and target organs.After peripheral nerve injury,the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves;changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord.The nerve will undergo axonal regeneration,activation of Schwann cells,inflammatory response,and vascular system regeneration at the injury site.Corresponding damage to target organs can occur,including skeletal muscle atrophy and sensory receptor disruption.We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury.The main current treatments are conducted passively and include physical factor rehabilitation,pharmacological treatments,cell-based therapies,and physical exercise.However,most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system-peripheral nervous system-target organ pathway.Therefore,we should further explore multilevel treatment options that produce effective,long-lasting results,perhaps requiring a combination of passive(traditional)and active(novel)treatment methods to stimulate rehabilitation at the central-peripheral-target organ levels to achieve better functional recovery.
基金supported in part by the National Natural Science Foundation of China Grants 62402085,61972062,62306060the Liaoning Doctoral Research Start-Up Fund 2023-BS-078+1 种基金the Dalian Youth Science and Technology Star Project 2023RQ023the Liaoning Basic Research Project 2023JH2/101300191.
文摘Underwater target detection is extensively applied in domains such as underwater search and rescue,environmental monitoring,and marine resource surveys.It is crucial in enabling autonomous underwater robot operations and promoting ocean exploration.Nevertheless,low imaging quality,harsh underwater environments,and obscured objects considerably increase the difficulty of detecting underwater targets,making it difficult for current detection methods to achieve optimal performance.In order to enhance underwater object perception and improve target detection precision,we propose a lightweight underwater target detection method using You Only Look Once(YOLO)v8 with multi-scale cross-channel attention(MSCCA),named YOLOv8-UOD.In the proposed multiscale cross-channel attention module,multi-scale attention(MSA)augments the variety of attentional perception by extracting information from innately diverse sensory fields.The cross-channel strategy utilizes RepVGGbased channel shuffling(RCS)and one-shot aggregation(OSA)to rearrange feature map channels according to specific rules.It aggregates all features only once in the final feature mapping,resulting in the extraction of more comprehensive and valuable feature information.The experimental results show that the proposed YOLOv8-UOD achieves a mAP50 of 95.67%and FLOPs of 23.8 G on the Underwater Robot Picking Contest 2017(URPC2017)dataset,outperforming other methods in terms of detection precision and computational cost-efficiency.
文摘This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.
文摘Nanotechnology in cancer therapy has significantly advanced treatment precision,effectiveness,and safety,improving patient outcomes and personalized care.Engineered smart nanoparticles and cell-based therapies are designed to target tumor cells,precisely sensing the tumor microenvironment(TME)and sparing normal cells.These nanoparticles enhance drug accumulation in tumors by solubilizing insoluble compounds or preventing their degradation,and they can also overcome therapy resistance and deliver multiple drugs simultaneously.Despite these benefits,challenges remain in patient-specific responses and regulatory approvals for cell-based or nanoparticle therapies.Cell-based drug delivery systems(DDSs)that primarily utilize the immune-recognition principle between ligands and receptors have shown promise in selectively targeting and destroying cancer cells.This review aims to provide a comprehensive overview of various nanoparticle and cell-based drug delivery system types used in cancer research.It covers approved and experimental nanoparticle therapies,including liposomes,micelles,protein-based and polymeric nanoparticles,as well as cell-based DDSs like macrophages,T-lymphocytes,dendritic cells,viruses,bacterial ghosts,minicells,SimCells,and outer membrane vesicles(OMVs).The review also explains the role of TME and its impact on developing smart DDSs in combination therapies and integrating nanoparticles with cell-based systems for targeting cancer cells.By detailing DDSs at different stages of development,from laboratory research to clinical trials and approved treatments,this review provides the latest insights and a collection of valuable citations of the innovative strategies that can be improved for the precise treatment of cancer.
