The Application of Aptamer and Research Progress in Liver Disease.

Aptamers, as a kind of small-molecule nucleic acid, have attracted much attention since their discovery. Compared with biological reagents such as antibodies, aptamers have the advantages of small molecular weight, low immunogenicity, low cost, and easy modification. At present, aptamers are mainly used in disease biomarker discovery, disease diagnosis, treatment, and targeted drug delivery vectors. In the process of screening and optimizing aptamers, it is found that there are still many problems need to be solved such as the design of the library, optimization of screening conditions, the truncation of screened aptamer, and the stability and toxicity of the aptamer. In recent years, the incidence of liver-related diseases is increasing year by year and the treatment measures are relatively lacking, which has attracted the people's attention in the application of aptamers in liver diseases. This article mainly summarizes the research status of aptamers in disease diagnosis and treatment, especially focusing on the application of aptamers in liver diseases, showing the crucial significance of aptamers in the diagnosis and treatment of liver diseases, and the use of Discovery Studio software to find the binding target and sequence of aptamers, and explore their possible interaction sites.

Inhibitory Effect of Jinkui Shenqi Pills on Glucocorticoid-Enhanced Axial Length Elongation in Experimentally Myopic Guinea Pigs.

OBJECTIVE: To explore the underlying mechanism of inhibition by Jinkui Shenqi Pills (JKSQP) on glucocorticoid-enhanced axial length elongation in experimental lens-induced myopia (LIM) guinea pigs. METHODS: Sixty 2-week old male guinea pigs were randomly divided into 4 groups with 15 guinea pigs in each group, according to the random numbers generated by SPSS software: control, LIM, saline and JKSQP groups. The control group includes animals with no treatment, while the guinea pigs in the other 3 groups received lens-induced myopization on the right eyes throughout the experiment (for 8 weeks). The saline and JKSQP groups were given daily intraperitoneal injections of 10 mg/kg hydrocortisone for 2 consecutive weeks at the same time, and then orally administered either saline or JKSQP [13.5 g/(kg•d) for 6 consecutive weeks. Body weight, anal temperature and animal appearance were observed and recorded to evaluate the GC-associated symptoms. The ocular parameters, including refraction and axial length, were measured by streak retinoscopy and A-scan ultrasonography, respectively. The levels of plasma hormones associated with the hypothalamic-pituitary-adrenal axis (HPAA), including free triiodothyronine, free thyroxine, estradiol and testosterone, were measured by radioimmunoassay, and cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate were measured by enzyme-linked immunosorbent assay. In addition, the mRNA and protein expressions of retinal amphiregulin (AREG) was measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. RESULTS: JKSQP effectively increased body weight and anal temperature, improved animal appearance and suppressed axial length elongation in glucocorticoid-enhanced myopic guinea pigs with normalization of 4 HPAA-associated plasma hormones (all P<0.05). The plasma level of cAMP was significantly increased, whereas the plasma level of cGMP and the mRNA and protein expressions of retinal AREG were decreased after treatment with JKSQP (all P<0.05). CONCLUSION: JKSQP exhibited a significant inhibitory effect on axial length elongation with decreased expression of AREG in the retina, and normalized 4 HPAA-associated plasma hormones and the expression of cAMP and cGMP in GC-enhanced myopic guinea pigs.

The roles of ETS transcription factors in liver fibrosis.

E26 transformation specific or E twenty-six (ETS) protein family consists of 28 transcription factors, five of which, named ETS1/2, PU.1, ERG and EHF, are known to involve in the development of liver fibrosis, and are expected to become diagnostic markers or therapeutic targets of liver fibrosis. In recent years, some small molecule inhibitors of ETS protein family have been discovered, which might open up a new path for the liver fibrosis therapy targeting ETS. This article reviews the research progress of ETS family members in the development liver fibrosis as well as their prospect of clinical application.

Current Status and Challenges of Aptamers Screening and Optimization.

