Flexible Aerogel Materials: A Review on Revolutionary Flexibility Strategies and the Multifunctional Applications.

The design and preparation of flexible aerogel materials with high deformability and versatility have become an emerging research topic in the aerogel fields, as the brittle nature of traditional aerogels severely affects their safety and reliability in use. Herein, we review the preparation methods and properties of flexible aerogels and summarize the various controlling and design methods of aerogels to overcome the fragility caused by high porosity and nanoporous network structure. The mechanical flexibility of aerogels can be revolutionarily improved by monomer regulation, nanofiber assembly, structural design and controlling, and constructing of aerogel composites, which can greatly broaden the multifunctionality and practical application prospects. The design and construction criterion of aerogel flexibility is summarized: constructing a flexible and deformable microstructure in an aerogel matrix. Besides, the derived multifunctional applications in the fields of flexible thermal insulation (flexible thermal protection at extreme temperatures), flexible wearable electronics (flexible sensors, flexible electrodes, electromagnetic shielding, and wave absorption), and environmental protection (oil/water separation and air filtration) are summarized. Furthermore, the future development prospects and challenges of flexible aerogel materials are also summarized. This review will provide a comprehensive research basis and guidance for the structural design, fabrication methods, and potential applications of flexible aerogels.

Hydrogen-bonded organic frameworks: new horizons in biomedical applications.

Hydrogen-bonded organic frameworks (HOFs) are an emerging attractive class of highly crystalline porous materials characterized by significant biocompatibility, rich chemical functionalities and well-defined porosity. The unique advantages including metal-free nature and reversible binding manner significantly distinguish HOFs from other porous materials in the biotechnology and biomedical field. However, the relevant HOF studies still remain in their infancy despite the promising and remarkable results that have been presented in recent years. Due to the intricate and dynamic nature of physiological conditions, the major challenge lies in the stability and structural diversity of HOFs in vivo. In this Tutorial Review, we summarize the common building blocks for the construction of HOF-based functional biomaterials and the latest developments in the biological field. Moreover, we highlight current challenges regarding the stability and functionalization of HOFs along with the corresponding potential solutions. This Tutorial Review will have a profound effect in future years on the design and applications of HOF-based biomaterials.

Enantioselective Degrader for Elimination of Extracellular Aggregation-Prone Proteins hIAPP Associated with Type 2 Diabetes.

Targeted protein degradation has demonstrated the power to modulate protein homeostasis. For overcoming the limitation to intracellular protein degradation, lysosome targeting chimeras have been recently developed and successfully utilized to degrade a range of disease-relevant extracellular and membrane proteins. Inspired by this strategy, here we describe our proof-of-concept studies using metallohelix-based degraders to deliver the extracellular human islet amyloid polypeptide (hIAPP) into the lysosomes for degradation. Our designed metallohelix can bind and inhibit hIAPP aggregation, and the conjugated tri-GalNAc motif can target macrophage galactose-type lectin 1 (MGL1), yielding chimeric molecules that can both inhibit hIAPP aggregation and direct the bound hIAPP for lysosomal degradation in macrophages. Further studies demonstrate that the enhanced hIAPP clearance has been through the endolysosomal system and depends on MGL1-mediated endocytosis. Intriguingly, Λ enantiomers show even better efficiency in preventing hIAPP aggregation and promoting internalization and degradation of hIAPP than Δ enantiomers. Moreover, metallohelix-based degraders also faciltate the clearance of hIAPP through asialoglycoprotein receptor in liver cells. Overall, our studies demonstrate that chiral metallohelix can be employed for targeted degradation of extracellular misfolded proteins and possess enantioselectivity.

Hydrogen-Bonded Organic Framework (HOF)-Based Single-Neural Stem Cell Encapsulation and Transplantation to Remodel Impaired Neural Networks.

