Nano-Medicine for Thrombosis:A Precise Diagnosis and Treatment Strategy

Thrombosis is a global health issue and one of the leading factors of death.However,its diagnosis has been limited to the late stages,and its therapeutic window is too narrow to provide reasonable and effective treatment.In addition,clinical thrombolytics suffer from a short half-life,allergic reactions,inactivation,and unwanted tissue hemorrhage.Nano-medicines have gained extensive attention in diagnosis,drug delivery,and photo/sound/magnetic-theranostics due to their convertible properties.Furthermore,diagnosis and treatment of thrombosis using nano-medicines have also been widely studied.This review summarizes the recent advances in this area,which revealed six types of nanoparticle approaches:(1)in vitro diagnostic kits using“synthetic biomarkers”;(2)in vivo imaging using nano-contrast agents;(3)targeted drug delivery systems using artificial nanoparticles;(4)microenvironment responsive drug delivery systems;(5)drug delivery systems using biological nanostructures;and(6)treatments with external irradiation.The investigations of nano-medicines are believed to be of great significance,and some of the advanced drug delivery systems show potential applications in clinical theranotics.

Toxicity of superparamagnetic iron oxide nanoparticles: Research strategies and implications for nanomedicine

Superparamagnetic iron oxide nanoparticles （SPIONs） are one of the most versatile and safe nanoparticles in a wide variety of biomedical applications. In the past decades, considerable efforts have been made to investigate the potential adverse biological effects and safety issues associated with SPIONs, which is essential for the development of next-generation SPIONs and for continued progress in translational research. In this mini review, we summarize recent developments in toxicity studies on SPIONs, focusing on the relationship between the physicochemical properties of SPIONs and their induced toxic biological responses for a better toxicological understanding of SPIONs.

Supercritical fluid technology:A game-changer for biomacromolecular nanomedicine preparation and biomedical application

Biomacromolecules are attractive in biomedical applications as therapeutic agents and potential drug carriers due to their natural active components,good biocompatibility,and high targeting.However,their large relative molecular weight,complex structure,susceptibility to degradation,and poor stability limit their usefulness.Nanotechnology can address these issues by improving the therapeutic value,bioavailability,permeability,and absorption of biomacromolecules while regulating their retention time in the body.Especially,compelling evidence has been reported that supercritical fluid(SCF)technology has emerged as an alternative that maintains the integrity of biomacromolecules and reduces environmental contamination.In this review,we highlight a set of unique nanosizing strategies based on SCF technology for biomacromolecular nanomedicine,and extensively discuss their characteristics and mechanisms.In particular,the protein-based,nucleic acid-based,and polysaccharide-based nanomedicine preparations via SCF technology and their biomedical applications are summarized,and the potential for industrial production of biomacromolecular drugs is also considered.We further provide perspectives on the opportunities and challenges in this excellent field of biomacromolecular drugs nanotechnology.

Chloride intracellular channel 1 regulates colon cancer cell migration and invasion through ROS/ERK pathway

AIM:To investigate the mechanisms of chloride intracellular channel 1(CLIC1)in the metastasis of colon cancer under hypoxia-reoxygenation(H-R)conditions.METHODS:Fluorescent probes were used to detect reactive oxygen species(ROS)in LOVO cells.Wound healing assay and transwell assay were performed to examine the migration and invasion of LOVO cells.Expression of CLIC1 mRNA and protein,p-ERK,MMP-2and MMP-9 proteins was analyzed by reverse transcription-polymerase chain reaction and Western blot.METHODS:H-R treatment increased the intracellular ROS level in LOVO cells.The mRNA and protein expression of CLIC1 was elevated under H-R conditions.Functional inhibition of CLIC1 markedly decreased the H-R-enhanced ROS generation,cell migration,invasion and phosphorylation of ERK in treated LOVO cells.Additionally,the expression of MMP-2 and MMP-9 could be regulated by CLIC1-mediated ROS/ERK pathway.CONCLUSION:Our results suggest that CLIC1 protein is involved in the metastasis of colon cancer LOVO cells via regulating the ROS/ERK pathway in the H-R process.

