Nanomaterials are finding increasing use for biomedical applications such as imaging, diagnostics, and drug delivery. While it is well understood that nanoparticle (NP) physico-chemical properties can dictate biological responses and interactions, it has been difficult to outline a unifying framework to directly link NP properties to expected in vitro and in vivo outcomes. When introduced to complex biological media containing electrolytes, proteins, lipids, etc., nanoparticles (NPs) are subjected to a range of forces which determine their behavior in this environment. One aspect of NP behavior in biological systems that is often understated or overlooked is aggregation. NP aggregation will significantly alter in vitro behavior (dosimetry, NP uptake, cytotoxicity), as well as in vivo fate (pharmacokinetics, toxicity, biodistribution). Thus, understanding the factors driving NP colloidal stability and aggregation is paramount. Furthermore, studying biological interactions with NPs at the nanoscale level requires an interdisciplinary effort with a robust understanding of multiple characterization techniques. This review examines the factors that determine NP colloidal stability, the various efforts to stabilize NP in biological media, the methods to characterize NP colloidal stability in situ, and provides a discussion regarding NP interactions with cells.

Transient activation of biochemical reactions by visible light and subsequent return to the inactive state in the absence of light is an essential feature of the biochemical processes in photoreceptor cells. To mimic such light-responsiveness with artificial nanosystems, polymersome nanoreactors were developed that can be switched on by visible light and self-revert fast in the dark at room temperature to their inactive state. Donor-acceptor Stenhouse adducts (DASAs), with their ability to isomerize upon irradiation with visible light, were employed to change the permeability of polymersome membranes by switching polarity from a nonpolar triene-enol form to a cyclopentenone with increased polarity. To this end, amphiphilic block copolymers containing poly(pentafluorophenyl methacrylate) in their hydrophobic block were synthesized by reversible addition-fragmentation chain-transfer (RAFT) radical polymerization and functionalized either with a DASA that is based on Meldrum's acid or with a novel fast-switching pyrazolone-based DASA. These polymers were self-assembled into vesicles. Release of hydrophilic payload could be triggered by light and stopped as soon as the light was turned off. The encapsulation of enzymes yielded photoresponsive nanoreactors that catalyzed reactions only if they were irradiated with light. A mixture of polymersome nanoreactors, one that switches in green light, the other switching in red light, permitted specific control of the individual reactions of a reaction cascade in one pot by irradiation with varied wavelengths, thus enabling light-controlled wavelength-selective catalysis. The DASA-based nanoreactors demonstrate the potential of DASAs to switch permeability of membranes and could find application to switch reactions on and off, on demand, e.g., in microfluidics or in drug delivery.

ABSTRACT:The transduction of mechanical force into useful chemical reactions is an emerging design approach to impart soft materials with new functions. Here, we report that mechanochemical transductions can be achieved in metallosupramolecular polymers. We show that both reversible and irreversible reactions are possible and useful to create mechanically responsive materials that display new functions. The metallopolymer studied was a crosslinked network assembled from a europium salt and a telechelic poly(ethylene-co-butylene) with 2,6-bis(1′-methylbenzimidazolyl)pyridine (Mebip) ligands at the termini. The Eu 3+ complexes serve both as mechanically responsive binding motifs and built-in optical probes that can monitor the extent of (dis)assembly due to their characteristic photoluminescent properties. Indeed, dose-dependent and reversible metal-ligand dissociation occurs upon exposure to ultrasound in solution. The absence of ultrasound-induced dissociation of a low-molecular weight model complex and in-depth studies of temperature effects confirm that the dissociation is indeed the result of mechanical activation. The influence of the strength of the metal-ligand interactions on the mechanically induced dissociation was also explored. Metallopolymers in which the Mebip ligands were substituted with more strongly coordinating dipicolinate (dpa) ligands do not dissociate upon exposure to ultrasound. Finally we show that mechanochemical transduction in metallosupramolecular polymers is also possible in the solid state. We demonstrate mending of damaged objects through ultrasound as well as mechanochromic behavior based on metal-exchange reactions in metallopolymers imbibed with an auxiliary metal salt.

