Research Progress of Zhuang Medicine Combined with Nanogels in Mastitis

Mastitis is a common and frequently-occurring disease among Chinese women, which seriously harms their mental and physical health. External application of Zhuang medicine has the effects of dredging collaterals, relieving pain, promoting blood circulation, removing blood stasis, and softening hardness to dissipate stagnation, and show definite curative effect in preventing and treating breast diseases. Nano-composite hydrogels have the advantages of small toxic and side effects, high bioavailability, high targeting and controllable drug release. Therefore, this paper summarized and analyzed relevant literature of Zhuang medicine in treating breast diseases and clinical research of nanogels, providing new ideas and scientific basis for the treatment of mastitis with Zhuang medicine combined with nanogels.

Redox-sensitive, PEG-shielded carboxymethyl PEI nanogels silencing MicroRNA-21, sensitizes resistant ovarian cancer cells to cisplatin

A series of branched polyethylenimine(PEI) modifications including PEGylation(PEG2 k-PEI) for steric shielding, redox-sensitive crosslinking for synthesis PEG2 k-PEI-ss nanogels and subsequent carboxymethylation(PEG2 k-CMPEI-ss) for modulation of the polymer pk a have been introduced for cellular delivery of Anti-mi R-21. The synthesis was characterized using 1 H NMR, FTIR, TNBS, potentiometric titration, particle size and ζ potential. Loading of Anti-mi R-21 at various N/P ratios was investigated by gel retardation, ethidium bromide dye exclusion, heparin sulfate competition and DNase I digestion experiments. The mi R-21 silencing was measured by stem-loop RT PCR in A2780 ovarian cancer cell lines whether it is sensitive to resistant to cisplatin. It has been shown that PEG2 k-CMPEI-ss was well suited for delivery of Anti-mi R-21 in terms of nucleic acid loading, preservation against extracellular matrix and nucleases and sequence-specific silencing of mi RNA-21 in vitro. Moreover, it has been demonstrated that pre-treating cells with Anti-mi R-21 loaded nanogels can sensitize them to cis-Pt even at non-toxic concentraions. The results indicate that PEG2 k-CMPEIss mediated micro RNA delivery can be considered as a novel strategy for ovarian cancer therapy.

Functional Capsules Encapsulating Molecular-Recognizable Nanogels for Facile Removal of Organic Micro-Pollutants from Water

A novel method has been successfully developed for the facile and efficient removal of organic micro-pollutants(OMP)from water based on novel functional capsules encapsulating molecular-recognizable nanogels.The functional capsules are composed of ultrathin calcium alginate(Ca-Alg)hydrogel shells as semipermeable membranes and encapsulated poly(N-isopropylacrylamide-co-acrylic acid-g-mono-(6-ethanediamine-6-deoxy)-β-cyclodextrin)(PNCD)nanogels withβ-cyclodextrin(CD)moieties as OMP capturers.The semipermeable membranes of the capsules enable the free transfer of OMP and water molecules across the capsule shells,but confine the encapsulated PNCD nanogels within the capsules.Bisphenol A(BPA),an endocrine-disrupting chemical that is released from many plastic water containers,was chosen as a model OMP molecule in this study.Based on the host–guest recognition complexation,the CD moieties in the PNCD nanogels can efficiently capture BPA molecules.Thus,the facile and efficient removal of BPA from water can be achieved by immersing the proposed functional capsules into BPA-containing aqueous solutions and then simply removing them,which is easily done due to the capsules’characteristically large size of up to several millimeters.The kinetics of adsorption of BPA molecules by the capsules is well described by a pseudo-second-order kinetic model,and the isothermal adsorption thermodynamics align well with the Freundlich and Langmuir isothermal adsorption models.The regeneration of capsules can be achieved simply by washing them with water at temperatures above the volume phase transition temperature of the PNCD nanogels.Thus,the proposed functional capsules encapsulating molecular-recognizable nanogels provide a novel strategy for the facile and efficient removal of OMP from water.