Beyond Antibiotics:Photo/Sonodynamic Approaches for Bacterial Theranostics

Rapid evolution and propagation of multidrug resistance among bacterial pathogens are outpacing the development of new antibiotics,but antimicrobial photodynamic therapy(aPDT)provides an excellent alternative.This treatment depends on the interaction between light and photoactivated sensitizer to generate reactive oxygen species(ROS),which are highly cytotoxic to induce apoptosis in virtually all microorganisms without resistance concern.When replacing light with low-frequency ultrasonic wave to activate sensitizer,a novel ultrasounddriven treatment emerges as antimicrobial sonodynamic therapy(aSDT).Recent advances in aPDT and aSDT reveal golden opportunities for the management of multidrug resistant bacterial infections,especially in the theranostic application where imaging diagnosis can be accomplished facilely with the inherent optical characteristics of sensitizers,and the generated ROS by aPDT/SDT cause broad-spectrum oxidative damage for sterilization.In this review,we systemically outline the mechanisms,targets,and current progress of aPDT/SDT for bacterial theranostic application.Furthermore,potential limitations and future perspectives are also highlighted.

Connecting Calcium-Based Nanomaterials and Cancer:From Diagnosis to Therapy

As the indispensable second cellular messenger,calcium signaling is involved in the regulation of almost all physiological processes by activating specific target proteins.The importance of calcium ions(Ca^(2+))makes its“Janus nature”strictly regulated by its concentration.Abnormal regulation of calcium signals may cause some diseases;however,artificial regulation of calcium homeostasis in local lesions may also play a therapeutic role.“Calcium overload,”for example,is characterized by excessive enrichment of intracellular Ca^(2+),which irreversibly switches calcium signaling from“positive regulation”to“reverse destruction,”leading to cell death.However,this undesirable death could be defined as“calcicoptosis”to offer a novel approach for cancer treatment.Indeed,Ca^(2+)is involved in various cancer diagnostic and therapeutic events,including calcium overload-induced calcium homeostasis disorder,calcium channels dysregulation,mitochondrial dysfunction,calcium-associated immunoregulation,cell/vascular/tumor calcification,and calcification-mediated CT imaging.In paral-lel,the development of multifunctional calcium-based nanomaterials(e.g.,calcium phosphate,calcium carbonate,calcium peroxide,and hydroxyapatite)is becoming abundantly available.This review will highlight the latest insights of the calcium-based nanomaterials,explain their application,and provide novel perspective.Identifying and characterizing new patterns of calcium-dependent signaling and exploiting the disease element linkage offer additional translational opportunities for cancer theranostics.

Bridging the preoperative gap of precision hepatectomy: Superstable homogeneous iodinated formulation technology

The in-situ post-embolization fluorescence-guided hepatectomy for hepatocellular carcinoma(HCC) requires precise embolic formulation that meets both preoperative and intraoperative needs of hepatobiliary surgeons.In this Editorial,we highlight the development of Superstable Homogeneous Iodinated Formulation Technology(SHIFT) for locoregional HCC treatment.It is believed that such an intelligent solution could resolve unmet formulation needs and make a major stride to bridge the preoperative gap of precision hepatectomy.

Multi-Classification of Polyps in Colonoscopy Images Based on an Improved Deep Convolutional Neural Network