Herein we present a new way to encapsulate neural stem cells (NSCs) by using hydrogen-bonded organic frameworks (HOFs) to overcome the common causes of low therapeutic efficacy during NSC transplantation: 1) loss of fundamental stem cell properties, "stemness", before transplantation, 2) cytomembrane damage during transplantation, and 3) apoptosis due to oxidative stress after transplantation. Porous carbon nanospheres (PCNs) are doped into the HOF shell during the process of mineralization to endow the cellular exoskeletons with hierarchical hydrogen bonds, and the ability to resist oxidative stress due to the catalase and superoxide dismutase-like activities of PCN. Under NIR-II irradiation, thermal-responsive hydrogen bonds dissociate to release NSCs. Stereotactic transplanting encapsulated NSC into the brain of an Alzheimer's disease (AD) mouse model further verifies that our design can enhance NSC viability, promote neurogenesis, and ameliorate cognitive impairment. As the first example of using HOFs to encapsulate NSCs, this work may inspire the design of HOF-based exoskeletons to ameliorate neurogenesis and cognitive behavioral symptoms associated with AD.

Site-Directed Chemical Modification of Amyloid by Polyoxometalates for Inhibition of Protein Misfolding and Aggregation.

Post-translational modification (PTM) of protein can significantly change protein conformation and function. Inspired by the natural PTM, we present a new approach to inhibit amyloid aggregation by chemical PTM modification. Polyoxometalates (POMs) were used as examples of inhibitors of ß-amyloid peptide (Aß) aggregation to illustrate the chemical PTM method. After the POMs were modified with thiazolidinethione (TZ), the resulting POMD-TZ acted as a chemical PTM agent and could covalently modify Aß site-selectively at Lys16. Multiple biophysical techniques and biochemical assays have been employed to show the superiority of the chemical PTM method compared to traditional Aß inhibitors. Since Aß oligomers are more cytotoxic, we further functionalized POMD-TZ with an Aß-targeted peptide and a fluorescent probe to obtain an "Aß oligomer sensitive" probe. The use of PTM agents for the site-directed chemical modification of proteins provides a new way to regulate amyloid aggregation.

NIR-II Hydrogen-Bonded Organic Frameworks (HOFs) Used for Target-Specific Amyloid-ß Photooxygenation in an Alzheimer's Disease Model.

Phototherapy has emerged as a powerful approach for interrupting ß-amyloid (Aß) self-assembly. However, deeper tissue penetration and safer photosensitizers are urgent to be exploited for avoiding damaging nearby normal tissues and improving therapeutic effectiveness. A hydrogen-bonded organic framework (HOF)-based NIR-II photooxygenation catalyst is presented here to settle the abovementioned challenges. By encapsulating the pyridinium hemicyanine dye DSM with a large two-photon absorption (TPA) cross-section in NIR-II window into the porphyrin-based HOF, the resultant DSM@n-HOF-6 exhibits significant two-photon NIR-II-excited Fluorescence Resonance Energy Transfer (FRET) to generate singlet oxygen (1 O2 ) for Aß oxidation. Further, the target peptides of KLVFFAED (KD8) are covalently grafted on DSM@n-HOF-6 to enhance the blood-brain barrier (BBB) permeability and Aß selectivity. The HOF-based photooxygenation catalyst shows an outstanding inhibitory effect of Aß aggregation upon the NIR-II irradiation. Further in vivo studies demonstrate the obvious decrease of craniocerebral Aß plaques and recovery of memory deficits in triple-transgenic AD (3×Tg-AD) model mice.

Glycoengineering artificial receptors for microglia to phagocytose Aß aggregates.

Oligomeric and fibrillar amyloid-ß (Aß) are principally internalized via receptor-mediated endocytosis (RME) by microglia, the main scavenger of Aß in the brain. Nevertheless, the inflammatory cascade will be evoked after vast Aß aggregate binding to pattern recognition receptors on the cell membrane, which then significantly decreases the expression of these receptors and further deteriorate Aß deposition. This vicious circle will weaken the ability of microglia for Aß elimination. Herein, a combination of metabolic glycoengineering and self-triggered click chemistry is utilized to engineer microglial membranes with ThS as artificial Aß receptors to promote microglia to phagocytose Aß aggregates. Additionally, to circumvent the undesirable immune response during the process of the bioorthogonal chemistry reaction and Aß-microglial interaction, Mn-porphyrin metal-organic frameworks (Mn-MOFs) with superoxide dismutase (SOD) and catalase (CAT) mimic activity are employed to carry N-azidoacetylmannosamine (AcManNAz) and eradicate over-expressed reactive oxygen species (ROSs). The artificial Aß receptors independent of a signal pathway involved in immunomodulation as well as Mn-MOFs with antioxidant properties can synergistically promote the phagocytosis and clearance of Aß with significantly enhanced activity and negligible adverse effects. The present study will not only provide valuable insight into the rational design of the microglial surface engineering strategy via bioorthogonal chemistry, but also hold great potential for other disease intervention associated with receptor starvation.

