Genome-Wide Association Analysis Identifies LILRB2 Gene for Pathological Myopia.

Pathological myopia (PM) is one of the leading causes of blindness, especially in Asia. To identify the genetic risk factors of PM, a two-stage genome-wide association study (GWAS) and replication analysis in East Asian populations is conducted. The analysis identified LILRB2 in 19q13.42 as a new candidate locus for PM. The increased protein expression of LILRB2/Pirb (mouse orthologous protein) in PM patients and myopia mouse models is validated. It is further revealed that the increase in LILRB2/Pirb promoted fatty acid synthesis and lipid accumulation, leading to the destruction of choroidal function and the development of PM. This study revealed the association between LILRB2 and PM, uncovering the molecular mechanism of lipid metabolism disorders leading to the pathogenesis of PM due to LILRB2 upregulation.

De novo design of a nanoregulator for the dynamic restoration of ovarian tissue in cryopreservation and transplantation.

The cryopreservation and transplantation of ovarian tissue underscore its paramount importance in safeguarding reproductive capacity and ameliorating reproductive disorders. However, challenges persist in ovarian tissue cryopreservation and transplantation (OTC-T), including the risk of tissue damage and dysfunction. Consequently, there has been a compelling exploration into the realm of nanoregulators to refine and enhance these procedures. This review embarks on a meticulous examination of the intricate anatomical structure of the ovary and its microenvironment, thereby establishing a robust groundwork for the development of nanomodulators. It systematically categorizes nanoregulators and delves deeply into their functions and mechanisms, meticulously tailored for optimizing ovarian tissue cryopreservation and transplantation. Furthermore, the review imparts valuable insights into the practical applications and obstacles encountered in clinical settings associated with OTC-T. Moreover, the review advocates for the utilization of microbially derived nanomodulators as a potent therapeutic intervention in ovarian tissue cryopreservation. The progression of these approaches holds the promise of seamlessly integrating nanoregulators into OTC-T practices, thereby heralding a new era of expansive applications and auspicious prospects in this pivotal domain.

Artificial Intelligence-Guided Gut-Microenvironment-Triggered Imaging Sensor Reveals Potential Indicators of Parkinson's Disease.

The gut-brain axis has recently emerged as a crucial link in the development and progression of Parkinson's disease (PD). Dysregulation of the gut microbiota has been implicated in the pathogenesis of this disease, sparking growing interest in the quest for non-invasive biomarkers derived from the gut for early PD diagnosis. Herein, an artificial intelligence-guided gut-microenvironment-triggered imaging sensor (Eu-MOF@Au-Aptmer) to achieve non-invasive, accurate screening for various stages of PD is presented. The sensor works by analyzing α-Syn in the gut using deep learning algorithms. By monitoring changes in α-Syn, the sensor can predict the onset of PD with high accuracy. This work has the potential to revolutionize the diagnosis and treatment of PD by allowing for early intervention and personalized treatment plans. Moreover, it exemplifies the promising prospects of integrating artificial intelligence (AI) and advanced sensors in the monitoring and prediction of a broad spectrum of diseases and health conditions.

Smart nanoparticles for cancer therapy.

Smart nanoparticles, which can respond to biological cues or be guided by them, are emerging as a promising drug delivery platform for precise cancer treatment. The field of oncology, nanotechnology, and biomedicine has witnessed rapid progress, leading to innovative developments in smart nanoparticles for safer and more effective cancer therapy. In this review, we will highlight recent advancements in smart nanoparticles, including polymeric nanoparticles, dendrimers, micelles, liposomes, protein nanoparticles, cell membrane nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, iron oxide nanoparticles, quantum dots, carbon nanotubes, black phosphorus, MOF nanoparticles, and others. We will focus on their classification, structures, synthesis, and intelligent features. These smart nanoparticles possess the ability to respond to various external and internal stimuli, such as enzymes, pH, temperature, optics, and magnetism, making them intelligent systems. Additionally, this review will explore the latest studies on tumor targeting by functionalizing the surfaces of smart nanoparticles with tumor-specific ligands like antibodies, peptides, transferrin, and folic acid. We will also summarize different types of drug delivery options, including small molecules, peptides, proteins, nucleic acids, and even living cells, for their potential use in cancer therapy. While the potential of smart nanoparticles is promising, we will also acknowledge the challenges and clinical prospects associated with their use. Finally, we will propose a blueprint that involves the use of artificial intelligence-powered nanoparticles in cancer treatment applications. By harnessing the potential of smart nanoparticles, this review aims to usher in a new era of precise and personalized cancer therapy, providing patients with individualized treatment options.

