Stabilization of Glucagon by Trehalose Glycopolymer Nanogels

Glucagon is a peptide hormone used for the treatment of hypoglycemia; however, its clinical potential is limited by its insolubility and instability in solution. Herein, the encapsulation, stabilization, and release of glucagon by trehalose glycopolymer nanogels are reported. Methacrylate‐functionalized trehalose is copolymerized with pyridyl disulfide ethyl methacrylate using free radical polymerization conditions to form trehalose glycopolymers with thiol‐reactive handles. Glucagon is chemically modified to contain two thiol groups and is subsequently utilized as the cross‐linker to form redox‐responsive trehalose nanogels with greater than 80% conjugation yield. Nanogel formation and subsequent glucagon stabilization are characterized using polyacrylamide gel electrophoresis, dynamic light scattering, and transmission electron microscopy. It is determined that the solution stability of the glucagon increased from less than 24 h to at least three weeks in the nanogel form. Additionally, in vitro activity of the synthesized glucagon analog and released glucagon is investigated, demonstrating that the glucagon remains active after modification. It is anticipated that these glucagon–nanogel conjugates will be useful as a stabilizing glucagon formulation, allowing for cargo release under mild reducing conditions.     

Multi-Responsive Biodegradable Cationic Nanogels for Highly Efficient Treatment of Tumors

The facile preparation, modular design, and multi-responsiveness are extremely critical for developing pervasive nanoplatforms to meet heterogeneous applications. Here, cationic nanogels (NGs) are modularly engineered with tunable responsiveness, versatility, and biodegradation. Cationic PVCL-based NGs with core/shell structure are fabricated by facile one-step synthesis. The formed PVCL-NH₂ NGs exhibit uniform size, thermal/pH dual-responsive behaviors, and redox-triggered degradation. Moreover, the NGs can be employed to modify or/and load with various functional agents to construct multipurpose nanoplatforms in a modular manner. Notably, the novel hybrid structure with copper sulfide (CuS) NPs loaded in the NGs shell is prepared, which leads to higher photothermal conversion efficiency (31.1%) than other CuS randomly loaded NGs reported. By personalized tailoring, these functionalized NGs display fluorescent property, r₁ relaxivity, strong near-infrared (NIR) absorption, good biocompatibility, and targeting specificity. The superior photothermal effect of hybrid NGs (CuS@NGs-LA) is presented under NIR II over NIR I. Importantly, hybrid NGs encapsulated doxorubicin (CuS@NGs-LA/DOX) show endogenous pH/redox and exogenous NIR multi-triggered drug release for efficient photothermal-chemotherapy, which can completely eliminate advanced tumors and effectively inhibit recurrence. Overall, the pervasive nanoplatforms based on intelligent cationic NGs with tunable responsiveness, versatility, and biodegradation are developed by engineered modular strategy for precision medicine applications.     

Inherent Guanidine Nanogels with Durable Antibacterial and Bacterially Antiadhesive Properties

Since bacterial infections seriously threaten human's health, considerable attention is devoted to the design of nanoscale antibacterial materials. Among them, metal nanoparticles cannot meet the requirements of durable antibacterial effects and are harmful to biological environments. In this study, environmentally friendly nanogels with durable antibacterial and antiadhesion properties are prepared by copolymerization of styrene, polycaprolactone‐hydroxyethyl methacrylate, and polyhexamethylene guanidine hydrochloride methacrylate. The resultant nanogels possess regular spherical morphologies with the size of about 200 nm. The nanogels exhibit a strong ability to kill bacteria and the mechanism is different from that of conventional antibacterial agent loaded nanoparticles. In addition, anti‐infection experiments explored by a wound model confirm the nanogels have the capability to prevent infection. Furthermore, the nanogels grafted on the surface of cotton fibers display good thermal stability, which is essential for finishing of fabrics. The cotton fabrics finished with nanogels can prevent the adhesion of bacteria by enhancing the hydrophobicity and the bacteriostatic rate. The antibacterial fabrics against Staphylococcus aureus and Escherichia coli are still more than 86% active after 50 times of mechanical washing. The biocompatible nanogels are unleachable from the antibacterial fabrics which demonstrate that they are ideal candidates for durable and environmental‐friendly nanoscaled antimicrobial materials.     