Stability of freeze-dried pH-responsive dextrin nanogels containing doxorubicin

Induction of non-specific toxicities by doxorubicin(DOX) has restricted conventional DOXbased chemotherapy. p H-responsive dextrin nanogels(DNGs) have been fabricated in order to incorporate and deliver DOX to specific(targeted) sites. However, adequate stability studies of DOX-loaded DNGs are required for selection of storage conditions. The aim of this study was therefore to evaluate the accelerated(25 °C/60% RH) and long-term(5 °C) stability of DNGs prepared with formaldehyde(FDNGs) and glyoxal(GDNGs) as cross-linker by determining the change in their physicochemical properties. The mean diameter decreased with time during long-term storage. The drug content between freshly prepared(initial day) and after storage at 5 °C for 180 days of DOX-loaded FDNGs and DOX-loaded GDNGs was not significantly different(p > 0.05), but decreased after storage under the accelerated condition. The release of DOX from all DNGs was pH-dependent. However, DNGs kept under the accelerated condition showed higher amount of DOX release than those stored at 5 °C and the freshly prepared ones. The results indicate that the stability of DNGs could be improved by their storage at 5 °C.

Conformationally Dynamic Supramolecular Single Chain Nanogels for Mutilscale Biomechanical Regulation of Stem Cells

Objective The binding of cell adhesive peptides(such as RGD)to integrins initiates the recruitment of cytoplasmic adaptor proteins(e.g.,vinculin)and the formation of focal adhesion(FA)complexes required for cell adhesion.The ability to manipulate this ligand-mediated cell adhesion process is crucial for regulating cell migration,cell differentiation,injury healing,and immune response.Some recent studies reported the importance of the tether length/mobility of the cell adhesive ligands in regulating the traction force development of cells.In the native cellular microenvironment,such a dynamic change in the nanoscale tether length of bioactive ligands is often mediated by conformational changes of the structural proteins due to protein folding or degradation.However,no prior studies have demonstrated the modulation of the ligand tether mobility by controlling the intramolecular folding of polymeric linkers.Unfoldable synthetic macromolecules with easy synthetic routes and controllable structures,such as supramolecular host-guest single chain nanogels(SCNGs),are ideal candidates for mimicking the changes in the tether mobility of bioactive ligands via biorthogonal triggers.Methods S,S’-bis(a’a’-dimethyl-a’’-propargyl acetate)trithiocarbonate was first used to mediate the RAFT polymerization of N,N-dimethyl acrylamide,vinyl-adamantane and vinyl-β-cyclodextrin to yield the ADA@CD-SCNGs.The preparation of the unfoldable host-guest SCNGs was evidenced by the by gel permeation chromatography,proton nuclear magnetic resonance spectroscopy,atomic force microscopy and dynamic light scattering.Then the RGD peptide was conjugated to the alkynyl group on one end of the SCNGs before immobilizing the material on the substrate,which was confirmed by scanning electron microscopy(SEM).The regulation of cell behaviours by unfolding of the SCNG-RGD was confirmed by immunofluorescence staining of vinculin and Yes-associated protein(YAP).Results The preparation of ADA@CD-SCNGs was confirmed by GPC which showed a unimodal molecular weight distribution.DLS and AFM data also proved that the SCNGs had an average diameter of 12±3nm.SEM images showed that SCNGs were conjugated as a linker of RGD peptide to thiolated glass substrate at an average density of 162±11 particles/μm2.These particles disappeared after adding free competitive ADA guest molecules,indicating the triggered unfolding of the tether SCNGs.In addition,the unfolding of supramolecular ADA@CD-SCNGs was also evidenced by a decrease in the GPC elution time and a slight increase in the apparent molecular weight.These results show that the immobilized ADA@CD-SCNGs can be unfolded to tune the tether length and mobility of the conjugated RGD ligands.Then we investigated the regulation of the cell behaviors on the substrate by triggering the unfolding of SCNG linkers.A critical level of traction force is required to effectively initiate and maintain integrin-mediated formation of FA complexes and subsequent mechano-transduction signaling.An increased tether length in cell-adhesive ligands can lead to a diminished cell traction force as if cells are adhering to soft substrates.Here,the unfolding of the ADA@CD-SCNG-RGD triggered by the addition of free ADA led to disassembly of the mature focal adhesions in the cells as evidenced by the reduced vinculin and F-actin in staining.Subsequently,nuclear YAP also decreased significantly because of the impaired mechano-sensing and diminished cell cytoskeleton tension.In addition,the extensively spread cells gradually became round after the medium was supplemented with free competitive ADA to unfold the SCNG linker.These finding demonstrates that the substrates with the unfolded ADA@CD-SCNG-RGD only supported weak cell adhesions.In contrast,on the substrate conjugated with the nonunfoldable MBA-SCNG-RGD linker,the addition of free ADA resulted in no change in the spread cell morphology and protein expressions.These results indicate that the unfoldable host-guest ADA@CD-SCNG can be used to manipulate the nanoscale presentation of ligands to regulate cell behaviors.Conclusions We demonstrate the application of SCNGs as the supramolecular linker to tune the nanoscale ligand tether length.These findings demonstrate that the strategy of manipulating the tether mobility of bioactive ligands by using supramolecular SCNGs as linkers provides a highly tunable,biomimetic,and bio-orthogonal approach to study the dynamic events of cell adhesion.

