Poly(vinyl alcohol)s and Their Glycoderivatives as Efficient Shell-Builders of Nanocapsules by Nanoprecipitation.

Poly(vinyl alcohol)s (PVAs) are very popular dispersants for the construction of colloids and common shell-constituents of microcapsules but remain mostly unexplored as building blocks for the design of nanocapsules through nanoprecipitation or other processes. Herein, we first show that model commercial PVAs and oils can be concomitantly engaged in solvent-shifting procedures to give rise to oil-filled nanocapsules in one step. Next, we report the synthesis of precisely defined water-soluble glyco-PVAs by reversible addition-fragmentation chain transfer (RAFT) copolymerization of 6-O-vinyladipoyl-d-glucopyranose and vinyl chloroacetate and selective alcoholysis reactions. We finally demonstrate that these glycopolymers are excellent candidates for the straightforward conception of oil- and drug-filled, surface- and/or core-tagged, stealth, and degradable nanocapsules by nanoprecipitation.

Sunlight-triggered prebiotic nanomotors for inhibition and elimination of pathogen and biofilm in aquatic environment.

Pathogen contamination in drinking water sources causes waterborne infectious diseases, seriously threatening human health. Nowadays, stimuli-responsive self-propelled nanomotors are appealing therapeutic agents for antibacterial therapy in vivo. However, achieving water disinfection using these nanobots is still a great challenge. Herein, we report on prebiotic galactooligosaccharide-based nanomotors for sunlight-regulated water disinfection. The nanomotors can utilize galactooligosaccharide-based N-nitrosamines as sunlight-responsive fuels for the spontaneous production of antibacterial nitric oxide. Such a solar-to-chemical energy conversion would power the nanomotors for self-diffusiophoresis, which could promote the diffusion of the nanomotors in water and their penetration in the biofilm, significantly enhancing the inhibition and elimination of the pathogens and their biofilms in aquatic environments. After water treatments, the prebiotic-based residual disinfectants can be selectively utilized by beneficial bacteria to effectively relieve safety risks to the environment and human health. The low-energy-cost, green and potent antibacterial nanobots show promising potential in water disinfection.

Organic nanomotors: emerging versatile nanobots.

Artificial nanomotors are self-propelled nanometer-scaled machines that are capable of converting external energy into mechanical motion. A significant progress on artificial nanomotors over the last decades has unlocked the potential of carrying out manipulatable transport and cargo delivery missions with enhanced efficiencies owing to their stimulus-responsive autonomous movement in various complex environments, allowing for future advances in a large range of applications. Emergent kinetic systems with programmable energy-converting mechanisms that are capable of powering the nanomotors are attracting increasing attention. This review highlights the most-recent representative examples of synthetic organic nanomotors having self-propelled motion exclusively powered by organic molecule- or their aggregate-based kinetic systems. The stimulus-responsive propulsion mechanism, motion behaviors, and performance in antitumor therapy of organic nanomotors developed so far are illustrated. A future perspective on the development of organic nanomotors is also proposed. With continuous innovation, it is believed that the scope and possible achievements in practical applications of organic nanomotors with diversified organic kinetic systems will expand.

Tetrazole Linkages as Photoactivated Fuels for Light-Regulated Photothermal/Photocatalytic Propulsion of Versatile Polymer Nanoplatforms.

Colloidal motors with multimode propulsion have attracted considerable attention because of enhanced transportability. It is a great challenge to fabricate colloidal motors powered by a single engine for multimode synergistic propulsion. Herein, we report on Janus versatile polymer nanoplatforms integrating various functionalities via tetrazole linkages for light-regulated multimode synergistic propulsion in the liquid. The presence of tetrazole linkages in the polymers endows the nanoparticles with various photoresponsive capabilities. A sole energy source (ultraviolet or visible light) simultaneously activates photocatalytic N2 release and photothermal conversion within the tetrazole-containing polymer phase at one side of asymmetric nanoparticles for converting light energy into photothermal/photocatalytic propulsion independent of the surrounding chemical medium. The photoactivated locomotion using tetrazoles as light-triggered fuels highly corresponds to light wavelengths, light powers and tetrazole contents. The tetrazole linkages capable of incorporating various functionalities to the polymer nanoparticles allow on-demand customizing of the colloidal motors, showing great potential in bio-applications.