Reduction‐Sensitive Dextran Nanogels Aimed for Intracellular Delivery of Antigens

Targeting of antigens to dendritic cells (DCs) to induce strong cellular immune response can be established by loading in a nano‐sized carrier and keeping the antigen associated with the particles until they are internalized by DCs. In the present study, a model antigen (ovalbumin, OVA) is immobilized in cationic dextran nanogels via disulfide bonds. These bonds are stable in the extracellular environment but are reduced in the cytosol of DCs due to the presence of glutathione. Reversible immobilization of OVA in the nanogels is demonstrated by the fact that hardly any release of the protein occurred at pH 7 in the absence of glutathione, whereas rapid release of OVA occurs once the nanogels are incubated in buffer with glutathione. Furthermore, these OVA conjugated nanogels show intracellular release of the antigen in DCs and boost the MHC class I antigen presentation, demonstrating the feasibility of this concept for the aimed intracellular antigen delivery.     

Reductively Dissociable siRNA‐Polymer Hybrid Nanogels for Efficient Targeted Gene Silencing

A highly efficient approach for target‐specific gene silencing based on a reductively dissociable nanogel incorporating small interfering RNA (siRNA) crosslinked with linear polyethylenimine (LPEI) via disulfide bonds is presented. Thiol‐terminated siRNA at both 3′‐ends is electrostatically complexed with thiol‐grafted LPEI. The prepared siRNA/LPEI complex contains inter‐ and intramolecular linkages, generating a mutually crosslinked siRNA/LPEI nanogel (MCN) that exhibits excellent structural stability against the addition of heparin but is readily disintegrated to biologically active, monomeric siRNA upon exposure to reductive conditions. Accordingly, the highly condensed, stable MCN shows greatly enhanced cellular uptake and gene silencing efficiency compared to the siRNA/LPEI complexes without crosslinks or with only LPEI‐mediated crosslinks.     

Synthesis,Reductive Cleavage,and Cellular Interaction Studies of Biodegradable,Polyglycerol Nanogels

In this paper we describe disulfide containing, polyglycerol nanogels as a new class of biodegradable materials. These nanoparticles are prepared in inverse miniemulsion via an acid catalyzed ring‐opening polyaddition of disulfide containing polyols and polyepoxides. Varying conditions allow us to tune particle size and disulfide content within the polymer network; particles can be prepared with narrow polydispersities and diameters in the range from 25 to 350 nm. Particle degradation under reductive intracellular conditions is studied by various analytical techniques. Gel permeation chromatography indicates that final degradation products have relatively low molecular weights (≤ 5 kDa). In addition, studies in cell culture show these nanoscale materials to be highly biocompatible. Dye‐labelled nanogels are shown by optical microscopy techniques to readily internalize into cells by endocytotic mechanisms. This study highlights the great potential of these particles to function as sophisticated nanotransporters that deliver cargo to a certain tissue or cell target and then biodegrade into smaller fragments which would be cleared from the body by the kidney. (with ≈ 30 kDa molecular weight cut off)     

One Stone,Two Birds: Spidroin-Inspired Nanogels for High-Performance Fibers and Photothermal Actuators

The exciting development of hydrogels makes it a promising candidate to be applied in various fields. However, it remains a great challenge to store the precursors of hydrogels and to process them after gelation, like synthetic polymer materials. Herein, spidroin-inspired novel nanogels with extraordinary processability, which can be spun into fibers via direct drawing and fabricated into thermal actuators easily after gelation are prepared. These soluble and spinnable nanogels are composed of a liquid metal core and a poly (acrylic acid) (PAA) shell and are entangled with each other. The as fabricated nanogels and diluted dope solution can be stored >1 month. The as-spun nanogel fibers with hierarchical structures achiev extraordinary mechanical properties (tensile stress of 575 MPa, toughness of 381 MJ m⁻³) and supercontraction at 60% RH. Besides, a photothermal actuator is prepared by coating the nanogels on a polyethylene substrate with a commercial shading ink, and the as-prepared actuator shows a rapid response to near-infrared light as well as a fast recovery. Molecular dynamics simulation reveals a possible working mechanism of the actuator. This study provides a new strategy to prepare processable nanogels with broad application prospects for smart textiles and soft robots.     