Aß aggregation behavior at interfaces with switchable wettability: a bioinspired perspective to understand amyloid formation.

An amphiphilic taurocholic acid (TCA) doped polypyrrole (PPy) film (PPy/TCA) was used as a dynamic mimic membrane model to explore how switchable surface wettability influences amyloid aggregation. Our results indicate that the hydrophobic surface, not the hydrophilic surface, plays important roles in Aß40 adsorption and aggregation.

MOF-encapsulated nanozyme enhanced siRNA combo: Control neural stem cell differentiation and ameliorate cognitive impairments in Alzheimer's disease model.

Neural stem cells (NSC) transplantation is garnering considerable attention in the treatment of neurodegenerative diseases that are associated with cognitive decline. Current methods are mainly based on neuron-directional differentiation and NSC niche components majorization to promote neurogenesis. Unfortunately, the pathologically high level of oxidative stress will damage the neurons derived from NSC during therapy, compromising the neurogenesis effect. Herein, a facile and effective strategy has been presented for modulation of neuron-directional differentiation and amelioration of oxidative stress by integrating antioxidative nanozymes (ceria) into metal-organic frameworks (MOF) for synergistically enhancing neurogenesis. Specially, small interfering RNA (siSOX9) and retinoic acid (RA) are loaded in the MOF. The H2O2-responsive MOF would release cargos in the lesion area to promote neuron-directional differentiation. Moreover, the integrated ceria can perform robust SOD and CAT mimetic activities, which are capable of eliminating ROS and circumventing its oxidative damage to newborn neurons, leading to the longer survival rate and more enhanced outgrowth of the newborn neurons. With the gratifying drug delivery efficiency of MOF and excellent antioxidative capacity of nanozymes, the rational-designed nanoparticles can considerably promote neurogenesis and improve the cognitive function of aged 3 × Tg-AD (triple transgenic AD mouse model) mice. Our work provides a new way to promote nerve regeneration with the help of nanozymes.

Target-driven supramolecular self-assembly for selective amyloid-ß photooxygenation against Alzheimer's disease.

Photo-oxygenation of ß-amyloid (Aß) has been considered an efficient way to inhibit Aß aggregation in Alzheimer's disease (AD). However, current photosensitizers cannot simultaneously achieve enhanced blood-brain barrier (BBB) permeability and selective photooxygenation of Aß, leading to poor therapeutic efficacy, severe off-target toxicity, and substandard bioavailability. Herein, an Aß target-driven supramolecular self-assembly (PKNPs) with enhanced BBB penetrability and switchable photoactivity is designed and demonstrated to be effective in preventing Aß aggregation in vivo. PKNPs are prepared by the self-assembly of the Aß-targeting peptide KLVFF and an FDA-approved porphyrin derivative (5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin). Due to the photothermal effect of PKNPs, the BBB permeability of PKNPs under irradiation is 8.5-fold higher than that of porphyrin alone. Moreover, upon selective interaction with Aß, PKNPs undergo morphological change from the spherical to the amorphous form, resulting in a smart transformation from photothermal activity to photodynamic activity. Consequently, the disassembled PKNPs can selectively oxygenate Aß without affecting off-target proteins (insulin, bovine serum albumin, and human serum albumin). The well-designed PKNPs exhibit not only improved BBB permeability but also highly selective Aß photooxygenation. Furthermore, in vivo experiments demonstrate that PKNPs can alleviate Aß-induced neurotoxicity and prolong the life span of the commonly used AD transgenic Caenorhabditis elegans CL2006. Our work may open a new path for using supramolecular self-assemblies as switchable phototheranostics for the selective and effective prevention of Aß aggregation and related neurotoxicity in AD.