Engineered Organic Nanorockets with Light-Driven Ultrafast Transportability for Antitumor Therapy.

Nanomedicines confront various complicated physiological barriers limiting the accumulation and deep penetration in the tumor microenvironment, which seriously restricts the efficacy of antitumor therapy. Self-propelled nanocarriers assembled with kinetic engines can translate external energy into orientated motion for tumor penetration. However, achieving a stable ultrafast permeability at the tumor site remains challenging. Here, sub-200 nm photoactivated completely organic nanorockets (NRs), with asymmetric geometry conveniently assembled from photothermal semiconducting polymer payload and thermo-driven macromolecular propulsion through a straightforward nanoprecipitation process, are presented. The artificial NRs can be remotely manipulated by 808 nm near-infrared light to trigger the photothermal conversion and Curtius rearrangement reaction within the particles for robustly pushing nitrogen out into the solution. Such a two-stage light-to-heat-to-chemical energy transition effectively powers the NRs for an ultrafast (≈300 µm s-1 ) and chemical medium-independent self-propulsion in the liquid media. That endows the NRs with high permeability against physiological barriers in the tumor microenvironment to directionally deliver therapeutic agents to target lesions for elevating tumor accumulation, deep penetration, and cellular uptake, resulting in a significant enhancement of antitumor efficacy. This work will inspire the design of advanced kinetic systems for powering intelligent nanomachines in biomedical applications.

Photoactivated Organic Nanomachines for Programmable Enhancement of Antitumor Efficacy.

Limited permeability in solid tumors significantly restricts the anticancer efficacy of nanomedicines. Light-driven nanomotors powered by photothermal converting engines are appealing carriers for directional drug delivery and simultaneous phototherapy. Nowadays, it is still a great challenge to construct metal-free photothermal nanomotors for a programmable anticancer treatment. Herein, one kind of photoactivated organic nanomachines is reported with asymmetric geometry assembled by light-to-heat converting semiconducting polymer engine and macromolecular anticancer payload through a straightforward nanoprecipitation process. The NIR-fueled polymer engine can be remotely controlled to power the nanomachines for light-driven thermophoresis in the liquid media and simultaneously thermal ablating the cancer cells. The great manipulability of the nanomachines allows for programming of their self-propulsion in the tumor microenvironment for effectively improving cellular uptake and tumor penetration of the anticancer payload. Taking the benefit from this behavior, a programmed treatment process is established at a low drug dose and a low photothermal temperature for significantly enhancing the antitumor efficacy.

Nanoprecipitation as a simple and straightforward process to create complex polymeric colloidal morphologies.

Polymeric nanoparticles are highly important functional nanomaterials for a large range of applications from therapeutics to energy. Advances in nanotechnology have enabled the engineering of multifunctional polymeric nanoparticles with a variety of shapes and inner morphologies. Thanks to its inherent simplicity, the nanoprecipitation technique has progressively become a popular approach to construct polymeric nanoparticles with precise control of nanostructure. The present review highlights the great capability of this technique in controlling the fabrication of various polymeric nanostructures of interest. In particular, we show here how the nanoprecipitation of either block copolymers or mixtures of homopolymers can afford a myriad of colloids displaying equilibrium (typically onion-like) or out-of-equilibrium (stacked lamellae, porous cores) morphologies, depending whether the system "freezes" while passing the glass transition or crystallization point of starting materials. We also show that core-shell morphologies, either from polymeric or oil/polymer mixtures, are attainable by this one-pot process. A final discussion proposes new directions to enlarge the scope and possible achievements of the process.

Nanocapsules Produced by Nanoprecipitation of Designed Suckerin-Silk Fusion Proteins.

Herein, we report on the precise design of a modular fusion protein amenable to the construction of nanocapsules by nanoprecipitation. The central squid suckerin-derived peptide block provides structural stability, whereas both termini from spider silk fibroins make the protein highly soluble at physiological pH, a critical requirement for the nanoprecipitation process. With this design, nanocapsules consisting of fusion protein shells and oily cores with sizes in the range of 190-250 nm are built in a straightforward manner.