A Multifuntional Nanoplatform Based on Responsive Fluorescent Plasmonic ZnO‐Au@PEG Hybrid Nanogels

Under a rational design, combining multiple constituents into a single nano‐object will not only bridge the unique properties of individual materials to leverage research both fundamentally and practically, but will also improve conventional sensing, imaging, and therapeutic efficacies. Such a nano‐object (<100 nm) can be constructed by covalently bonding ZnO quantum dots (QDs) to nonlinear poly(ethylene glycol)‐based nanogel network chains, followed by appropriate growth of metallic Au. With the polymer gel network serving as a three‐dimensional scaffold, the fluorescence of ZnO QDs can be well protected, while metal Au still retains its surface plasmon resonance property. The ZnO QDs covalently bonded to the thermo‐responsive gel network chains can sensitively respond to temperature change of the surrounding fluids over the physiologically important range of 37–42 °C, converting the disruptions in homeostasis of local temperature into stable, robust and high‐resolution fluorescent signals. The thermoresponsive hybrid nanogels can not only enter into and light up B16F10 cells, but also regulate the release of a model anticancer drug, temozolomide, in response to either local environmental temperature change or external near‐infrared light‐induced localized hyperthermia from metal Au. The combined chemo‐photothermal therapy can significantly improve the therapeutic efficacy due to a synergistic effect.     

Biodegradable Dextran Nanogels for RNA Interference: Focusing on Endosomal Escape and Intracellular siRNA Delivery

The successful therapeutic application of small interfering RNA (siRNA) largely relies on the development of safe and effective delivery systems that are able to guide the siRNA therapeutics to the cytoplasm of the target cell. In this report, biodegradable cationic dextran nanogels are engineered by inverse emulsion photopolymerization and their potential as siRNA carriers is evaluated. The nanogels are able to entrap siRNA with a high loading capacity, based on electrostatic interaction. Confocal microscopy and flow cytometry analysis reveal that large amounts of siRNA‐loaded nanogels can be internalized by HuH‐7 human hepatoma cells without significant cytotoxicity. Following their cellular uptake, it is found that the nanogels are mainly trafficked towards the endolysosomes. The influence of two different strategies to enhance endosomal escape on the extent of gene silencing is investigated. It is found that both the application of photochemical internalization (PCI) and the use of an influenza‐derived fusogenic peptide (diINF‐7) can significantly improve the silencing efficiency of siRNA‐loaded nanogels. Furthermore, it is shown that an efficient gene silencing requires the degradation of the nanogels. As the degradation kinetics of the nanogels can easily be tailored, these particles show potential for intracellular controlled release of short interfering RNA.     

Imidazole‐Grafted Nanogels for the Fabrication of Organic–Inorganic Protein Hybrids

Here, a platform for the development of highly responsive organic–inorganic enzyme hybrids is provided. The approach entails a first step of protein engineering, in which individual enzymes are armored with a porous nanogel decorated with imidazole motifs. In a second step, by mimicking the biomineralization mechanism, the assembly of the imidazole nanogels with CuSO₄ and phosphate salts is triggered. A full characterization of the new composites reveals the first reported example in which the assembly mechanism is triggered by the sum of Cu(II)–imidazole interaction and Cu₃(PO₄)₂ inorganic salt formation. It is demonstrated that the organic component of the hybrids, namely the imidazole‐modified polyacrylamide hydrogel, provides a favorable spatial distribution for the enzyme. This results in enhanced conversion rates, robustness of the composite at low pH values, and a remarkable thermal stability at 65 °C, exhibiting 400% of the activity of the mineralized enzyme lacking the organic constituent. Importantly, unlike in previous works, the protocol applies to the use of a broad range of transition metal cations (including mono‐, di‐, and trivalent cations) to trigger the mineralization mechanism, which eventually broadens the chemical and structural diversity of organic–inorganic protein hybrids.     