Achieving accurate classification of colorectal polyps during colonoscopy can avoid unnecessary endoscopic biopsy or resection.This study aimed to develop a deep learning model that can automatically classify colorectal polyps histologically on white-light and narrow-band imaging(NBI)colonoscopy images based on World Health Organization(WHO)and Workgroup serrAted polypS and Polyposis(WASP)classification criteria for colorectal polyps.White-light and NBI colonoscopy images of colorectal polyps exhibiting pathological results were firstly collected and classified into four categories:conventional adenoma,hyperplastic polyp,sessile serrated adenoma/polyp(SSAP)and normal,among which conventional adenoma could be further divided into three sub-categories of tubular adenoma,villous adenoma and villioustublar adenoma,subsequently the images were re-classified into six categories.In this paper,we proposed a novel convolutional neural network termed Polyp-DedNet for the four-and six-category classification tasks of colorectal polyps.Based on the existing classification network ResNet50,Polyp-DedNet adopted dilated convolution to retain more high-dimensional spatial information and an Efficient Channel Attention(ECA)module to improve the classification performance further.To eliminate gridding artifacts caused by dilated convolutions,traditional convolutional layers were used instead of the max pooling layer,and two convolutional layers with progressively decreasing dilation were added at the end of the network.Due to the inevitable imbalance of medical image data,a regularization method DropBlock and a Class-Balanced(CB)Loss were performed to prevent network overfitting.Furthermore,the 5-fold cross-validation was adopted to estimate the performance of Polyp-DedNet for the multi-classification task of colorectal polyps.Mean accuracies of the proposed Polyp-DedNet for the four-and six-category classifications of colorectal polyps were 89.91%±0.92%and 85.13%±1.10%,respectively.The metrics of precision,recall and F1-score were also improved by 1%∼2%compared to the baseline ResNet50.The proposed Polyp-DedNet presented state-of-the-art performance for colorectal polyp classifying on white-light and NBI colonoscopy images,highlighting its considerable potential as an AI-assistant system for accurate colorectal polyp diagnosis in colonoscopy.

Metal-based nanoparticles for cardiovascular disease diagnosis and therapy

Cardiovascular diseases (CVDs) are the most prominent cause of disability and mortality in the world. Although there have been a variety of therapeutic options for the management of CVDs, most of the traditional therapeutic strategies could not sufficiently stop or reduce the progression of these diseases and may result in some side effects. With the advance in nanotechnology, a number of metal-based nanoparticles have been developed and shown promising potentials in the treatment of CVDs. In this review, we provide a comprehensive review of researches on recent development of metal-based nanoparticles in diagnosis and therapy in CVDs as biomedical materials. We also discuss the challenges in the clinical translation and potential risks in their application of CVD therapy. Based on the ongoing research and applications, we can conclude metal-based nanoparticles are expected to become potential therapeutics for the treatment of CVDs. But their application is still in its infancy and much more efforts should be made to enforce a clinical breakthrough.

A new track for antibacterial treatment:Progress and challenges of using cytomembrane-based vesicles to combat bacteria

The emergence and re-emergence of antibiotic-resistant bacteria,especially superbugs,are leading to complicated infections that are increasingly difficult to treat.Therefore,novel alternative antimicrobial therapies are urgently needed to reduce the morbidity and mortality caused by antibiotic resistance.The development of biomimetic-based therapy is expected to provide innovative means for addressing this challenging task.As a kind of novel biomaterial,cytomembrane-based vesicles(MVs)continue to receive considerable attention in antimicrobial therapy owing to their inherent biocompatibility,design flexi-bility,and remarkable ability to interact with biological molecules or the surrounding environment.These remarkable cell-like properties and their inherent interaction with pathogens,toxins,and the immune system underlie MVs-based functional protein therapy and targeted delivery to develop advanced therapeutic strategies against bacterial infection.This review provides a fundamental under-standing of the characteristics and physiological functions of cytomembrane-based vesicles,focusing on their potential to combat bacterial infections,including detoxification,immune modulation,antibiotics delivery,and physical therapy.In addition,the future possibilities and remaining challenges for clinically implementing MVs in the field of antibacterial treatment are discussed.

Mineral iron based self-assembling: bridging the small molecular drugs and transformative application

The nanoparticle-based treatment and diagnosis of cancer remain challenging in clinical translation, mainly due to the hurdles that can be associated with the development of targeted delivery, biological side effects, poor drug loading efficiency (DLE), and instability and so on [1,2].