Cracking the intestinal lymphatic system window utilizing oral delivery vehicles for precise therapy.

Oral administration is preferred over other drug delivery methods due to its safety, high patient compliance, ease of ingestion without discomfort, and tolerance of a wide range of medications. However, oral drug delivery is limited by the poor oral bioavailability of many drugs, caused by extreme conditions and absorption challenges in the gastrointestinal tract. This review thoroughly discusses the targeted drug vehicles to the intestinal lymphatic system (ILS). It explores the structure and physiological barriers of the ILS, highlighting its significance in dietary lipid and medication absorption and transport. The review presents various approaches to targeting the ILS using spatially precise vehicles, aiming to enhance bioavailability, achieve targeted delivery, and reduce first-pass metabolism with serve in clinic. Furthermore, the review outlines several methods for leveraging these vehicles to open the ILS window, paving the way for potential clinical applications in cancer treatment and oral vaccine delivery. By focusing on targeted drug vehicles to the ILS, this article emphasizes the critical role of these strategies in improving therapeutic efficacy and patient outcomes. Overall, this article emphasizes the critical role of targeted drug vehicles to the ILS and the potential impact of these strategies on improving therapeutic efficacy and patient outcomes.

Cracking Brain Diseases from Gut Microbes-Mediated Metabolites for Precise Treatment.

The gut-brain axis has been a subject of significant interest in recent years. Understanding the link between the gut and brain axis is crucial for the treatment of disorders. Here, the intricate components and unique relationship between gut microbiota-derived metabolites and the brain are explained in detail. Additionally, the association between gut microbiota-derived metabolites and the integrity of the blood-brain barrier and brain health is emphasized. Meanwhile, gut microbiota-derived metabolites with their recent applications, challenges and opportunities their pathways on different disease treatment are focus discussed. The prospective strategy of gut microbiota-derived metabolites potential applies to the brain disease treatments, such as Parkinson's disease and Alzheimer's disease, is proposed. This review provides a broad perspective on gut microbiota-derived metabolites characteristics facilitate understand the connection between gut and brain and pave the way for the development of a new medication delivery system for gut microbiota-derived metabolites.

Customizing delivery nano-vehicles for precise brain tumor therapy.

Although some tumor has become a curable disease for many patients, involvement of the central nervous system (CNS) is still a major concern. The blood-brain barrier (BBB), a special structure in the CNS, protects the brain from bloodborne pathogens via its excellent barrier properties and hinders new drug development for brain tumor. Recent breakthroughs in nanotechnology have resulted in various nanovehicless (NPs) as drug carriers to cross the BBB by different strategys. Here, the complex compositions and special characteristics of causes of brain tumor formation and BBB are elucidated exhaustively. Additionally, versatile drug nanovehicles with their recent applications and their pathways on different drug delivery strategies to overcome the BBB obstacle for anti-brain tumor are briefly discussed. Customizing nanoparticles for brain tumor treatments is proposed to improve the efficacy of brain tumor treatments via drug delivery from the gut to the brain. This review provides a broad perspective on customizing delivery nano-vehicles characteristics facilitate drug distribution across the brain and pave the way for the creation of innovative nanotechnology-based nanomaterials for brain tumor treatments.