Functional Nanogels as Platforms for Imparting Antibacterial,Antibiofilm, and Antiadhesion Activities to Stainless Steel

In this work, long‐term antibacterial, antiadhesion, and antibiofilm activities are afforded to industrial stainless steel surfaces following a green and bio‐inspired strategy. Starting from catechol bearing synthetic polymers, the film cross‐linking and the grafting of active (bio)molecules are possible under environmentally friendly conditions (in aqueous media and at room temperature). A bio‐inspired polyelectrolyte, a polycation‐bearing catechol, is used as the film‐anchoring polymer while a poly(methacrylamide)‐bearing quinone groups serves as the cross‐linking agent in combination with a polymer bearing primary amine groups. The amine/quinone reaction is exploited to prepare stable solutions of nanogels in water at room temperature that can be easily deposited to stainless steel. This coating provides quinone‐functionalized surfaces that are then used to covalently anchor active (bio)molecules (antibiofilm enzyme and antiadhesion polymer) through thiol/quinone reactions.     

Tumor‐Specific Self‐Degradable Nanogels as Potential Carriers for Systemic Delivery of Anticancer Proteins

Development of a safe and effective carrier for systemic protein delivery is highly desirable, which depends on management of the relationship among loading capacity, stability, delivery efficiency, and degradability. Here, a tumor‐specific self‐degradable nanogel composed of hyaluronidase (HAase)‐degradable hyaluronic acid (HA) matrices entrapping acid‐activatable HAase (aHAase) for systemic delivery of anticancer proteins is reported. Collaboratively crosslinked nanogels (cNG) obtained by the synthetic cholesteryl methacrylated HA show high protein‐loading capacity and stability. The aHAase is engineered by modifying the HAase with citraconic anhydride to shield its HA‐degrading activity, which can be reversibly activated by hydrolysis of the citraconic amide under acidic condition. In the tumor microenvironment, the mild acidity activates the aHAase partially, which results in swelling of the cNG and releasing of the aHAase. The released reactivated aHAase can degrade the HA that is also a major constituent of tumor extracellular matrix to increase perfusion of the cNG in the tumor stroma. In the acidic endocytic vesicles, the aHAase is fully reactivated. The active aHAase completely degrades the cNG to release the encapsulated anticancer protein, deoxyribonuclease I intracellularly, which digests the DNA to cause tumor cell death for enhanced antitumor efficacy.     

Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.     

A Smart Nanoprobe Based On Fluorescence‐Quenching PEGylated Nanogels Containing Gold Nanoparticles for Monitoring the Response to Cancer Therapy

A biocompatible, caspase‐3‐responsive, and fluorescence‐quenching smart apoptosis nanoprobe based on a PEGylated nanogel that contains gold nanoparticles (GNPs) (fluorescence quenchers) in the cross‐linked polyamine gel core and fluorescein isothiocyanate (FITC)‐labeled DEVD peptides at the tethered PEG chain ends is prepared for monitoring the cancer response to therapy. FITC–DEVD–nanogel–GNP shows very little fluorescence in the absence of activated caspase‐3 (normal cells) through the fluorescence resonance energy transfer (FRET) process between the GNPs and the FITC molecules, while pronounced fluorescence signals are observed in apoptotic cells because of the cleavage of the DEVD peptide by activated caspase‐3 present in the cells, which results in the release of FITC molecules. Thus, remarkable quenching and dequenching of fluorescence signals in response to activated caspase‐3 is observed. Apoptotic cells are detected in human hepatocyte (HuH‐7) multicellular tumor spheroids (MCTSs), a commonly used three‐dimensional in vitro model mimicking the in vivo biology of tumors, as early as one day post‐treatment with staurosporine, an apoptosis‐inducing agent; while growth inhibition (i.e., change in size) of the HuH‐7 MCTSs is only observed after a delay of three days (i.e., on day 4). This demonstrates the effectiveness of the FITC–DEVD–nanogel–GNP probe as a smart nanoprobe for real‐time monitoring as well as a more rapid assessment of the early response to cancer therapy.     