Desalted duck egg white nanogels as Pickering stabilizers for food-grade oil-in-water emulsion

Achieving the reuse of traditional egg by-products,salted duck egg whites(SEW),is an urgent problem to be solved.In this current work,we constructed a heat-induced gel-assisted desalination method for SEW.Subsequently,a top-down way was utilized to prepare desalted duck egg protein nanogels(DEPN)with uniformly distributed diameters and their application in the oil/water(O/W)interface system was explored.The results revealed that the increase of DEPN concentration could lower the droplet size,however,the size was negatively correlated with the oil phase fraction.Moreover,the effect of pH,ionic strength,and temperature on the emulsion stability demonstrated that the DEPN-stabilized emulsion displayed superior physical stability under different conditions.The addition of NaCl resulted in the significant decrease in droplet size of the emulsion,while further increasing the NaCl concentration,the droplet size did not decrease accordingly.Besides,heat-treatment and cold-treatment had little negative effect on the stability of the emulsion.Even if the droplet size of the emulsion increased at 80℃for 3 h,the morphology of the emulsion remained unchanged.Our study demonstrated DEPN had great potential as a stabilizer for food-grade Pickering emulsions.

Radiation-Induced Synthesis of Polyvinylpyrrolidone （PVP） Nanogels

Nanogels-particles of polymer gels having the dimensions in the order of nanometers-are gaining attention for their wide application as biomaterials. Mainly, the nanogels are promising novel pharmaceutical carriers for small biologically active agents, bin macromolecules and can be chemically modified to incorporate various ligands for targeted drug delivery. This important factor has stimulated research on dissimilar science field such as nanotechnology and biotechnology, polymer and materials sciences, biochemistry, radiation chemistry and pharmaceutical sciences. A multitude of techniques have been described for the synthesis of this nanomaterial from polymers. However, the use of ionizing radiation （γ, e-） has demonstrated to be especially suitable for obtaining polymeric nanogels with a high degree of purity for biomedical applications, although the gamma radiation has not been widely utilized for these purposes. The aim of this paper is to develop the synthesis of PVP （polyvynilpyrrolidone） nanogels by gamma irradiation, for their evaluation as potential pharmaceutical carriers. Experiments were performed using argon saturated solution of PVP （0.1-1%）. Crosstinking reactions were carried out in a gamma irradiation chamber with a 60Co source （ISOGAMMA LLCo）, at room temperature. The PVP concentration influence was evaluated in PVP solutions （0.1% and 0.25%） at 15 kGy. The SEM （scanning electron microscopy）, ATR （attenuate total reflection spectroscopy）, DLS （dynamic light scattering）, and viscosimetry were used as characterization techniques.

Phase Transition of Poly（acrylic acid-co-N-isopropylacrylamide） Core-shell Nanogels

A series of poly（acrylic acid） macromolecular chain transfer agents with different molecular weights were synthesized by reversible addition-fragmentation chain transfer （RAFT） poly- merization and characterized by 1^H NMR and gel permeation chromatography. Multiresponsive core-shell nanogels were prepared by dispersion polymerization of N-isopropylacrylamide in water using these poly（potassium acrylate） macro-RAFT agents as the electrostcric stabilizer. The size of the nanogels decreases with the amount of the macro-RAFT agent, indicating that the surface area occupied by per polyelectrolyte group is a critical parameter for stabilizing the nanogels. The volume phase transition and the zeta potentials of the nanogels in aqueous solutions were studied by dynamic light scattering and zetasizer analyzer, respectively.

ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape

In the field of cancer therapy,inhibiting autophagy has emerged as a promising strategy.However,pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1(PD-L1),enabling tumor immune evasion.To address this issue,we developed innovative ROS-responsive cationic poly(ethylene imine)(PEI)nanogels using selenol chemistry-mediated multicomponent reaction(MCR)technology.This procedure involved simple mixing of low-molecular-weight PEI(LMW PEI),γ-selenobutylacetone(γ-SBL),and poly(ethylene glycol)methacrylate(PEGMA).Through high-throughput screening,we constructed a library of AxSeyOz nanogels and identified the optimized A1.8Se3O0.5/siPD-L1 nanogels,which exhibited a size of approximately 200 nm,excellent colloidal stability,and the most effective PD-L1 silencing efficacy.These nanogels demonstrated enhanced uptake by tumor cells,excellent oxidative degradation ability,and inhibited autophagy by alkalinizing lysosomes.The A1.8Se3O0.5/siPD-L1 nanogels significantly downregulated PD-L1 expression and increased the expression of major histocompatibility complex class I(MHC-I),resulting in robust proliferation of specific CD8+T cells and a decrease in MC38 tumor growth.As a result,the A1.8Se3O0.5/siPD-L1 nanogels inhibited tumor growth through self-inhibition of autophagy,upregulation of MHC-I,and downregulation of PD-L1.Designed with dynamic diselenide bonds,the A1.8Se3O0.5/siPD-L1 nanogels showed synergistic antitumor efficacy through self-inhibition of autophagy and prevention of immune escape.

In-situ synthesis of PHEMA magnetic nanogels via photochemical method

One-pot synthesis of magnetic nanogels via photochemical method is reported in this paper. Poly(2-hydroxyethyl methacrylate)(PHEMA) magnetic nanogels are synthesized by in-situ polymeriza-tion of 2-hydroxyethyl methacrylate(HEMA) and N,N'-methylene-bis-(acrylamide)(MBA) in Fe3O4 aqueous suspension under UV irradiation. The structure and compositions of magnetic nanogels are characterized by FTIR,TGA,SEM,TEM and PCS. TGA measurement indicates that magnetic nanogels contain 90% magnetite. Both naked Fe3O4 and magnetic nanogels are superparamagnatic at room temperature according to magnetization curves. The swollen capability of the hydrogel shell is proved by contrasting the particles sizes obtained by SEM,TEM and PCS. Particle diameters can be manipu-lated by changing monomer concentration and irradiation time. A mechanism of the coating process is proposed.

Nanogels:A novel approach in antimicrobial delivery systems and antimicrobial coatings

The implementation of nanotechnology to develop efficient antimicrobial systems has a significant impact on the prospects of the biomedical field.Nanogels are soft polymeric particles with an internally cross-linked structure,which behave as hydrogels and can be reversibly hydrated/dehydrated(swollen/shrunken)by the dispersing solvent and external stimuli.Their excellent properties,such as biocompatibility,colloidal stability,high water content,desirable mechanical properties,tunable chemical functionalities,and interior gel-like network for the incorporation of biomolecules,make them fascinating in the field of biological/biomedical applications.In this review,various approaches will be discussed and compared to the newly developed nanogel technology in terms of efficiency and applicability for determining their potential role in combating infections in the biomedical area including implant-associated infections.

Poly(PEGMA) magnetic nanogels:Preparation via photochemical method,characterization and application as drug carrier

One-pot synthesis of magnetic nanogels with excellent biocompatibility via the photochemical method is reported in this paper.Poly(PEGMA) modified superparamagnetic nanogels(poly(PEGMA) magnetic nanogels) were synthesized by in-situ polymerization using poly(ethylene glycol) methacrylate(PEGMA) as the monomer and N,N'-methylene-bis-(acrylamide)(MBA) as the cross-linking agent in magnetite aqueous suspension under UV irradiation.The surface functional groups and components of magnetic nanogels were analyzed by Fourier transform infrared spectroscopy(FTIR) and a thermogra-vimetric analyzer(TGA).The results indicated that the poly(PEGMA) magnetic nanogels were synthe-sized successfully by coating poly(PEGMA) on the Fe3O4 nanoparticles under UV irradiation,and the Fe3O4 nanoparticles content in this nanogels was above 50 wt%.The morphology,size,zeta-potential and magnetic property were also characterized.The magnetic nanogels had a nearly spherical shape and core-shell structure,the average size in aqueous system measured by photon correlation spec-troscopy(PCS) was 68.4 nm,which was much bigger than that in the dry state,the nanogels behaved superparamagnetically with saturated magnetization of 58.6 emu/g,and the zeta-potential was-16.3-_17.3 mV at physiological pH(6.8-7.4) which could help to maintain stability in blood.The preliminary application as drug carrier was made and the doxorubicin-loaded magnetic nanogels had an excellent property in slow-release.The experiment indicated that the magnetic nanogel was an ideal candidate carrier in target drug delivery systems and other biomedical application.