Engineering a thermostable biosensor based on biomimetic mineralization HRP@Fe-MOF for Alzheimer's disease.

The development of disease detection by biosensors represents one of the key components of medical science. However, millions of people are still misdiagnosed each year due to the poor efficacy and thermal instability of biosensors. Using horseradish peroxidase (HRP) as a paradigm, we offer a rational design strategy to optimize the thermostability and activity of biosensors by biomimetic mineralization. To overcome the weak thermostability of the biosensor, the mineralization of Fe-MOF forms an armor on HRP that protects against high temperature. Additionally, the biomimetic mineralization HRP@Fe-MOF can double-catalyze the TMB/H2O2 chromogenic system for color development. The biosensor can also be recycled through simple heat treatment due to the thermally stable aptamer and biomimetic mineralization HRP@Fe-MOF. The optical biosensor based on this sensitive spectral transformation was successfully developed for the measurement of AßO with an outstanding linear range (0.0001-10 nM) and a low limit of detection (LOD) of 0.03 pM. This promising platform will open up new avenues for the detection of AßO in the early diagnosis of Alzheimer's disease (AD).

Ultrasound-Activated, Tumor-Specific In Situ Synthesis of a Chemotherapeutic Agent Using ZIF-8 Nanoreactors for Precision Cancer Therapy.

The in situ transformation of low-toxicity precursors into a chemotherapeutic agent at a tumor site to enhance the efficacy of its treatment has long been an elusive goal. In this work, a zinc-based zeolitic imidazolate framework that incorporates pharmaceutically acceptable precursors is prepared as a nanoreactor (NR) system for the localized synthesis of an antitumor drug. The as-prepared NRs are administered intratumorally in a tumor-bearing mouse model and then irradiated with ultrasound (US) to activate the chemical synthesis. The US promotes the penetration of the administered NRs into the tumor tissue to cover the lesion entirely, although some NRs leak into the surrounding normal tissue. Nevertheless, only the tumor tissue, where the H2O2 concentration is high, is adequately exposed to the as-synthesized antitumor drug, which markedly impedes development of the tumor. No significant chemical synthesis is detected in the surrounding normal tissue, where the local H2O2 concentration is negligible and the US irradiation is not directly applied. The as-proposed tumor-specific in situ synthesis of therapeutic molecules induces hardly any significant in vivo toxicity and, thus, is potentially a potent biocompatible approach to precision chemotherapy.

Engineering Nano- and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport.

Targeted oral delivery of a drug via the intestinal lymphatic system (ILS) has the advantages of protecting against hepatic first-pass metabolism of the drug and improving its pharmacokinetic performance. It is also a promising route for the oral delivery of vaccines and therapeutic agents to induce mucosal immune responses and treat lymphatic diseases, respectively. This article describes the anatomical structures and physiological characteristics of the ILS, with an emphasis on enterocytes and microfold (M) cells, which are the main gateways for the transport of particulate delivery vehicles across the intestinal epithelium into the lymphatics. A comprehensive overview of recent advances in the rational engineering of particulate vehicles, along with the challenges and opportunities that they present for improving ILS drug delivery, is provided, and the mechanisms by which such vehicles target and transport through enterocytes or M cells are discussed. The use of naturally sourced materials, such as yeast microcapsules and their derived polymeric ß-glucans, as novel ILS-targeting delivery vehicles is also reviewed. Such use is the focus of an emerging field of research. Their potential use in the oral delivery of nucleic acids, such as mRNA vaccines, is proposed.

A Noninvasive Gut-to-Brain Oral Drug Delivery System for Treating Brain Tumors.