Smart Supramolecular “Trojan Horse”‐Inspired Nanogels for Realizing Light‐Triggered Nuclear Drug Influx in Drug‐Resistant Cancer Cells

Efficient nuclear delivery of anticancer drugs evading drug efflux transporters (DETs) on the plasma and nuclear membranes of multidrug‐resistant cancer cells is highly challenging. Here, smart nanogels are designed via a one‐step self‐assembly of three functional components including a biocompatible copolymer, a fluorescent organosilica nanodot, and a photodegradable near‐infrared (NIR) dye indocyanine green (ICG). The rationally designed nanogels have high drug encapsulation efficiency (≈99%) for anticancer drug doxorubicin (Dox), self‐traceability for bioimaging, proper size for passive tumor targeting, prolonged blood circulation time for enhanced drug accumulation in tumor, and photocontrolled disassemblability. Moreover, the Dox‐loaded nanogels can effectively kill multidrug‐resistant cells via two steps: 1) They behave like a “Trojan horse” to escape from the DETs on the plasma membrane for efficiently transporting the anticancer “soldier” (Dox) into the cytoplasm and preventing the drugs from being excreted from the cells; 2) Upon NIR light irradiation, the photodegradation of ICG leads to the disassembly of the nanogels to release massive Dox molecules, which can evade the DETs on the nuclear membrane to exert their intranuclear efficacy in multidrug‐resistant cells. Combined with their excellent biocompatibility, the nanogels may provide an alternative solution for overcoming cancer multidrug resistance.     

Biocompatible PEG‐Chitosan@Carbon Dots Hybrid Nanogels for Two‐Photon Fluorescence Imaging,Near‐Infrared Light/pH Dual‐Responsive Drug Carrier,and Synergistic Therapy

This work designs a class of biocompatible PEG‐chitosan@CDs hybrid nanogels by integrating nonlinear poly(ethylene glycol) (PEG), chitosan, and graphitic carbon dots (CDs) into a single nanoparticle for two‐photon fluorescence (TPF) bioimaging, pH and near‐infrared (NIR) light dual‐responsive drug release, and synergistic therapy. Such hybrid nanogels can be simply prepared from a one‐pot surfactant‐free precipitation polymerization of the PEG macromonomers complexed with chitosan and CDs in water, resulting in a semi‐interpenetration of chitosan chains and an immobilization of CDs in the nonlinear PEG networks. The embedded CDs in hybrid nanogels not only serve as an excellent confocal and TPF imaging contrast agent and fluorescent pH‐sensing probe, but also enhance the loading capacity of the hybrid nanogels for hydrophobic anticancer drug. The chitosan can induce a pH‐sensitive swelling/deswelling of the hybrid nanogels for pH‐regulated drug release over the physiologically important range of 5.0–7.4 and surface modulation of embedded CDs to realize fluorescent pH sensing. The thermosensitive nonlinear PEG network can promote the drug release through the local heat produced by the embedded CDs under NIR irradiation. The in vitro results indicate that the hybrid nanogels demonstrated high therapeutic efficacy through the synergistic effect of combined chemo–photothermal treatments.     

Power m.o.s.f.e.t. linear h.f. amplifiers

N-channel silicon m.o.s. transistors for h.f. power applications have been fabricated which are optimised for linear amplification. These devices exhibit 2 W output power and 11 dB power gain at 630 MHz in class-A operation. The intercept point for third-order intermodulation distortion is 48dBm, which is considerably more than the same data obtainable with bipolar transistors.