Functional Hybrid Glyconanocapsules by a One-Pot Nanoprecipitation Process.

Herein, we report on one-pot fabrication of oil-filled nanocapsules wrapped with both RAFT-made glycopolymers and neutral polysaccharides (dextran and pullulan). We have made use of the nanoprecipitation technique, relying on coprecipitation of both oil and polymers in conditions thoroughly established from phase diagrams' interpretation. Mixed mono- or multilayered nanocapsules were obtained through simultaneous or sequential nanoprecipitations, respectively. Incorporation of synthetic glycopolymer chains allows for precisely tailoring the dimensions of the nanocapsules (size and membrane thickness of the polymeric shell), whereas the insertion of polysaccharides enables to tune the (bio)degradability of the nanocapsules. Shell-functionalized and/or core-loaded capsules could also be achieved in a similar one-pot process, by introducing a drug and/or biotin in the organic and aqueous phase, respectively.

Programmable Hierarchical Construction of Mixed/Multilayered Polysaccharide Nanocapsules through Simultaneous/Sequential Nanoprecipitation Steps.

We report here on a one-pot construction of oil-filled hierarchical capsular assemblies using the nanoprecipitation technique. Relying on multicomponent phase diagrams, we show that simultaneous and/or sequential nanoprecipitations involving polymer combinations can be precisely programmed to design a new class of mixed/multilayered multicomponent nanocapsules, with a precise control of the dimensions, shell thickness/composition, and spatial distribution of the building blocks. The simplicity and tunability of this approach are exemplified here with a library of neutral and ionic polysaccharides giving access to a range of functional multilayered nanocarriers of interest for biomedical applications.

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases.

Sialidases (SAs) hydrolyze sialyl residues from glycoconjugates of the eukaryotic cell surface and are virulence factors expressed by pathogenic bacteria, viruses, and parasites. The catalytic domains of SAs are often flanked with carbohydrate-binding module(s) previously shown to bind sialosides and to enhance enzymatic catalytic efficiency. Herein, non-hydrolyzable multivalent thiosialosides were designed as probes and inhibitors of V. cholerae, T. cruzi, and S. pneumoniae (NanA) sialidases. NanA was truncated from the catalytic and lectinic domains (NanA-L and NanA-C) to probe their respective roles upon interacting with sialylated surfaces and the synthetically designed di- and polymeric thiosialosides. The NanA-L domain was shown to fully drive NanA binding, improving affinity for the thiosialylated surface and compounds by more than two orders of magnitude. Importantly, each thiosialoside grafted onto the polymer was also shown to reduce NanA and NanA-C catalytic activity with efficiency that was 3000-fold higher than that of the monovalent thiosialoside reference. These results extend the concept of multivalency for designing potent bacterial and parasitic sialidase inhibitors.

General and Scalable Approach to Bright, Stable, and Functional AIE Fluorogen Colloidal Nanocrystals for in Vivo Imaging.

Fluorescent nanoparticles built from aggregation-induced emission-active organic molecules (AIE-FONs) have emerged as powerful tools in life science research for in vivo bioimaging of organs, biosensing, and therapy. However, the practical use of such biotracers has been hindered owing to the difficulty of designing bright nanoparticles with controlled dimensions (typically below 200 nm), narrow size dispersity and long shelf stability. In this article, we present a very simple yet effective approach to produce monodisperse sub-200 nm AIE fluorescent organic solid dispersions with excellent redispersibility and colloidal stability in aqueous medium by combination of nanoprecipitation and freeze-drying procedures. By selecting polymer additives that simultaneously act as stabilizers, promoters of amorphous-crystalline transition, and functionalization/cross-linking platforms, we demonstrate a straightforward access to stable nanocrystalline FONs that exhibit significantly higher brightness than their amorphous precursors and constitute efficient probes for in vivo imaging of the normal and tumor vasculature. FONs design principles reported here are universal, applicable to a range of fluorophores with different chemical structures and crystallization abilities, and are suitable for high-throughput production and manufacturing of functional imaging probes.