Phenol-like group functionalized graphene quantum dots structurally mimicking natural antioxidants for highly efficient acute kidney injury treatment.

Acute kidney injury (AKI) is a syndrome characterized by rapid loss of renal excretory function with high in-hospital mortality. The excess generation of reactive oxygen species (ROS) in the kidneys during AKI has been considered a major cause of renal failure. Currently available antioxidants for AKI treatment often lack the required antioxidative efficacy or renal accumulation rate. Herein, inspired by the structure of natural phenolic antioxidants, phenol-like group functionalized graphene quantum dots (h-GQDs) with both high ROS scavenging efficacy and renal specificity are constructed for AKI antioxidative therapy. Similar to natural polyphenols, the abundant phenol-like groups on h-GQDs are demonstrated to be the active components exerting antioxidative effects. Further exhaustive mechanistic investigations indicate that the ultrahigh antioxidative activity of h-GQDs originates not solely from the phenol-like groups, but also from the synergy between adjacent phenol-like groups, as well as the removal of unfavorable carbonyl groups on h-GQDs. In AKI mice, h-GQDs can effectively protect the kidneys from oxidative injury with only a one-sixteenth dose of the clinical antioxidant N-acetylcysteine (NAC) and show no evidence of toxicity. The findings of this study will facilitate development of high-performance carbon-based antioxidative platforms via structure-activity relationships for treating AKI and other ROS-related diseases.

Renal-Clearable Porphyrinic Metal-Organic Framework Nanodots for Enhanced Photodynamic Therapy.

Nanoscale porphyrinic metal-organic frameworks (NMOFs) have emerged as promising therapeutic platforms for the photodynamic therapy (PDT) of cancer in recent years. However, the relatively large sizes of current NMOFs ranging from tens to hundreds of nanometers usually lead to inefficient body clearance and unsatisfactory PDT effect, thus amplifying their long-term toxicity and restricting their further usage. To overcome these shortcomings, herein, ultrasmall porphyrinic metal-organic framework nanodots (MOF QDs) prepared from NMOFs are rationally synthesized via a facile method and used as renal-clearable nanoagents for the enhanced PDT of cancer. Compared with the precursor NMOFs, our well-prepared MOF QDs can generate 2-fold effective toxic reactive oxygen species (ROS) upon the same light irradiation and greatly decrease the inefficacy of PDT caused by the inefficient use of ROS generated from the interior of NMOFs. Meanwhile, the IC50 value of ultrasmall MOF QDs is nearly one-third that of NMOFs, and in vivo results demonstrate that our MOF QDs exhibit better PDT efficacy than NMOFs under the same treatment owing to their overcoming the limited ROS diffusion distance. Significantly, these ultrasmall MOF QDs show efficient tumor accumulation and rapid renal clearance in vivo, indicating their potential in biomedical utility. Last but not least, comprehensive investigations of long-term toxicity of these MOF QDs well demonstrate their overall safety. Therefore, this study will offer valuable insight into the development of safe and high-performance PDT nanoplatforms for further clinical translation.

Wireless near-infrared electrical stimulation of neurite outgrowth.

Herein, through using electropolymerized pyrrole (PPy) to coat near-infrared upconversion nanoparticles (UCNPs) on an indium tin oxide (ITO) electrode, the as-prepared PPy/UCNPs photoelectrode could generate an interfacial electric field, release rare earth ions and induce reactive oxygen species (ROS) in PC12 cells under NIR irradiation, which could realize wireless neurite development and outgrowth.

Near-Infrared Activated Black Phosphorus as a Nontoxic Photo-Oxidant for Alzheimer's Amyloid-ß Peptide.