Safety profile of two-dimensional Pd nanosheets for photothermal therapy and photoacoustic imaging

Two-dimensional （2D） nanosheets have emerged as an important class of nanomaterial with great potential in the field of biomedicines, particularly in cancer theranostics. However, owing to the lack of effective methods that synthesize uniform 2D nanomaterials with controlled size, systematic evaluation of size-dependent bio-behaviors of 2D nanomaterials is rarely reported. To the best of our knowledge, we are the first to report a systematic evaluation of the influence of size of 2D nanomaterials on their bio-behaviors. 2D Pd nanosheets with diameters ranging from 5 to 80 nm were synthesized and tested in cell and animal models to assess their size-dependent bioapplication, biodistribution, elimination, toxicity, and genomic gene expression profiles. Our results showed size significantly influences the biological behaviors of Pd nanosheets, including their photothermal and photoacoustic effects, pharmacokinetics, and toxicity. Compared to larger-sized Pd nanosheets, smaller-sized Pd nanosheets exhibited more advanced photoacoustic imaging and photothermal effects upon ultralow laser irradiation. Moreover, in vivo results indicated that 5-nm Pd nanosheets escape from the reticuloendothelial system with a longer blood half-life and can be cleared by renal excretion, while Pd nanosheets with larger sizes mainly accumulate in the liver and spleen. The 30-nm Pd nanosheets exhibited the highest tumor accumulation. Although Pd nanosheets did not cause any appreciable toxicity at the cellular level, we observed slight lipid accumulation in the liver and inflammation in the spleen. Genomic gene expression analysis showed that 80-nm Pd nanosheets interacted with more cellular components and affected more biological processes in the liver, as compared to 5-nm Pd nanosheets. We believe this work will provide valuable information and insights into the clinical application of 2D Pd nanosheets as nanomedicines.

The blooming intersection of transcatheter hepatic artery chemoembolization and nanomedicine

Transcatheter hepatic artery chemoembolization(TACE)is a universal treatment for patients with hepatocellular carcinoma(HCC)that inhibits tumor growth by cutting off the blood supply and provides chemotherapeutics locally to the tumor.The strategy of combining TACE formulation with image-guided ablation holds tremendous potential,but patient tolerance and undesired toxicity/immunosuppression remains a challenge.The application of nanotechnology in TACE opens new doors for the treatment of HCC.Strikingly,nanomaterials or nano-drugs dispersed in the TACE formulation can effectively improve the delivery efficiency of drugs by achieving both controlled and continuous release.In addition,the utilization of multifunctional nanoparticles can provide guidance and monitoring for various advanced imaging methods for TACE treatment,and can realize the combination therapy of thermal ablation,microwave ablation,in situ radiotherapy,and other therapies,greatly expanding the therapeutic strategies available for HCC treatment.Here,the current exploration of nanotechnology in TACE of HCC is briefly summarized and the challenges of TACE with nanoformulations for clinical translation are comprehensively discussed.

LiF@SiO2 nanocapsules for controlled lithium release and osteoarthritis treatment

Electrolytes can be taken orally or intravenously as supplements or thera- peutics. However, their therapeutic window may exceed the serum toxicity threshold, making systemic delivery a poor option. Local injection is also not adequate due to rapid diffusion of electrolytes. Here, we solved this issue with a nanocapsule technolog~ comprising an electrolyte nanocrystal as the drug filling and a silica sheath to regulate drug release rates. In particular, we prepared LiF@SiO2 nanocapsules and investigated their potential as a delivery system for lithium, which was shown in recent studies to be an effective therapeutic agent for osteoarthritis （OA）. We demonstrated that LiF@SiO2 can extend lithium release time from minutes to more than 60 h. After intra- articular （i.a.） injection into a rat OA model, the nanocapsules reduced the Osteoarthritis Research Society International （OARSI） score by 71% in 8 weeks while inducing no systemic toxicity. Our study opens new doors for improved delivery of electrolyte therapeutics, which have rarely been studied in the past.