Most orally administered drugs fail to reach the intracerebral regions because of the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), which are located between the gut and the brain. Herein, an oral prodrug delivery system that can overcome both the IEB and the BBB noninvasively is developed for treating gliomas. The prodrug is prepared by conjugating an anticancer drug on ß-glucans using a disulfide-containing linker. Following oral administration in glioma-bearing mice, the as-prepared prodrug can specifically target intestinal M cells, transpass the IEB, and be phagocytosed/hitchhiked by local macrophages (Mϕ). The Mϕ-hitchhiked prodrug is transported to the circulatory system via the lymphatic system, crossing the BBB. The tumor-overexpressed glutathione then cleaves the disulfide bond within the prodrug, releasing the active drug, improving its therapeutic efficacy. These findings reveal that the developed prodrug may serve as a gut-to-brain oral drug delivery platform for the well-targeted treatment of gliomas.

A label-free reusable aptasensor for Alzheimer's disease.

To early effectively detect amyloid-beta (Aß) oligomers, a label-free reusable aptasensor was designed. This aptasensor based on a luminescent nanoscale lanthanum-based metal-organic framework (L-MOF)-armored single-stranded DNA antibody (MOF-armored-anti-DNA antibody) as signal tags and aptamer bound to magnetic beads (Apt-MB) as capture probe. The reusable aptasensor combines signal tag and capture probe with antigen-antibody interaction. When the reusable aptasensor is formed, the strong fluorescence intensity of L-MOF will "turn off" by photo-induced electron transfer from excited states to an unfilled d shell of iron cations on the nanoparticle surface. Upon the presence of Aß oligomers in serum samples, they can be especially distinguished with the Aß oligomers aptamer in capture probes and then signal tags are released into the solution for developing the fluorescence aptasensor under excitation/emission 365 nm/430 nm. Meanwhile, the aptamer was recovered from the complex of Aß oligomers/Apt-MB by heat treatment. When the temperature returns to room temperature, the recovered aptamer in the capture probe can once again bound to the MOF-armored-anti-DNA antibody for reuse. The label-free reusable aptasensor system detection has high sensitivity and selectivity toward Aß oligomers (LOD = 0.4 pg/mL) and an excellent linear range (0.001-100 ng/mL). This strategy is a fruitful step for the development of reusable aptasensor and may turn on new avenues for the applications of Aß oligomer detection in clinical diagnosis.Graphical abstract.

A bubble bursting-mediated oral drug delivery system that enables concurrent delivery of lipophilic and hydrophilic chemotherapeutics for treating pancreatic tumors in rats.

The therapeutic outcome of pancreatic cancer remains unsatisfactory, despite many attempts to improve it. To address this challenge, an oral drug delivery system that spontaneously initiates an effervescent reaction to form gas-bubble carriers is proposed. These carriers concurrently deliver lipophilic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) in the small intestine. The bursting of the bubbles promotes the intestinal absorption of the drugs. The antitumor efficacy of this proposed oral drug delivery system is evaluated in rats with experimentally created orthotopic pancreatic tumors. The combined administration of equivalent amounts of PTX and GEM via the intravenous (i.v.) route, which is clinically used for treating pancreatic cancer, serves as a control. Following oral administration, the lipophilic PTX is initially absorbed through the intestinal lymphatic system and then enters systemic circulation, whereas the hydrophilic GEM is directly taken up into the blood circulation, ultimately accumulating in the tumorous pancreatic tissues. A pharmacokinetic study reveals that the orally delivered formulation has none of the toxic side-effects that are associated with the i.v. injected formulation; changes the pharmacokinetic profiles of the drugs; and increases the bioavailability of PTX. The oral formulation has a greater impact than the i.v. formulation on tumor-specific stromal depletion, resulting in greater inhibition of tumor growth with no evidence of metastatic spread. As well as enhancing the therapeutic efficacy, this unique approach of oral chemotherapy has potential for use on outpatients, greatly improving their quality of life.

An aptamer based fluorometric assay for amyloid-ß oligomers using a metal-organic framework of type Ru@MIL-101(Al) and enzyme-assisted recycling.

