Cathepsin B-responsive nanodrug delivery systems for precise diagnosis and targeted therapy of malignant tumors

The tumor microenvironment(TME)significantly influences cancer evolution and therapeutic efficacy.Targeting biofunctional molecules to the TME has long been appreciated as a means of raising local drug concentrations and reducing systemic toxicities.The booming nanotechnology field has realized the importance of cathepsin B to derive a variety of intelligent enzyme-responsive nanosized drug delivery systems(nanoDDS)to improve treatment responses and clinical outcomes.In this tutorial review,after introducing the molecular structure and physiological/pathological functions of cathepsin B,the outstanding achievements of cathepsin B-responsive nanoplatforms in the precise diagnosis,targeted therapy,and synergistic theranostics of malignant tumors are systematically described.Finally,the challenges of enzyme-substrate incompatibility,low diagnostic sensitivity,mass production and biocompatibility of multifunctional nanoDDS are considered in order to successfully promote them to clinical applications.

Amyotrophic Lateral Sclerosis： Precise Diagnosis and Individualized Treatment

INTRODUCTION Amyotrophic lateral sclerosis （ALS） is a progressive neurodegenerative disease characterized by selective death of upper motor neurons （UMNs） and lower motor neurons （LMNs）, typically may die from respiratory failure within 2-5 years of symptorn onset）H About 10% orALS patients are familial whereas the remaining patients are sporadic. ALS is highly heterogeneous in genetic and clinical phenotype, with lack of definitive diagnostic tools, making it extremely difficult to make early diagnosis.

Metal-organic framework nanofilm enhances serum metabolic profiles for diagnosis and subtype of cardiovascular disease

Cardiovascular disease(CVD)is a global health problem and is thought to be responsible for almost half of all deaths in the world.Nevertheless,currently available diagnostic methods for CVD are strongly depended on clinical observation and monitoring,which commonly result in false diagnosis.Herein,an attractive strategy of a metal-organic framework(MOF)nanofilm-based laser desorption/ionization mass spectrometry(LDI-MS)was developed for enhancing serum metabolic profiling,which could provide precise diagnosis and molecular subtyping of CVD.The porous MOF nanofilm fabricated on indium-tin oxide(ITO)glass possessed enhanced ionization efficiency and size-exclusion effect,which endowed it as substrate with high sensitivity and selectivity for serum metabolites.Furthermore,the MOF nanofilm with uniform surface and high orientation provided high-quality and high-reproducibility serum metabolic profiles(SMPs)without any tedious pretreatment.Further analysis of extracted serum metabolic fingerprints could successfully distinguish patients with CVD from healthy controls and also differentiate two major subtypes of CVD.This work not only extends the application of MOF nanofilm as an attractive MS probe,but also provide an alternative way for precise diagnosis of CVD in molecular level.

Precision interventional radiology

The recent interest in precision medicine among interventionists has led to the establishment of the concept of precision interventional radiology(PIR).This concept focuses not only on the accuracy of interventional operations using traditional image-guided techniques,but also on the comprehensive evaluation of diseases.The invisible features extracted from CT,MRI,or US improve the accuracy and specificity of diagnosis.The integration of multi-omics and molecule imaging provides more information for interventional operations.The development and application of drugs,embolic materials,and devices broaden the concept of PIR.Integrating medicine and engineering brings new image-guided techniques that increase the efficacy of interventional operations while reducing the complications of interventional treatment.In all,PIR,an important part of precision medicine,emphasizing the whole disease management process,including precision diagnosis,comprehensive evaluation,and interventional therapy,maximizes the benefits of patients with limited damage.

mNGS-based dynamic pathogen monitoring for accurate diagnosis and treatment of severe pneumonia caused by fungal infections

Metagenomic next-generation sequencing(mNGs)has been widely applied to identify pathogens associated with infectious diseases.However,limited studies have explored the use of mNGs-based dynamic pathogen monitoring in intensive care unit patients with severe pneumonia.Here,we present a clinical case of an 86-year-old male patient with severe pneumonia caused by a fungal infection.During the clinical treatment,four mNGS analyses were performed within two consecutive weeks.Various respiratory fungal pathogens,including Candida orthopsilosis,Candida albicans,and Aspergillus fumigatus were detected by mNGS of bronchoalveolar lavage fluid(BALF).Based on conventional pathogen identification and clinical symptoms,the patient was diagnosed with severe pneumonia caused by a fungal infection.The abundance of fungal species decreased gradually in response to antifungal and empirical therapies,and the fungal infections were effectively con-trolled.In summary,our results demonstrated that mNGS could effectively identify pathogens in patients with severe pneumonia.Additionally,dynamic pathogen monitoring based on mNGS could assist in the precise diag-nosis of complex infections and may facilitate rapid induction of the most appropriate therapy.

Protease-triggered bioresponsive drug delivery for the targeted theranostics of malignancy

Proteases have a fundamental role in maintaining physiological homeostasis,but their dysregulation results in severe activity imbalance and pathological conditions,including cancer onset,progression,invasion,and metastasis.This striking importance plus superior biological recognition and catalytic performance of proteases,combining with the excellent physicochemical characteristics of nanomaterials,results in enzyme-activated nano-drug delivery systems(nanoDDS)that perform theranostic functions in highly specific response to the tumor phenotype stimulus.In the tutorial review,the key advances of protease-responsive nanoDDS in the specific diagnosis and targeted treatment for malignancies are emphatically classified according to the effector biomolecule types,on the premise of summarizing the structure and function of each protease.Subsequently,the incomplete matching and recognition between enzyme and substrate,structural design complexity,volume production,and toxicological issues related to the nanocomposites are highlighted to clarify the direction of efforts in nanotheranostics.This will facilitate the promotion of nanotechnology in the management of malignant tumors.

Novel directions of precision oncology:circulating microbial DNA emerging in cancer-microbiome areas

Microbiome research has extended into the cancer area in the past decades.Microbes can affect oncogenesis,progression,and treatment response through various mechanisms,including direct regulation and indirect impacts.Microbiota-associated detectionmethods and agents have been developed to facilitate cancer diagnosis and therapy.Additionally,the cancermicrobiome has recently been redefined.The identification of intra-tumoral microbes and cancer-related circulating microbial DNA(cmDNA)has promoted novel research in the cancer–microbiome area.In this review,we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy.We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine,as well as critical problems to be overcome in this burgeoning field.