Standard transmission electron microscopy nanoparticle sample preparation generally requires the complete removal of the suspending liquid. Drying often introduces artifacts, which can obscure the state of the dispersion prior to drying and preclude automated image analysis typically used to obtain number-weighted particle size distribution. Here we present a straightforward protocol for prevention of the onset of drying artifacts, thereby allowing the preservation of in-situ colloidal features of nanoparticles during TEM sample preparation. This is achieved by adding a suitable macromolecular agent to the suspension. Both research- and economically-relevant particles with high polydispersity and/or shape anisotropy are easily characterized following our approach (http://bsa.bionanomaterials.ch), which allows for rapid and quantitative classification in terms of dimensionality and size: features that are major targets of European Union recommendations and legislation.

Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio-nano papers, the community responds. Below we report short extracts highlighting the main messages of the correspondences we received. The interested readers can find the complete pieces in the accompanying Supplementary Information.

The ligand shell (LS) determines a number of nanoparticles’ properties. Nanoparticles’ cores can be accurately characterized; yet the structure of the LS, when composed of mixture of molecules, can be described only qualitatively (e.g., patchy, Janus, and random). Here we show that quantitative description of the LS’ morphology of monodisperse nanoparticles can be obtained using small-angle neutron scattering (SANS), measured at multiple contrasts, achieved by either ligand or solvent deuteration. Three-dimensional models of the nanoparticles’ core and LS are generated using an ab initio reconstruction method. Characteristic length scales extracted from the models are compared with simulations. We also characterize the evolution of the LS upon thermal annealing, and investigate the LS morphology of mixed-ligand copper and silver nanoparticles as well as gold nanoparticles coated with ternary mixtures. Our results suggest that SANS combined with multiphase modeling is a versatile approach for the characterization of nanoparticles’ LS.

We report the preparation and characterization of light-healable nanocomposites based on cellulose nanocrystals (CNCs) and a metallosupramolecular polymer (MSP) assembled from a telechelic poly(ethylene-co-butylene) that was end-functionalized with 2,6-bis(1′-methylbenzimidazolyl) pyridine (Mebip) ligands and Zn(NTf2)2. The polymer absorbs incident ultraviolet (UV) radiation and converts it into heat, which causes dissociation of the metal–ligand motifs. This process liquefies the material, and small defects are readily filled. When the UV light is switched off, the MSP reassembles and the original properties are restored. The introduction of CNCs into the MSP matrix leads to a significant increase of the stiffness and strength, from 52 and 1.7 MPa for the neat polymer to 135 and 5.6 MPa upon introduction of 10% w/w CNCs. The Zn2+ ions bind to the CNCs which means the metal:ligand ratio of the MSP must be adjusted accordingly. In nanocomposites thus made, deliberately introduced defects can be efficiently healed.

As a highly interdisciplinary field, working with nanoparticles in a biomedical context requires a robust understanding of soft matter physics, colloidal behaviors, nano-characterization methods, biology, and bio-nano interactions. When reporting results, it can be easy to overlook simple, seemingly trivial experimental details. In this context, we set out to understand how in vitro technique, specifically the way we administer particles in 2D culture, can influence experimental outcomes. Gold nanoparticles coated with poly(vinylpyrrolidone) were added to J774A.1 mouse monocyte/macrophage cultures as either a concentrated bolus, a bolus then mixed via aspiration, or pre-mixed in cell culture media. Particle-cell interaction was monitored via inductively coupled plasma-optical emission spectroscopy and we found that particles administered in a concentrated dose interacted more with cells compared to the pre-mixed administration method. Spectroscopy studies reveal that the initial formation of the protein corona upon introduction to cell culture media may be responsible for the differences in particle-cell interaction. Modeling of particle deposition using the in vitro sedimentation, diffusion and dosimetry model helped to clarify what particle phenomena may be occurring at the cellular interface. We found that particle administration method in vitro has an effect on particle-cell interactions (i.e. cellular adsorption and uptake). Initial introduction of particles in to complex biological media has a lasting effect on the formation of the protein corona, which in turn mediates particle-cell interaction. It is of note that a minor detail, the way in which we administer particles in cell culture, can have a significant effect on what we observe regarding particle interactions in vitro.