Amyloid-beta (Aß) oligomers causing neuron damage are regarded as potential therapeutic targets and diagnostic markers for Alzheimer's disease (AD). A homogeneous turn-on fluorometric aptasensor is described for Aß oligomers. It is highly selective and non-invasive and based on (a) the use of a luminescent metal-organic framework carrying aptamer-modified AuNPs (L-MOF/Apt-Au) as tracking agent, and (b) enzyme-assisted target recycling signal amplification. The tracking agent does not emit fluoresce by fluorescence resonance energy transfer (FRET) between the luminescent MOF as donor and Apt-Au as the acceptor under the excitation wavelength of 466 nm. When Aß oligomers are added to the tracking agent solution, the Apt-Au on tracking agent can preferentially bind with Aß oligomers and then be released. This turns the "off" signal of the luminescent MOF tracer to the "on" state. The enzyme (Rec Jf exonuclease) added into the supernatant further improves sensitivity due to enzyme-assisted target-recycling signal amplification. The assay has an excellent linear response to Aß oligomers from 1.0 pM to 10 nM, with a detection limit of 0.3 pM. This homogeneous turn-on fluorometric method is expected to have potential and applications in clinical diagnosis. Graphical abstractSchematic representation of fluorometric assay for amyloid-ß oligomers based on luminescence metal-organic framework nanocomposites as tracking agent with exonuclease-assisted target recycling.

Visualization and colorimetric determination of clenbuterol in pork by using magnetic beads modified with aptamer and complementary DNA as capture probes, and G-quadruplex/hemin and DNA antibody on the metal-organic framework MIL-101(Fe) acting as a peroxidase mimic.

A visualization strategy is described for the detection of clenbuterol (CLB). It is using of antibody against dsDNA and G-quadruplex/hemin labeled on a metal organic framework of type MIL-101(Fe) (G-quadruplex/hemin-anti-DNA/MIL-101) acting as a peroxidase mimetic, and magnetic beads modified with aptamer and complementary DNA (MB/Apt-cDNA) as capture probes. The detection reagent was prepared via the reactions between the double stranded DNA (Apt-cDNA) in capture probes and anti-DNA in peroxidase mimetic. In the presence of CLB, the aptamer on the magnetic beads preferentially binds CLB, and the peroxidase mimetic is released to the supernatant after magnetic separation. The released peroxidase mimetic can catalyze the TMB/H2O2 chromogenic system under mild conditions. This leads to the development of a blue-green coloration whose absorbance is measured at 650 nm. The detection limit is as low as 34 fM of CLB. The method was applied to the determination of CLB in pork samples and gave results that were consistent with data obtained with an ELISA kit. Graphical abstract A visualization strategy is described for the detection of clenbuterol. The selectivity of detection system for clenbuterol is excellent compared with other interferents. The method was applied to the determination of CLB in pork samples.

Strategies for improving diabetic therapy via alternative administration routes that involve stimuli-responsive insulin-delivering systems.

The encapsulation of insulin in micro- or nanodelivery systems may eliminate the need for frequent subcutaneous injections, improving the quality of life of diabetic patients. Formulations for oral, intranasal, pulmonary, subcutaneous, and transdermal administration have been developed. The use of stimuli-responsive polymeric carriers that can release the encapsulated drug in response to changes of the environmental stimuli or external activation enables the design of less invasive or non-invasive systems for smart insulin delivery from depots in the body. This article will look at strategies for the development of responsive delivery systems and the future meeting of the demands of new modes of insulin delivery.

An Intestinal "Transformers"-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs.

