Nanotechnologies meeting natural sources:Engineered lipoproteins for precise brain disease theranostics

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity,from preventive and diagnostic to therapeutic fields.Lipoproteins,because of their inherent blood-brain barrier permeability and lesion-homing capability,have been identified as promising strategies for high-performance theranostics of brain diseases.However,the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes,which can be critical for individual therapeutics and clinical translation.To address these issues,lipoprotein-inspired nano drug-delivery systems(nano-DDSs),which have been learned from nature,have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions.In this review,the barriers in brain disease treatment,advantages of state-of-the-art lipoprotein-inspired nano-DDSs,and bio-interactions of such nano-DDSs are highlighted.Furthermore,the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized.Specifically,the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed.Finally,the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles,such as exosomes,cell membranes,and bacteria,are discussed.

MOF负载Weel抑制剂实现p53突变胆囊癌的合成致死靶向治疗

Adavosertib(ADA)is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer(GBC).However,drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications.Herein,estrone-targeted ADA-encapsulated metal–organic frameworks(ADA@MOF-EPL)for GBC synthetic lethal treatment by inducing conditional factors are developed.The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment.Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species(ROS),which leads to a further increase in DNA damage,resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality.The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity.Moreover,ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors,revealing its potential as a broad-spectrum antitumor drug.

Self-fertilization in a gonochoristic fish yellow catfish

Sex control techniques are in great demand for aquaculture because of the huge benefits of mono-sex production.In a previous study on yellow catfish(Tachysurus fulvidraco),intersex individuals were produced by administrating 17α-methyltestosterone(MT)or aromatase inhibitor letrozole(LZ).The ovarian and testicular portions of intersexual gonads developed well and were completely separated,arousing our interest in producing self-fertilizable fish and clone-like fish populations.In this study,yellow catfish fry were treated with a combination of MT and LZ at a low dose(5 mg kg^(-1)MT,300 mg kg^(-1)LZ)at a low water temperature(27.0℃,mixed sex-producing temperature,LL group)and a high temperature(33.5◦C,male-producing temperature,HL group),and with a high dose(10 mg kg^(-1) MT,600 mg kg^(-1) LZ)at a low water temperature(LH group),during 12-65 days post-hatching,the critical period of sex differentiation.Both XX and XY intersex were produced with different percentages at the same time through co-treatment with MT and LZ,with or without the help of male-producing temperature.The highest percentage of XY intersex(53%in XY,36%in XX and XY)and XX intersex(47%in XX,25%in XX and XY)was produced in LH and HL groups,respectively.Results of gonadal morphology,histology,and sperm dynamic analysis indicate that some XX and XY intersex individuals were capable of self-fertilization through artificial insemination.The reproductive performance of these intersex individuals was then investigated by injecting spawning agents,dissecting gonads,and artificially fertilizing eggs with their own sperm.The XX,XY,and YY genotypic individuals were produced by the self-fertilization of XY intersex individuals.The present study successfully produced high percentages of XX and XY intersex and conducted self-fertilization by mating the eggs and sperm of a single intersex individual.Self-fertilization in fish will show great potential in aquaculture genetics and breeding,for example,generating highly homozygous(or"clonal")genetic material,producing mono-sex populations,and identifying unknown sex determination modes.In particular,the cloning method of producing genetic materials will be greatly beneficial for maintaining advantageous traits through self-fertilization generation after generation.

Effective and biocompatible antibacterial surfaces via facile synthesis and surface modification of peptide polymers

It is an urgent need to tackle drug-resistance microbial infections that are associated with implantable biomedical devices.Host defense peptide-mimicking polymers have been actively explored in recent years to fight against drug-resistant microbes.Our recent report on lithium hexamethyldisilazide-initiated superfast polymerization on amino acid N-carboxyanhydrides enables the quick synthesis of host defense peptide-mimicking peptide polymers.Here we reported a facile and cost-effective thermoplastic polyurethane(TPU)surface modification of peptide polymer(DLL:BLG=90:10)using plasma surface activation and substitution reaction between thiol and bromide groups.The peptide polymer-modified TPU surfaces exhibited board-spectrum antibacterial property as well as effective contact-killing ability in vitro.Furthermore,the peptide polymer-modified TPU surfaces showed excellent biocompatibility,displaying no hemolysis and cytotoxicity.In vivo study using methicillin-resistant Staphylococcus aureus(MRSA)for subcutaneous implantation infectious model showed that peptide polymer-modified TPU surfaces revealed obvious suppression of infection and great histocompatibility,compared to bare TPU surfaces.We further explored the antimicrobial mechanism of the peptide polymer-modified TPU surfaces,which revealed a surface contact-killing mechanism by disrupting the bacterial membrane.These results demonstrated great potential of the peptide-modified TPU surfaces for practical application to combat bacterial infections that are associated with implantable materials and devices.

Identification of publication characteristics and research trends in the management of gallbladder cancer

Background:To date,no comprehensive analysis of gallbladder cancer(GBC)management has been reported.We aimed to identify the publication characteristics and research trends in managing GBC over the past three decades.Methods:We selected the 100 most cited articles and performed a bibliometric analysis to summarize the publication characteristics,explore research hotspots,and identify research trends in the management of GBC.Results:The total citations of the included articles ranged from 123 to 1822.Period II(2001–2010)yielded the highest number of included articles,whereas the lowest was in Period III(2011–2020).The United States and Japan published the most papers,in which the Memorial Sloan–Kettering Cancer Center and Nagoya University were the leading institutions,respectively.The most influential authors were Blumgart LH and Fong YM from the United States.Cooperation among countries,institutions,and authors was weak.The Annals of Surgery contributed the most articles with the highest number of total citations.The most researched topic was surgery,followed by systemic therapy and adjuvant therapy.Since Period I,the percentage of surgery-related publications continuously decreased(Periods II and III versus Period I,both p<0.001),with a concomitant increase in those of adjuvant therapy(Period III versus Period I,p=0.004)and systemic therapy(Period II versus Period I,p=0.004;Period III versus Period I,p=0.002).Conclusions:Surgery remains the preferred treatment,while there is a tendency toward adjuvant and systemic therapy in GBC management.An increase in local and international collaboration for managing GBC is required.