BACKGROUND: Aptamers, consisting of single-stranded DNA or RNA, have secondary and tertiary structures which could bind specifically to target molecules. They are characterized by strong specificity, high affinity, low molecular weight, and low immunogenicity; therefore, the current research focuses on their potential as a targeted drug carrier, a diagnostic probe for diseases, or as a direct therapeutic drug. OBJECTIVE: In this review, how to improve the success rate of adaptor screening and the optimization after screening is described. RESULTS: For aptamer screening, an efficient selection strategy is needed. In this article, by analyzing key aspects of SELEX such as initial library design, screening procedures, truncation and modification after screening, a comprehensive analysis of each step that might meet obstacles in SELEX is provided. CONCLUSION: Aptamers, which possess the specificity and affinity with the target, can serve as targeted drug carriers or biosensors for diagnosing a disease. If the problems in the screening process in cell-SELEX technology, truncation, and modification after screening are solved, it will have a broader range of applications.

Possible roles of Golgi protein-73 in liver diseases.

Golgi protein 73 (also known as GP73 or GOLPH2) is a transmembrane glycoprotein present in the Golgi apparatus. In diseased states, GP73 is expressed by hepatocytes rather than by bile duct epithelial cells. Many studies have reported that serum GP73 (sGP73) is a marker for hepatocellular carcinoma (HCC). For HCC diagnosis, the sensitivities of sGP73 were higher than that of other markers but the specificities were lower. Considering that the concentration of GP73 is consistent with the stage of liver fibrosis and cirrhosis, some studies have implied that GP73 may be a marker for liver fibrosis and cirrhosis. Increased sGP73 levels may result from hepatic inflammatory activity. During liver inflammation, GP73 facilitates liver tissue regeneration. By summarizing the studies on GP73 in liver diseases, we wish to focus on the mechanism of GP73 in diseases.

The miR-23b/27b/24-1 Cluster Inhibits Hepatic Fibrosis by Inactivating Hepatic Stellate Cells.

BACKGROUND & AIMS: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-ß (TGF-ß) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. METHODS: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. RESULTS: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-ß2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-ß signaling pathway by down-regulation of TGF-ß2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-ß signaling increased ECM degradation. CONCLUSIONS: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.

Relationship between the structure and function of the transcriptional regulator E2A.

E proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.

Analysis of key genes and related transcription factors in liver fibrosis based on bioinformatic technology.

OBJECTIVE: To analyze differentially expressed genes (DEGs) related to liver fibrosis, and clarify the key genes and the possible targets in the progression of liver fibrosis. METHODS: Using microarray datasets, GSE38199 was extracted from Gene Expression Omnibus (GEO), and a bioinformatics method was performed to find DEGs and transcription factors related to liver fibrosis. RESULTS: A total of 58 DEGs were screened out according to GEO2R online analysis tool, which included 49 up-regulated and 9 down-regulated genes. These DEGs were mainly involved in formation with the extracellular region and extracellular exosome through gene ontology (GO) enrichment analysis. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs mainly participated in the PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, and metabolic pathways. Based on the results of the Protein-Protein Interaction (PPI) network and Molecular Complex Detection (MCODE) analysis, 9 key genes (COL1A1, FBN1, BGN, COL6A3, MMP2, FBLN5, LUM, PDGFRB, LOXL1) were screened out. A total of 30 transcription factors were found according to these 9 key genes, of which 4 transcription factors (Stat3, Trp53, NF-κB1, Sp1) were enriched. CONCLUSION: Stat3, Trp53, NF-κB1, and Sp1 were all related to the development of liver fibrosis, and FBLN5 might be a target for liver fibrosis.

Interaction of non­parenchymal hepatocytes in the process of hepatic fibrosis (Review).

Hepatic fibrosis (HF) is the process of fibrous scar formation caused by chronic liver injury of different etiologies. Previous studies have hypothesized that the activation of hepatic stellate cells (HSCs) is the central process in HF. The interaction between HSCs and surrounding cells is also crucial. Additionally, hepatic sinusoids capillarization, inflammation, angiogenesis and fibrosis develop during HF. The process involves multiple cell types that are highly connected and work in unison to maintain the homeostasis of the hepatic microenvironment, which serves a key role in the initiation and progression of HF. The current review provides novel insight into the intercellular interaction among liver sinusoidal endothelial cells, HSCs and Kupffer cells, as well as the hepatic microenvironment in the development of HF.

Can acoustic radiation force impulse imaging (ARFI) accurately diagnose renal masses?: A protocol of systematic review and meta-analysis.