文摘Background:Aberrant expression of RNA-binding proteins(RBPs)has been linked to a variety of diseases,including hematological disorders,cardiovascular diseases,and multiple types of cancer.Heterogeneous nuclear ribonucleoprotein C(HNRNPC),a member belonging to the heterogeneous nuclear ribonucleoprotein(hnRNP)family,plays a pivotal role in nucleic acid metabolism.Previous studies have underscored the significance of HNRNPC in tumorigenesis;however,its specific role in malignant tumor progression remains inadequately characterized.Methods:We leveraged publicly available databases,including The Cancer Genome Atlas(TCGA),to explore the potential involvement of HNRNPC across various cancers.Additionally,we performed experimental validation studies focused on liver cancer.Results:Our analysis revealed that HNRNPC is overexpressed in a wide range of common malignancies,including liver and lung cancers,and is strongly linked to unfavorable outcomes.Furthermore,HNRNPC was observed to be closely linked to tumor immunity.Through immune checkpoint analysis and immune cell infiltration assessment,HNRNPC emerged as a potential target for modulating tumor immunotherapy.Notably,silencing of HNRNPC markedly inhibited the proliferation,metastasis,and infiltration of liver cancer cells.Conclusion:In summary,our findings highlight HNRNPC as a prognostic marker in various cancers,including liver cancer,and suggest its involvement in shaping the tumor immune microenvironment.These insights offer potential avenues for improving clinical outcomes in tumors with elevated HNRNPC expression,particularly through immunotherapeutic strategies.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
文摘Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms, requiring histopathology for diagnosis. Surgery remains the standard of care for localized disease, serving both diagnostic and therapeutic purposes, though adjuvant chemotherapy has shown limited efficacy. In metastatic CDC, the gemcitabine-cisplatin regimen is commonly used due to its resemblance to urothelial cancer and supportive data from prospective studies. Newer therapies offer promise in advanced cases. Immune checkpoint inhibitors, such as nivolumab alone or with ipilimumab, have shown benefits in patients with high PD-L1 expression. Targeted therapies like cabozantinib demonstrated efficacy and safety as first-line treatments in phase II trials, while sunitinib and sorafenib have shown responses in various case reports and cohorts. However, combining chemotherapy with bevacizumab did not improve outcomes in phase II trials. Despite therapeutic advances in urothelial cancers and clear cell renal tumors, the CDC entity remains a challenging malignancy, emphasizing the need for continued research to understand the true efficacy of treatment and to prolong survival in advanced disease.
基金supported by the National Natural Science Foundation of China,Nos.82171363,82371381(to PL),82171458(to XJ)Key Research and Development Project of Shaa nxi Province,Nos.2024SF-YBXM-404(to KY)。
文摘Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.
文摘The application of deep learning for target detection in aerial images captured by Unmanned Aerial Vehicles(UAV)has emerged as a prominent research focus.Due to the considerable distance between UAVs and the photographed objects,coupled with complex shooting environments,existing models often struggle to achieve accurate real-time target detection.In this paper,a You Only Look Once v8(YOLOv8)model is modified from four aspects:the detection head,the up-sampling module,the feature extraction module,and the parameter optimization of positive sample screening,and the YOLO-S3DT model is proposed to improve the performance of the model for detecting small targets in aerial images.Experimental results show that all detection indexes of the proposed model are significantly improved without increasing the number of model parameters and with the limited growth of computation.Moreover,this model also has the best performance compared to other detecting models,demonstrating its advancement within this category of tasks.
基金supported by grants from National Key R&D Program of China,No.2023YFC2506100(to JZ)the National Natural Science Foundation of China,No.82171062(to JZ).
文摘Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.
文摘A measurement system for the scattering characteristics of warhead fragments based on high-speed imaging systems offers advantages such as simple deployment,flexible maneuverability,and high spatiotemporal resolution,enabling the acquisition of full-process data of the fragment scattering process.However,mismatches between camera frame rates and target velocities can lead to long motion blur tails of high-speed fragment targets,resulting in low signal-to-noise ratios and rendering conventional detection algorithms ineffective in dynamic strong interference testing environments.In this study,we propose a detection framework centered on dynamic strong interference disturbance signal separation and suppression.We introduce a mixture Gaussian model constrained under a joint spatialtemporal-transform domain Dirichlet process,combined with total variation regularization to achieve disturbance signal suppression.Experimental results demonstrate that the proposed disturbance suppression method can be integrated with certain conventional motion target detection tasks,enabling adaptation to real-world data to a certain extent.Moreover,we provide a specific implementation of this process,which achieves a detection rate close to 100%with an approximate 0%false alarm rate in multiple sets of real target field test data.This research effectively advances the development of the field of damage parameter testing.