Precise nanomedicine for intelligent therapy of cancer

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

Porous hollow palladium nanoplafform for imaging-guided trimodal chemo-, photothermal-, and radiotherapy

Cancer is one of the major causes of human death. There are many types of cancer treatment including surgery, chemotherapy, radiotherapy, and photothermal therapy. Combining different therapies can synergistically enhance the therapeutic effect. We developed porous hollow palladium nanoparticles （PHPdNPs） to co-deliver ^131I （a radioisotope that is commonly used in radiotherapy） and doxorubicin （DOX; a chemotherapy drug）. Compared with other mesoporous nanocarriers, our PHPdNPs exhibited impressive photothermal conversion efficiency and stability. Drug loading is high and drug release is controllable by repeated laser irradiation and acidic pH in tumor microenvironments. Owing to the specific interaction between palladium and iodine, the PHPdNPs serve as effective ^131I delivery vehicles with excellent radiochemical stability. A single dose of [^131I]PHPdNPs-DOX has superior antitumor efficacy because it enables a combination of chemo-, photothermal-, and radio-therapy. Moreover, the nanocomplex has no obvious side-effects in mice. Therefore, we believe that PHPdNPs are excellent candidates for multimodal imaging-guided therapy.

Advanced radionuclides in diagnosis and therapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common primary malignant tumor of the liver,but early diagnosis and effective treatment are still difficult.With the development of radionuclide applications in medicine,nuclear medicine is playing an increasingly important role in the diagnosis and treatment of HCC.Radionuclide-based positron emission tomography-computed tomography and single-photon emission computed tomography-computed tomography molecular imaging are indispensable for assessing progression,staging,differentiation,preoperative planning,postoperative prediction,and evaluation of HCC in clinical applications.Moreover,radionuclide-based endoradiotherapy provides an objective therapeutic strategy for patients with unresectable advanced HCC.This review highlights the application and development of radionuclides in the diagnosis and treatment of HCC.More efforts are warranted for the development of advanced radionuclides to make significant contributions in the treatment of HCC.

Automated segmentation and quantitative study of retinal pigment epithelium cells for photoacoustic microscopy imaging

We develop an improved region growing method to realize automatic retinal pigment epithelium （RPE） cell segmentation for photoacoustic microscopy （PAM） imaging. The minimum bounding rectangle of the segmented region is used in this method to dynamically update the growing threshold for optimal segmentation. Phantom images and PAM imaging results of normal porcine RPE are applied to demonstrate the effectiveness of the segmentation. The method realizes accurate segmentation of RPE cells and also provides the basis for quantitative analysis of cell features such as cell area and component content, which can have potential applications in studying RPE cell functions for PAM imaging.

Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention

Regulatory T cells(Treg cells)are crucial for maintaining immune tolerance.Compromising the regulatory function of Treg cells can lead to autoimmune liver disease.However,how Treg cell function is regulated has not been fully clarified.Here,we report that mice with AMP-activated protein kinase alpha 1(AMPKα1)globally knocked out spontaneously develop immune-mediated liver injury,with massive lymphocyte infiltration in the liver,elevated serum alanine aminotransferase levels,and greater production of autoantibodies.Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice.In addition,Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease,greater production of autoantibodies,and hyperactivation of CD4^(+)T cells.AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation.Furthermore,AMPK is activated upon T cell receptor(TCR)stimulation,which triggers Foxp3 phosphorylation,suppressing Foxp3 ubiquitination and proteasomal degradation.Importantly,the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases.Conclusion:Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.

Cell membrane-encapsulated nanoparticles for vaccines and immunotherapy

Functionalized nanoparticles are widely used in drug targeted delivery and immune microenvironment regulation.As a new type of biomaterial,cell-derived carriers are receiving considerable attention in clinical translation owing to their desirable biocompatibility and lower toxicity.Importantly,cell membrane-encapsulated nanoparticles can achieve specific biological effects from the benefit of their parent cell characteristics.In this review,we introduce the cell membrane coating technologies that are under extensive investigation,we also summarize various applications that have been developed for immunotherapy,and discuss the prospects in this field.With further understanding and integration with advanced biotechnology methods,it is believed that the continuing development of cell membrane-encapsulated nanoparticles will achieve promotion in clinical application.