BACKGROUND: Renal masses are increasingly being discovered because of the wide accessibility of modern high resolution imaging procedures. Previous clinical studies have reported that acoustic radiation force impulse imaging (ARFI) is used for diagnosis of renal masses. However, no study has investigated this topic systematically. Therefore, this study will evaluate the diagnostic value of ARFI for the diagnosis of renal masses. METHODS: A systematic search using the databases of Cochrane Library, EMBASE, Pubmed, WANGFANG, and China National Knowledge Infrastructure will be performed to identify studies in which patients with renal masses are assessed by ARFI. Two investigators will independently screen the literature and extract the data. Any discrepancies will be resolved via discussion with the senior author. Study quality will be assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 tool, and pooled sensitivity and specificity of various ARFI findings for the diagnosis of renal masses will be determined. Summary receiver operating characteristic curve will be used to assess the overall performance of ARFI. RESULTS: This study will evaluate the diagnostic value of ARFI for the diagnosis of renal masses through sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. CONCLUSION: This study will summarize the most recent evidence that focusing on the diagnosis of ARFI for renal masses. STUDY REGISTRATION: INPLASY202060105.

Diagnostic accuracy of contrast-enhanced ultrasound in the detection of small renal masses: A protocol of systematic review and meta-analysis.

BACKGROUND: The small renal masses (SRMs) were defined that the diameter of renal masses measured by enhanced image was ≤4 cm. The diagnostic accuracy of contrast-enhanced ultrasound (CEUS) for SRMs is apparently variable among previous studies. Hence, this study will evaluate the diagnostic accuracy of CEUS in the identification of benign and malignant SRMs. METHODS: A comprehensive search using the databases of Cochrane Library, Embase, PubMed, WANGFANG, and China National Knowledge Infrastructure will be carried out to identify studies in which patients with SRMs are assessed by CEUS. Two investigators will independently screen the literature and extract the data. Any discrepancies will be resolved via discussion with the senior author. Study quality will be assessed by the Quality Assessment of Diagnostic Accuracy Studies 2 tool, and pooled sensitivity and specificity of various CEUS findings for the diagnosis of SRMs will be determined. Summary receiver operating characteristic curve will be used to assess the overall performance of CEUS. RESULTS: This study will evaluate the diagnostic accuracy of CEUS for the diagnosis of SRMs through sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. CONCLUSION: This study will summarize the most recent evidence that focusing on the diagnosis of CEUS for SRMs. STUDY REGISTRATION: INPLASY202060040.

The influencing factors and functions of DNA G-quadruplexes.

G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy.

Class C1 decoy oligodeoxynucleotide inhibits profibrotic genes expression in rat hepatic stellate cells.

The aim of the present study was to investigate whether class C1 decoy oligodeoxynucleotides (ODNs) can inhibit the expression of pro­fibrotic genes associated with rat hepatic stellate cell (HSC) activation and hepatic fibrosis. Luciferase reporter assays were performed to test the promoter activities of transforming growth factor (TGF)­ß and its downstream target genes following transfection of decoy ODNs and plasmids into HSC­T6 cells, and western blot assays were performed to measure the protein expression of those genes following decoy ODN transfection. Class C1 decoy ODNs were confirmed to inhibit the promoter activity of TGF­ß and its downstream target genes, such as type 1 collagen (COLI)α1, tissue inhibitor of metalloproteinases (TIMP)1 and α­smooth muscle actin by Gaussia luciferase reporter assay, and to further downregulate the expression of TGF­ß, SMAD3, COLIα1 and TIMP1 by western blotting in activated HSC­T6 cells. In conclusion, class C1 decoy ODNs inhibited pro­fibrotic gene expression in rat HSCS by downregulating TGF­ß signaling.

An exploration of aptamer internalization mechanisms and their applications in drug delivery.

INTRODUCTION: As 'chemical antibodies', aptamers have some advantages, such as lack of immunogenicity, rapid tissue penetration, cell internalization and so on. Consequently, more and more aptamers have been screened out by the systematic evolution of ligands through exponential enrichment for the desired cells or membrane receptors. On the basis of the result, researchers use aptamers to guide drug targeting to the desired cells and internalization in vivo. AREAS COVERED: In this review, we explore the mechanisms of cargo- or aptamer-mediated internalization, and then briefly summarize five strategies for exploring the mechanism of aptamer internalization. Finally, we focus on four types of applications involving aptamer internalization: aptamers as drugs, aptamers as chemical drug-delivery systems, aptamer-based chimeras and aptamer-conjugated nanoparticles or block copolymer micelles. EXPERT OPINION: Two aptamer-internalization mechanisms are known, namely receptor-mediated endocytosis and macropinocytosis. The latter mechanism, which is has only been verified in the internalization of nucleolin aptamer shuttles between the nucleus and cytoplasm, may be important for nuclear internalization and cargo molecule escape from the endosomal compartment. Thus, it is feasible to use some strategies to further explore the macropinocytosis internalization mechanism and then to screen for aptamers similar to the nucleolin aptamer for use with the desired cell types as a targeted delivery tool.