Nanogels as Contrast Agents for Molecular Imaging

Nanogels （NGs） as soft nanosized materials have gained a variety of interests in biomedical fields. The versatile NG scaffolds with 3-dimensional spherical shape, high loading efficiency, tunable surface functionalization, and excellent biocompatibility afford their uses as carrier to load mono- or multi-mode molecular imaging contrast agents （CAs）. This review summarizes the synthesis routes and applications of NGs as CAs for molecular imaging applications including magnetic resonance （MR）, computed tomography （CT）, radionuclide, optical, and dual/mul- ti-modality imaging.

Near-infrared chemiluminescent carbon nanogels for oncology imaging and therapy

Carbon nanogels(CNGs)with dual ability of reactive oxygen species(ROS)imaging and photodynamic therapy have been designed with selfassembled chemiluminescent carbonized polymer dots(CPDs).With efficient deep-red/near-infrared chemiluminescence(CL)emission and distinctive photodynamic capacity,the H2O2-driven chemiluminescent CNGs are further designed by assembling the polymeric conjugate and CL donors,enabling an in vitro and in vivo ROS bioimaging capability in animal inflammation models and a high-performance therapy for xenograft tumors.Mechanistically,ROS generated in inflammatory sites or tumor microenvironment can trigger the chemically initiated electron exchange luminescence in the chemical reaction of peroxalate and H2O2,enabling in vivo CL imaging.Meanwhile,part of the excited-state electrons will transfer to the ambient H2O or dissolved oxygen and in turn lead to the type I and type II photochemical ROS production of hydroxyl radicals or singlet oxygen,endowing the apoptosis of tumor cells and thus enabling cancer therapy.These results open up a new avenue for the design of multifunctional nanomaterials for bioimaging and antienoplastic agents.

Dendrimer-decorated nanogels:Efficient nanocarriers for biodistribution in vivo and chemotherapy of ovarian carcinoma

Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.

Highly photostable nanogels for fluorescence-based theranostics

A novel photo-crosslinkable nanogel is prepared from a biodegradable polymer template with intrinsic photoluminescence and high photostability.The fluorescent nanogels display excellent biodegradability and cytocompatibility owed to the facile synthesis scheme involving a solvent-and surfactant-free onepot reaction,derived entirely from biocompatible monomers citric acid,maleic acid,L-cysteine,and poly(ethylene glycol).The resultant nanogels are less than 200 nm in diameter with a narrow size distribution and monodispersity,and demonstrate long-term structural stability in biological buffer for two weeks.To gauge potential in theranostic applications,the fluorescent nanogels were surface functionalized with biologically active RGD peptides and encapsulated with active anti-cancer drug Doxorubicin,resulting in a pH-responsive controlled drug release in acidic pH resembling tumor environments.The strong fluorescence of the nanogels enabled tracking of targeted drug delivery,showing that drug-loaded nanogels homed into the cytoplasmic regions of prostate cancer cells to significantly induce cell death.These photo-crosslinkable and biodegradable nanogels pose as a strong candidate for theranostic medicine,demonstrating versatile functionalization,high stability in biological buffers,and capacity for real-time fluorescence-based monitoring of targeted drug delivery.