基金supported by the National Natural Science Foundation of China(32072428)。
文摘Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton has further exacerbated its pest status and amplified the need for more sustainable methods of control.RNA interference(RNAi)-based pest management strategies,such as root soaking and transgenic plants that express dsRNAs,have proven to be reliable,eco-friendly pest control strategies.To identify new RNAi targets for potential A.suturalis population control,we investigated the target of rapamycin(TOR)signaling pathway.A critical role for this pathway in A.suturalis reproductive regulation was suggested by pharmacological analyses.Subsequent RNAi-mediated knockdown of the A.suturalis TOR pathway genes TOR,Ras homolog enriched in the brain(Rheb),and ribosomal S6 kinase(S6K)reduced fertility.Moreover,a spray-induced and nanocarrier-delivered gene silencing(SI-NDGS)system targeting TOR successfully suppressed ovarian development,which demonstrates its effectiveness as a pest control target.These results provide a critical foundation for understanding reproductive regulation in A.suturalis and introduce new candidates for RNAi-based A.suturalis management.
基金supported by the National Key Research and Development Program of China(2022YFA1105304)the National Natural Science Foundation of China(T2225003 and 61927805)+5 种基金the Nanjing Medical Science and Technique Development Foundation(ZKX21019)the Clinical Trials from Nanjing Drum Tower Hospital(2022-LCYJ-ZD-01)the Jiangsu Funding Program for Excellent Postdoctoral Talent(2023ZB032)the Natural Science Foundation of Jiangsu Province(BK20240223)the Project of Institute of Chinese Medicine of Nanjing University(ICM2024011)the Aid Project of Nanjing Drum Tower Hospital Health,Education&Research Foundation.
文摘The emerging messenger RNA(mRNA)nanomedicines have sprung up for disease treatment.Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years,as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects.Herein,we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions.mRNA and its carriers are first described in detail.Then,mechanisms of passive targeting,endogenous targeting,and active targeting are outlined,with a focus on various biological barriers that mRNA may encounter during in vivo delivery.Next,emphasis is placed on summarizing mRNA-based organtargeting strategies.Lastly,the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned.This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.
基金Zhongheng Zhang received funding from the National Natural Science Foundation of China(82272180,82472243)the China National Key Research and Development Program(2023YFC3603104)+5 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(LHDMD24H150001)the China National Key Research and Development Program(2022YFC2504500)a collaborative scientific project co-established by the Science and Technology Department of the National Administration of Traditional Chinese Medicine and the Zhejiang Provincial Administration of Traditional Chinese Medicine(GZY-ZJKJ-24082)the General Health Science and Technology Program of Zhejiang Province(2024KY1099)Project of Zhejiang University Longquan Innovation Center(ZJDXLQCXZCJBGS2024016)Hongying Ni received funding from Jinhua Science and Technology Planning Project(2024-3-047).
文摘Objective:To develop and demonstrate a comprehensive methodological framework for target trial emulation(TTE)implementation via post-laparoscopic septic shock fluid management as a clinical case study.Methods:We designed a simulated study of 10,000 patients in which colloid resuscitation was compared with crystalloid resuscitation.The framework incorporated precise eligibility criteria,standardized intervention protocols,and balanced treatment allocation with temporal anchoring.The primary analyses focused on 28-day mortality and were evaluated through survival analysis and comparative statistics.Results:The methodological framework successfully demonstrated the systematic implementation of TTE principles,providing reproducible protocols for eligibility determination,intervention standardization,and outcome assessment in observational studies.Conclusion:This work bridges the gap between TTE theory and practice by providing a detailed technical roadmap that enhances methodological transparency and reproducibility in comparative effectiveness research.
文摘Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly accepted that disruption of SS18-SSX function represents a therapeutic means of treating synovial sarcoma,but emerging evidence suggests that upon depletion of SS18-SSX,an anti-apoptotic signal surprisingly arises to protect synovial sarcoma cell survival.In this article,we discuss the controversial roles of SS18-SSX’s transcriptional activity in synovial sarcoma biology and outline a synergistic strategy for overcoming the resistance of synovial sarcoma cells to SS18-SSX targeted therapeutics.
基金supported by the National Natural Science Foundation of China(Nos.82272847,82304417,82303529,82171333)China Postdoctoral Science Foundation(Nos.2023TQ0307,2023M743231,2023M730971)+2 种基金Science and Technology Project of Henan Province(No.242102311204)Postdoctoral Fellowship Program of CPSF(No.GZB20230675)Modern Analysis and Computer Center of Zhengzhou University.
文摘Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.
基金supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-026,China).