The roles of lncRNA in hepatic fibrosis.

Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate gene or protein expression; however, their function in the progression of hepatic fibrosis remains unclear. Hepatic fibrosis is a continuous wound-healing process caused by numerous chronic hepatic diseases, and the activation of hepatic stellate cells (HSCs) is generally considered to be a pivotal step in hepatic fibrosis. In the process of hepatic fibrosis, some lncRNAs regulates diverse cellular processes. Here are several examples: the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and liver fibrosis-associated lncRNA1 (lnc-LFAR1) promote HSC activation in the progression of hepatic fibrosis via the transforming growth factor-ß signaling pathway; the lncRNA HIF 1 alpha-antisense RNA 1 (HIF1A-AS1) and Maternally expressed gene 3 reduce HSC activation which are associated with DNA methylation; the lncRNA plasmacytoma variant translocation 1, Homeobox (HOX) transcript antisense RNA and MALAT1 promote HSC activation as competing endogenous RNAs (ceRNAs); the long intergenic non-coding RNA-p21 (lncRNA-p21) and Growth arrest-specific transcript 5 reduce HSC activation as ceRNAs. As we get to know more about the function of lncRNAs in hepatic fibrosis, more and more ideas for the molecular targeted therapy in hepatic fibrosis will be put forward.

The miR-290-295 cluster as multi-faceted players in mouse embryonic stem cells.

Increasing evidence indicates that embryonic stem cell specific microRNAs (miRNAs) play an essential role in the early development of embryo. Among them, the miR-290-295 cluster is the most highly expressed in the mouse embryonic stem cells and involved in various biological processes. In this paper, we reviewed the research progress of the function of the miR-290-295 cluster in embryonic stem cells. The miR-290-295 cluster is involved in regulating embryonic stem cell pluripotency maintenance, self-renewal, and reprogramming somatic cells to an embryonic stem cell-like state. Moreover, the miR-290-295 cluster has a latent pro-survival function in embryonic stem cells and involved in tumourigenesis and senescence with a great significance. Elucidating the interaction between the miR-290-295 cluster and other modes of gene regulation will provide us new ideas on the biology of pluripotent stem cells. In the near future, the broad prospects of the miRNA cluster will be shown in the stem cell field, such as altering cell identities with high efficiency through the transient introduction of tissue-specific miRNA cluster.

The roles of microRNA families in hepatic fibrosis.

When hepatocytes are damaged severely, a variety of signaling pathways will be triggered by inflammatory factors and cytokines involving in the process of hepatic fibrosis. The microRNA (miRNA) family consists of several miRNAs which have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of miRNA family as a whole in hepatic fibrosis. Increasing studies have suggested several miRNA families are related with activation of hepatic stellate cells and hepatic fibrosis through cooperatively regulating certain signaling pathways. During the process of hepatic fibrosis, miR-29 family primarily induces cell apoptosis by modulating phosphatidylinositol 3-kinase/AKT signaling pathway and regulates extracellular matrix accumulation. miR-34 family promotes the progression of hepatic fibrosis by inducing activation of hepatic stellate cells, while miR-378 family suppresses the process in Glis dependent manner. miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and miR-200 family are responsible for extracellular matrix deposition and the release of pro-fibrotic cytokines. These miRNA family members play pro-fibrotic or anti-fibrotic roles by targeting genes collectively or respectively which involve in hepatic fibrosis related signaling pathways and hepatic stellate cell activation. Thus, good understandings of molecular mechanisms which are based on miRNA families may provide new ideas for the molecular targeted therapy of hepatic fibrosis in the future.

K+ -Responsive Block Copolymer Micelles for Targeted Intracellular Drug Delivery.