Central Role of Bicarbonate Anions in Charging Water/Hydrophobic Interfaces.

Aqueous interfaces are ubiquitous in Nature and play a fundamental role in environmental or biological processes or modern nanotechnologies. These interfaces are negatively charged, and despite several decades of research, the rationale behind this phenomenon is still under debate. Two main controversial schools of thought argue on this issue; the first relies on the adsorption of hydroxide anions on hydrophobic surfaces, whereas the second one supports a self-rearrangement of water molecules at the interface bearing hydronium ions. Here, we report on two series of independent experimental studies (nanoprecipitation and interfacial tension measurements) that demonstrate that in the pH 5-10 range the negative interfacial charge of the colloids mostly stems from bicarbonate ions, whereas at lower and higher pH, protons and hydroxide ions contribute, with bicarbonate ions, to the interfacial charging. This new interpretation complies with previous studies and opens new perspectives to this striking physical chemical issue.

Modular construction of single-component polymer nanocapsules through a one-step surfactant-free microemulsion templated synthesis.

Formation of O/W surfactant-free microemulsions from water/oil/acetone ternary systems is exploited to construct precisely-defined shell-functionalized core-loaded nanocapsules with tunable diameters (ranging from 50 to 190 nm) in one step.

Nanoprecipitation of PHPMA (Co)Polymers into Nanocapsules Displaying Tunable Compositions, Dimensions, and Surface Properties.

A series of PHPMA homopolymers and of mannose- and dimethylamino-functionalized copolymers, were prepared by RAFT polymerization and engaged in the preparation of oil-loaded nanocapsules using the "Shift'N'Go" process. Playing with the phase diagrams of both oil and homo- or copolymers afforded the preparation of functional camptothecin-loaded nanocapsules displaying tunable dimensions (90-350 nm), compositions and surface properties.

Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease.

UNLABELLED: The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or ß-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE: Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.

Brilliant glyconanocapsules for trapping of bacteria.

Nanoprecipitation of miglyol into droplets surrounded by a functional glycopolymer generates nanocapsules of biointerest. Fluorophores are trapped in situ or post-grafted onto the crosslinked polymer shell for efficient imaging. The resulting colloids induce aggregation of bacteria through strong specific interactions and promote their facile removal.

Glycopolymers as Antiadhesives of E. coli Strains Inducing Inflammatory Bowel Diseases.

n-Heptyl α-d-mannose (HM) is a nanomolar antagonist of FimH, a virulence factor of E. coli. Herein we report on the construction of multivalent HM-based glycopolymers as potent antiadhesives of type 1 piliated E. coli. We investigate glycopolymer/FimH and glycopolymer/bacteria interactions and show that HM-based glycopolymers efficiently inhibit bacterial adhesion and disrupt established cell-bacteria interactions in vitro at very low concentration (0.1 µM on a mannose unit basis). On a valency-corrected basis, HM-based glycopolymers are, respectively, 10(2) and 10(6) times more potent than HM and d-mannose for their capacity to disrupt the binding of adherent-invasive E. coli to T84 intestinal epithelial cells. Finally, we demonstrate that the antiadhesive capacities of HM-based glycopolymers are preserved ex vivo in the colonic loop of a transgenic mouse model of Crohn's disease. All together, these results underline the promising scope of HM-based macromolecular ligands for the antiadhesive treatment of E. coli induced inflammatory bowel diseases.

Aqueous RAFT Polymerization of Imidazolium-Type Ionic Liquid Monomers: En Route to Poly(ionic liquid)-Based Nanoparticles through RAFT Polymerization-Induced Self-Assembly.

The synthesis by aqueous RAFT polymerization of hydrophilic narrowly dispersed imidazolium-based poly(ionic liquid)s (D typically below 1.20) is reported. Full monomer conversion is achieved within hours and high end-group fidelity of the living end groups affords the preparation of well-defined block copolymers. The resulting poly(ionic liquid) macroRAFT agents are finally exploited to polymerize 2-vinylpyridine in water and generate PIL-based nanoparticles of various morphologies (spheres, vesicles, or worms) in a one-pot surfactant-free process.