文摘Gliomas are the most common intracranial tumors with poor survival and high mortality.Furthermore,the clinical efficacy of current drugs is still not ideal;despite the development of several therapeutic drugs over the past decades and tumor progression or recurrence is inevitable in many patients.RNAibased therapy presents a novel disease-related gene targeting therapy,including otherwise undruggable genes,and generates therapeutic options.However,the therapeutic effect of siRNA is hindered by multiple biological barriers,primarily the blood-brain barrier(BBB).A glycoprotein-derived peptide-mediated delivery system is the preferred option to resolve this phenomenon.RDP,a polypeptide composed of 15 amino acids derived from rabies virus glycoprotein(RVG),possesses an N-type acetylcholine receptor(nAChR)-binding efficiency similar to that of RVG29.Given its lower cost and small particle size when used as a ligand,RDP should be extensively evaluated.First,we verified the brain-targeting efficacyy of RDP at the cellular and animal levels and further explored the possibility of using the RDP-oligoarginine peptide(designated RDP-5R)as a bio-safe vehicle to deliver therapeutic siRNA into glioma cells in vitro and in vivo.The polypeptide carrier possesses a diblock design composed of oligoarginine for binding siRNA through electrostatic interactions and RDP for cascade BBB-and glioma cell-targeting.The results indicated that RDP-R5/siRNA nanoparticles exhibited stable and suitable physicochemical properties for in vivo application,desirable glioma-targeting effects,and therapeutic efficiency.As a novel and efficient polypeptide carrier,RDP-based polypeptides hold great promise as a noninvasive,safe,and efficient treatment for various brain diseases.
基金supported by the National Key Research and Development Plan(2022YFC3500202,China)the National Natural Science Foundation of China(Nos.82230116,81872877,82204715,81803142,82404639,and 82073975)+7 种基金the Natural Science Foundation of Jiangsu Province(No.BK20220476,China)the Jiangsu Provincial Double-Innovation Doctor Program(No.JSSCBS20220477,China)the Natural Science Foundation of Nanjing University of Chinese Medicine(No.XPT82204715,China)the Fundamental Research Funds for the Central Universities(Nos.020814380179 and 020814380174,China)the Fundamental Science(Natural Science)Research Project of the Jiangsu Higher Education Institutions of China(No.22KJB360005)the Innovation Project of Guangdong Provincial Education Department(No.2023KTSCX320,China)the Shenzhen Science and Technology Program(Nos.20231126130044001 and 20230731094501002,China)the School of Life Science(NJU)-Sipimo Joint Funds,and the Mountain-Climbing Talents Project of Nanjing.
文摘Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.
基金support from the National Natural Science Foundation of China(Nos.22277056,21977052)the Distinguished Young Scholars of Jiangsu Province(No.BK20230006)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20230977,BK20231090)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.23KJB150020)the Jiangsu Excellent Postdoctoral Program(No.2022ZB758)。
文摘Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.
基金supported by the National Natural Science Foundation of China(T2325019,22077092)the Basic Research Program of Jiangsu(BK20243030)+3 种基金the Special Project of“Technological Innovation”Project of CNNC Medical Industry Co.Ltd.(ZHYLYB2021001)the Four“Batches"Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province(2022XM19)the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection(GZK12024016,GZK12023050,GZK12024013)a Project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic clearance;and short tumor retention.Therefore;developing advanced radiopharmaceuticals with great tumor specificity and prolonged retention time is highly desirable for efficient tumor treatment.Herein;we report a tumor-targeted covalently anchoring strategy that selectively crosslinks the radiopharmaceuticals to intratumoral macromolecules for prolonged tumor theranostics.A covalent multi-targeted radiopharmaceutical(CMTR)d-IR-2(^(125)IRGD)that includes a sulfenic acid-reactive 1;3-cyclohexanedione group was developed.We demonstrated this probe could specifically accumulate at the tumor site and bind to the sulfenated proteins that are overexpressed within tumors;which greatly prevents the efflux of probes in tumor tissues while having faster clearance in healthy tissues resulting in 12 h longer tumor retention than conventional probes for sensitive NIR and SPECT/CT detection of tumors in vivo.More notably;the 131I-labeled probe could significantly suppress the growth of lung tumor A549.We thus envision that this work may offer a promising approach to developing effective radiopharmaceuticals for precise diagnosis and treatment of various tumors.