In this work, a novel type of block copolymer micelles with K+ -responsive characteristics for targeted intracellular drug delivery is developed. The proposed smart micelles are prepared by self-assembly of poly(ethylene glycol)-b-poly(N-isopropylacry-lamide-co-benzo-18-crown-6-acrylamide) (PEG-b-P(NIPAM-co-B18C6Am)) block copolymers. Prednisolone acetate (PA) is successfully loaded into the micelles as the model drug, with loading content of 4.7 wt%. The PA-loaded micelles display a significantly boosted drug release in simulated intracellular fluid with a high K+ concentration of 150 × 10-3 m, as compared with that in simulated extracellular fluid. Moreover, the in vitro cell experiments indicate that the fluorescent molecules encapsulated in the micelles can be delivered and specifically released inside the HSC-T6 and HepG2 cells responding to the increase of K+ concentration in intracellular compartments, which confirms the successful endocytosis and efficient K+ -induced intracellular release. Such K+ -responsive block copolymer micelles are highly potential as new-generation of smart nanocarriers for targeted intracellular delivery of drugs.

Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression.

Gremlin1, the antagonist of bone morphogenetic protein-7 and one of the target genes of transforming growth factor (TGF)-ß signal pathway, plays an important role in embryonic development and its expression decreases along with aging. To explore the expression of gremlin1 in liver fibrosis and the causal link between gremlin1 and hepatic stellate cell (HSC) activation, we detected the expression of gremlin1 in mice with hepatic fibrosis induced by porcine serum using real time quantitative PCR (RT-qPCR) and immunohistochemical staining. The hepatic fibrosis mice were evaluated by the external feature of the liver, histology, hepatic function, collagen deposition, and the expression of fibrosis-related genes (genes COLIα2 and COLIVα2) in the liver. In the HSC-T6, western blotting was used to analyze the expression of α-smooth muscle actin (α-SMA), COL1α, and TGF-ß1 in conditions of overexpression of gremlin1 or gremlin1 being knocked down by specific siRNA, respectively. The results showed that the mRNA expression of the gremlin1 gene was significantly increased consistent with increased expression of COLIα2 and COLIVα2 in the liver tissue of the hepatic fibrosis mice. Increased expression of gremlin1 coincided with the same area of the collagen deposition. Furthermore, the results also showed that the expression of α-SMA, COLIα1, and TGF-ß1 was consistent with the expression of gremlin1 not only in the HSC-T6 overexpressing gremlin1 but also in the HSC-T6 that gremlin1 is knocked down by specific siRNA. The findings suggest that gremlin1 might play an important role in the progression of hepatic fibrosis and that it modulates HSC activation.

Stimuli-Responsive Capsule Membranes for Controlled Release in Pharmaceutical Applications.

BACKGROUND: In conventional drug delivery, the drug concentration in the blood raises once the drug taken, and then peaks and declines. Since each drug has a level above which it is toxic and another level below which it is ineffective, the drug concentration in a patient at a particular time depends on compliance with the prescribed routine. METHODS: To achieve more effective efficacy and fewer side effects of drugs, the drug carriers with desirable dosing and controllable release property of drugs are highly desired. Stimuli-responsive capsules with smart gating membranes or hydrogel-based membranes as capsule shells are ideal candidates. The smart capsule membranes enable efficient encapsulation of drugs within the large inner volume, and the responsive gating membranes or hydrogel-based membranes could control the release rate of encapsulated drugs in responding to environmental stimuli. The trigger stimuli could be either artificial or natural ones corresponding to specific diseases, such as temperature, pH, glucose concentration, specific ion, light, and magnetic field. RESULTS: This review highlights the recent development in stimuli-responsive capsule membranes for controlled release in pharmaceutical applications, including two types of stimuli-responsive capsule membranes with different architectures for on/off release and burst release, which can achieve potential uses of case-dependent on/off release and burst release. CONCLUSION: The preponderances of the smart capsule membranes are that the capsules are with controllable inner space for drug vehicles with desired dose and stimuli-responsive membrane as shell to release drugs at a desired site and/or moment. However, the actual difficulties for the stimuli-responsive capsule membrane systems to go before they can be applied widely in the biomedical fields are discussed. The future works should focus on the improvements of biocompatibility, biodegradability and stimuli-responsiveness of the capsule membranes, easy and scalable fabrication techniques with further decrease of the capsule size for more efficient in vivo applications, and the diversification of the multi-compartmental capsule architectures with multi-stimuli-responsive characteristics for controlled release.