Increasing the intestinal dissolution of orally administered poorly water-soluble drugs that have poor oral bioavailability to a therapeutically effective level has long been an elusive goal. In this work, an approach that can greatly enhance the oral bioavailability of a poorly water-soluble drug such as curcumin (CUR) is developed, using a "Transformers"-like nanocarrier system (TLNS) that can self-emulsify the drug molecules in the intestinal lumen to form nanoemulsions. Owing to its known anti-inflammation activity, the use of CUR in treating pancreatitis is evaluated herein. Structural changes of the TLNS in the intestinal environment to form the CUR-laden nanoemulsions are confirmed in vitro. The therapeutic efficacy of this TLNS is evaluated in rats with experimentally induced acute pancreatitis (AP). Notably, the CUR-laden nanoemulsions that are obtained using the proposed TLNS can passively target intestinal M cells, in which they are transcytosed and then transported into the pancreatic tissues via the intestinal lymphatic system. The pancreases in rats that are treated with the TLNS yield approximately 12 times stronger CUR signals than their counterparts receiving free CUR, potentially improving the recovery of AP. These findings demonstrate that the proposed TLNS can markedly increase the intestinal drug dissolution, making oral delivery a favorable noninvasive means of administering poorly water-soluble drugs.

A triple-amplification SPR electrochemiluminescence assay for chloramphenicol based on polymer enzyme-linked nanotracers and exonuclease-assisted target recycling.

The present study aimed to explore a novel triple-amplification electrochemiluminescence (ECL) assay for detecting of chloramphenicol (CAP). This strategy was based on single-stranded DNA-binding protein (SSB) and horseradish peroxidase (HRP) enzyme-linked polymer (EnVision reagent, EV) labeled on Au nanoparticles (EV-Au-SSB) as nanotracer and exonuclease-assisted target recycling. The composite probes were prepared via immunoreactions between the CdS nanocrystal (CdS NC)-functionalized partial complementary DNA and aptamer (CdSNCs/Apt-ssDNA1) as capture probes, and EV-Au-SSB as nanotracer. When the composite probe solution co-existed with CAP and Exo I, the aptamer on the capture probes preferentially combined with CAP, and then CAP-Apt and nanotracer complex were released into the solution. Subsequently, Exo I in the solution could further digest the CAP-Apt from the 3'-end of the aptamer and release CAP, which could participate in further reaction with the probes. It was worth mentioning that EV contained a large number of HRPs on its dendritic chain. In the EV-Au-SSB, Au could enhance ECL intensity of CdS NCs by surface plasmon resonance. What's more, HRPs on EV could catalyze the reaction of H2O2, which could obviously enhance ECL intensity of CdS NCs. This study demonstrated excellent performance of the triple-amplification ECL assay, which makes this aptasensor system suitable and promising for the practical application of CAP residues in fish samples. Moreover, the assay might provide a promising avenue to develop efficient aptasensors to determine small-molecule harmful substances in environmental monitoring and food safety.

A homogeneous and "off-on" fluorescence aptamer-based assay for chloramphenicol using vesicle quantum dot-gold colloid composite probes.

In this work, a novel homogeneous and signal "off-on" aptamer based fluorescence assay was successfully developed to detect chloramphenicol (CAP) residues in food based on the fluorescence resonance energy transfer (FRET). The vesicle nanotracer was prepared through labeling single stranded DNA binding protein (SSB) on limposome-CdSe/ZnS quantum dot (SSB/L-QD) complexes. It was worth mentioning that the signal tracer (SSB/L-QD) with vesicle shape, which was fabricated being encapsulated with a number of quantum dots and SSB. The nanotracer has excellent signal amplification effects. The vesicle composite probe was formed by combining aptamer labeled nano-gold (Au-Apt) and SSB/L-QD. Which based on SSB's specific affinity towards aptamer. This probe can't emit fluoresce which is in "off" state because the signal from SSB/L-QD as donor can be quenched by the Au-aptas acceptor. When CAP was added in the composite probe solution, the aptamer on the Au-Apt can be preferentially bounded with CAP then release from the composite probe, which can turn the "off" signal of SSB/L-QD tracer into "on" state. The assay indicates excellent linear response to CAP from 0.001 nM to 10 nM and detection limit down to 0.3 pM. The vesicle probes with size of 88 nm have strong signal amplification. Because a larger number of QDs can be labeled inside the double phosphorus lipid membrane. Besides, it was employed to detect CAP residues in the milk samples with results being agreed well with those from ELISA, verifying its accuracy and reliability.