A networked swellable dextrin nanogels loading Bcl2 siRNA for melanoma tumor therapy

In this study, a networked swellable dextrin nanogel （DNG） was developed to achieve stimulated responsive small interfering RNA （siRNA） release for melanoma tumor therapy, siRNA was loaded into multidimensional dextrin nanogels by charge condensation with positive arginine residues modified in the dextrin backbone. Moreover, the networked nanogel was destroyed and loosened based on its bioreducible responsive property to control accelerated siRNA release in a bioreducible intracellular environment, while it remained stable under normal physiological conditions. We demonstrated that DNGs had swellable and disassembly properties under reduced buffer condition by transmission electron microscopy evaluation. The DNGs achieved an endosomal escape followed by selective release of the cargo into the cytosol by glutathione- triggered disassembly according to confocal microscopy observation. Thus, this smart nanogel achieved outstanding luciferase gene silencing efficiency and decreased Bcl2 protein expression in vitro and in vivo based on western blot analysis. Moreover, this nanogel exhibited superior anti-tumor activity for B16F10 xenograft tumors in C57BL/6 mice. These results demonstrate that the networked DNGs are effective for gene condensation and controlled intracellular release for tumor therapy. Overall, these findings suggest that this multidimensional swellable stimuli-responsive dextrin nanogel is an innovative strategy with great promise for gene and drug delivery.

Intelligent nanogels with self-adaptive responsiveness for improved tumor drug delivery and augmented chemotherapy

For cancer nanomedicine,the main goal is to deliver therapeutic agents effectively to solid tumors.Here,we report the unique design of self-adaptive ultrafast charge-reversible chitosan-polypyrrole nanogels(CH-PPy NGs)for enhanced tumor delivery and augmented chemotherapy.CH was first grafted with PPy to form CH-PPy polymers that were used to form CH-PPy NGs through glutaraldehyde cross-linking via a miniemulsion method.The CH-PPy NGs could be finely treated with an alkaline solution to generate ultrafast charge-reversible CH-PPy-OH-4 NGs(R-NGs)with a negative charge at a physiological pH and a positive charge at a slightly acidic pH.The R-NGs display good cytocompatibility,excellent protein resistance,and high doxorubicin(DOX)loading efficiency.Encouragingly,the prepared R-NGs/DOX have prolonged blood circulation time,enhanced tumor accumulation,penetration and tumor cell uptake due to their self-adaptive charge switching to be positively charged,and responsive drug delivery for augmented chemotherapy of ovarian carcinoma in vivo.Notably,the tumor accumulation of R-NGs/DOX(around 4.7%)is much higher than the average tumor accumulation of other nanocarriers(less than 1%)reported elsewhere.The developed self-adaptive PPy-grafted CH NGs represent one of the advanced designs of nanomedicine that could be used for augmented antitumor therapy with low side effects.

Edaravone-loaded poly(amino acid) nanogel inhibits ferroptosis for neuroprotection in cerebral ischemia injury

Neurological injury caused by ischemic stroke is a major cause of permanent disability and death. The currently available neuroprotective drugs fail to achieve desired therapeutic efficacy mainly due to short circulation half-life and poor blood−brain barrier (BBB) permeability. For that, an edaravone-loaded pH/glutathione (pH/GSH) dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to improve the neuroprotection of EDA. The nanogel was triggered by acidic and EDA-induced high-level GSH microenvironments, which enabled the selective and sustained release of EDA at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm. NG/EDA efficiently accumulated at the cerebral ischemic injury site of permanent middle cerebral artery occlusion (pMCAO) mice, showing an efficient BBB crossing feature. Notably, NG/EDA with 50 µM EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. In addition, administering NG/EDA for 7 d significantly reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. Such a pH/GSH dual-responsive nanoplatform might provide a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.

Thermoresponsive Nanogels from Dendronized Copolymers for Complexation,Protection and Release of Nucleic Acids

A series of thermoresponsive cationic dendronized copolymers and their corresponding nano gels containing den dritic oligoethylene glycol(OEG)units and guanidine groups were prepared,and their complexation,protect!on,and release of nucleic acids were investigated.The dendritic OEGs endow these copolymer materials with good biocompatibility and characteristic thermoresponsiveness,while cationic guanidine groups can efficiently bind with the nucleic acids.The dendritic topology also affords the copolymers specific shielding effect which plays an essential role in protecting the activity of nucleic acids.At room temperature,dendronized copolymers and the corresponding nanogels could efficiently capture and condense the nucleic acids,while above their cloud points(Tcps),more than 75%of siRNA could be released in 1 h triggered by ATP.More importantly,the copolymer showed protective capability to siRNA,while nano gels exhibit even better protection when compared to the copolymers due to the synergetic effect from the three-dimensional cross-linked network and high density of dendritic units in vicinity.This kind of smart dendr on ized copolymer nano gels form a no vel class of scaffolds as promisi ng materials for biomedical applicatio ns.