The inhibition of amyloid-ß (Aß) aggregation by photo-oxygenation has become an effective way of treating Alzheimer's disease (AD). New near-infrared (NIR) activated treatment agents, which not only possess high photo-oxygenation efficiency, but also show low biotoxicity, are urgently needed. Herein, for the first time, it is demonstrated that NIR activated black phosphorus (BP) could serve as an effective nontoxic photo-oxidant for amyloid-ß peptide in vitro and in vivo. The nanoplatform BP@BTA (BTA: one of thioflavin-T derivatives) possesses high affinity to the Aß peptide due to specific amyloid selectivity of BTA. Importantly, under NIR light, BP@BTA can significantly generate a high quantum yield of singlet oxygen (1 O2 ) to oxygenate Aß, thereby resulting in inhibiting the aggregation and attenuating Aß-induced cytotoxicity. In addition, BP could finally degrade into nontoxic phosphate, which guarantees the biosafety. Using transgenic Caenorhabditis elegans CL2006 as AD model, the results demonstrate that the 1 O2 -generation system could dramatically promote life-span extension of CL2006 strain by decreasing the neurotoxicity of Aß.

Ultrasensitive magnetic resonance imaging of systemic reactive oxygen species in vivo for early diagnosis of sepsis using activatable nanoprobes.

Current diagnostic methods for sepsis lack required speed or precision, often failing to make timely accurate diagnosis for early medical treatment. The systemic excess generation of reactive oxygen species (ROS) during sepsis has been considered as an early indicator of sepsis. Herein, we present the rational design of novel activatable nanoprobes (ROS CAs) composed of a clinically approved iron oxide core, Gd-DTPA, and hyaluronic acid (HA) that can image ROS down to sub-micromolar concentrations via magnetic resonance imaging (MRI), and use them as sensitive contrast agents for sepsis evaluation. Such a well-defined nanostructure allows them to undergo ROS-triggered degradation and release Gd-DTPA in the presence of ROS, leading to the recovery of the quenched T 1-weighted MRI signal with fast response. With outstanding sensitivity and unlimited tissue penetration depth, ROS CAs are capable of imaging systemic ROS overproduction in mice with early sepsis. Moreover, by using these well-prepared ROS CAs, the severity of the sepsis can be rapidly evaluated by monitoring the systemic ROS levels in vivo. Overall, the present study will not only provide a new strategy to aid in the early diagnosis and risk assessment of sepsis, but also offer valuable insight for the study of sepsis and ROS biology.

Metal-Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid ß Aggregation in Vivo.

Recently, photooxygenation of amyloidâ€…ß (Aß) has emerged as an effective way to inhibit Aß aggregation in Alzheimer's disease (AD) treatment. However, their further application has been highly obstructed by self-aggregation, no metal chelating ability, and poor protein-enrichment capacity. Herein, porphyrinic metal-organic frameworks (PMOFs) are utilized as a superior CuII chelating and photooxidation agent for inhibiting Aß aggregation. We selected only four classical kinds of POMFs (Zr-MOF, Al-MOF, Ni-MOF, Hf-MOF) for further investigation in our study, which are stable in physiological conditions and exhibit excellent biocompatibility. Among them, Hf-MOF was the most efficient Aß photooxidant. A possible explanation about the difference in capacity of 1 O2 generation of these four PMOFs has been provided according to the experimental results and DFT calculations. Furthermore, Hf-MOFs are modified with Aß-targeting peptide, LPFFD. This can not only enhance Hf-MOFs targeting cellular Aß to decrease Aß-induced cytotoxicity, but also improve Aß photooxidation in the complicated living environment. More intriguingly, in vivo studies indicate that the well-designed LPFFD modified Hf-MOFs can decrease Aß-induced neurotoxicity and extend the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Our work may open a new avenue for using MOFs as neurotoxic-metal-chelating and photo-therapeutic agents for AD treatment.

MiR-149-5p regulates cisplatin chemosensitivity, cell growth, and metastasis of oral squamous cell carcinoma cells by targeting TGFß2.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a public health problem worldwide. MicroRNAs, acting as either oncogenes or tumor suppressors, have gathered much attention. The aim of this study was to characterize the role of miR-149-5p in drug resistance, cell growth, and metastasis and its underlying mechanism in oral squamous cell carcinoma. METHODS: The expressions of miR-149-5p and TGFß2 were measured by quantitative real-time polymerase chain reaction. The survival rate of cells treated with different concentrations of CDDP was checked by CCK-8. The cell proliferation and apoptosis was determined by CCK-8 and flow cytometry, respectively. Cell migration and invasion were examined using transwell assay. The interaction of miR-149-5p and TGFß2 was predicted by online software Targetscan and confirmed by luciferase reporter assay. The protein expression of TGFß2, p-SMAD2 and p-SMAD3 was quantified using western blot. RESULTS: The expression of miR-149-5p was obviously decreased in OSCC tissues and cell lines, and its expression was lower in a cisplatin resistant cell line (CAL-27/CDDP) than that of a normal OSCC cell line (CAL-27). CCK-8 assay suggested that miR-149-5p increased drug sensitivity in CAL-27 and CAL-27/CDDP cells. miR-149-5p attenuated proliferation, migration and invasion, and promoted apoptosis of CAL-27 and CAL-27/CDDP cells. In addition, TGFß2 was up-regulated in OSCC cells at both mRNA and protein levels. Moreover, miR-149-5p promoted cisplatin chemosensitivity and regulated cell proliferation, apoptosis, migration and invasion by targeting TGFß2 in CAL-27 and CAL-27/CDDP cells. CONCLUSION: miR-149-5p regulates cisplatin chemosensitivity, cell growth, apoptosis and metastasis by targeting TGFß2. miR-149-5p/TGFß2 axis has potential for therapy of OSCC.

Self-triggered click reaction in an Alzheimer's disease model: in situ bifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-ß plaques.

Cu is one of the essential elements for life. Its dyshomeostasis has been demonstrated to be closely related to neurodegenerative disorders, such as Alzheimer's disease (AD), which is characterized by amyloid-ß (Aß) aggregation and Cu accumulation. It is a great challenge as to how to take advantage of neurotoxic Cu to fight disease and make it helpful. Herein, we report that the accumulated Cu in Aß plaques can effectively catalyze an azide-alkyne bioorthogonal cycloaddition reaction for fluorophore activation and drug synthesis in living cells, a transgenic AD model of Caenorhabditis elegans CL2006, and brain slices of triple transgenic AD mice. More importantly, the in situ synthesized bifunctional drug 6 can disassemble Aß-Cu aggregates by extracting Cu and photo-oxygenating Aß synergistically, suppressing Aß-mediated paralysis and diminishing the locomotion defects of the AD model CL2006 strain. Our results demonstrate that taking the accumulated Cu ions in the Aß plaque for an in situ click reaction can achieve both a self-triggered and self-regulated drug synthesis for AD therapy. To the best of our knowledge, a click reaction catalyzed by local Cu in a physiological environment has not been reported. This work may open up a new avenue for in situ multifunctional drug synthesis by using endogenous neurotoxic metal ions for the treatment of neurodegenerative diseases.

Unraveling the Enzymatic Activity of Oxygenated Carbon Nanotubes and Their Application in the Treatment of Bacterial Infections.

Carbon nanotubes (CNTs) and their derivatives have emerged as a series of efficient biocatalysts to mimic the function of natural enzymes in recent years. However, the unsatisfiable enzymatic efficiency usually limits their practical usage ranging from materials science to biotechnology. Here, for the first time, we present the synthesis of several oxygenated-group-enriched carbon nanotubes (o-CNTs) via a facile but green approach, as well as their usage as high-performance peroxidase mimics for biocatalytic reaction. Exhaustive characterizations of the enzymatic activity of o-CNTs have been provided by exploring the accurate effect of various oxygenated groups on their surface including carbonyl, carboxyl, and hydroxyl groups. Because of the "competitive inhibition" effect among all of these oxygenated groups, the catalytic efficiency of o-CNTs is significantly enhanced by weakening the presence of noncatalytic sites. Furthermore, the admirable enzymatic activity of these o-CNTs has been successfully applied in the treatment of bacterial infections, and the results of both in vitro and in vivo nanozyme-mediated bacterial clearance clearly demonstrate the feasibility of o-CNTs as robust peroxidase mimics to effectively decrease the bacterial viability under physiological conditions. We believe that the present study will not only facilitate the construction of novel efficient nanozymes by rationally adjusting the degree of the "competitive inhibition" effect, but also broaden the biological usage of o-CNT-based nanomaterials via their satisfactory enzymatic activity.