Phenolic-Compound-Based Functional Coatings: Versatile Surface Chemistry and Biomedical Applications.

Phenolic-compound-based functional coatings that allow for flexible modulation of chemical and surface properties have found widespread uses in a diverse range of biomedical applications from antibiofouling and antioxidation to bioimaging, therapeutics, and controlled drug delivery. It is imperative to understand the formation mechanism of phenolic coatings to fully meet the needs of their emerging applications in controlling the surface properties of biomaterials and medical devices. In this Perspective, we highlight the versatile chemical and self-assembly approaches to generate phenolic coatings with tailored surface properties and reactivities and also discuss how the surface properties and chemical reactivities impart functional materials for translational research.

Caging Cationic Polymer Brush-Coated Plasmonic Nanostructures for Traceable Selective Antimicrobial Activities.

Cationic polymers are under intense research to achieve prominent antimicrobial activity. However, the cellular and in vivo toxicity caused by nonspecific electrostatic interaction has become a major challenge for their practical applications. Here, the development of a "caging" strategy based on the use of a block copolymer consisting of a stealth block and an anionic block that undergoes degradation in presence of enzymes secreted by selective bacterial pathogens of interest is reported. The results have shown that antimicrobial cationic polymer brushes-coated gold nanorods (AuNRs) can be caged by the block polymer of poly(ethylene glycol) and anionic, lipase-degradable block of ε-caprolactone and methacrylic acid copolymer to afford neutrally charged surfaces. The caged AuNRs are activated by lipase released by bacteria of interest to endow an excellent bactericidal effect but show minimal binding and toxicity against mammalian cells and nonspecific bacteria that do not produce lipase. In this design, AuNRs play multifunctional roles as the scaffolds for polymer brushes, photothermal transducers, and imaging probes for traceable delivery of the activation and delivery of bactericidal cationic polymer brushes. The caging strategy opens new opportunities for the safe delivery of antimicrobial materials for the treatment of bacterial infections.

Antibiofilm Activity of Gallium(III) Complexed Anionic Polymers in Combination with Antibiotics.

Pseudomonas aeruginosa (P. aeruginosa) is a life-threatening pathogen associated with multiantibiotic resistance, which is largely caused by its strong ability to form biofilms. Recent research has revealed that gallium (III) shows an activity against the biofilm of P. aeruginosa by interfering with Fe metabolism. The antibacterial activity of the combination of Ga3+ ion and antibiotic rifampicin (RMP) against P. aeruginosa PAO1 is investigated. An anionic polymer poly{{2-[(2-methylprop-2-enoyl)oxy]ethyl}phosphonic acid} (PDMPOH) is exploited to form complexes (GaPD) with Ga3+ . The GaPD complexes act as a carrier of Ga3+ and release Ga3+ via enzymatic degradation by bacterial lipases. GaPD is found to damage the outer membrane, leading to enhanced cellular uptake of RMP and Ga3+ due to increased outer membrane permeability, which inhibits the RNA polymerase and interferes with Fe metabolism. The antibiofilm activity and biocompatibility of the GaPD system offer a promising treatment option for P. aeruginosa biofilm-related infections.

Charge-Reversal Polymer Nano-modulators for Photodynamic Immunotherapy of Cancer.

Nanomedicine can regulate the balance between cytotoxic T lymphocytes (CTLs) and suppressive regulatory T lymphocytes (Tregs), which however has been rarely exploited for cancer immunotherapy. We report a charge-reversal polymer nano-modulator (SPDMC N) activated by tumor microenvironment (TME) for photodynamic immunotherapy of cancer. SPDMC N is constructed by conjugating an immunomodulator (demethylcantharidin, DMC) to the side chains of a photodynamic polymer via an acid-liable linker. The negative charge of SPDMC N ensures its high stability in blood circulation and ideal tumor accumulation; exposure to acidic TME reverses its surface charge to positive, enhancing tumor penetration and locally releasing DMC. Upon near-infrared photoirradiation, SPDMC N generates singlet oxygen to ablate tumors and promote maturation of dendritic cells. Released DMC inhibits protein phosphatase 2 (PP2A) activity and decreases Tregs differentiation. Such combinational action induces a sharp increase in CTL/Treg ratio in TME and effectively inhibits both primary and distant tumors in living mice.

Bioinspired Production of Noniridescent Structural Colors by Adhesive Melanin-like Particles.

Structural color printing of colloidal photonic films with tunable structures or optical properties is of great importance owing to their practical applications. In this article, we present a general method for the fabrication of colloidal particle films with tailored packing geometries by self-assembly of adhesive melanin-like polydopamine (PDA)-coated particles. The adhesion of particles is controlled by varying the thickness of the PDA coating, making it possible for dip coating of colloidal crystals, partly ordered or amorphous colloidal arrays (ACAs) with a tunable degree of order. We further studied the structural color printing of adhesive particles by infiltration-assisted or standard inkjet printing methods. Compared with bare particles, PDA-coated particles not only allow for control over color brightness/angle dependence of the photonic films but also significantly enhance the color quality of ACAs, both of which are useful for display, anticounterfeiting, or sensing applications. Owing to the inherent strong adhesiveness of PDA to virtually all types of surfaces, this PDA-based methodology can be potentially extended to a diverse range of colloidal particles toward the development of photonic devices.

Self-Assembly of Polymer-Coated Plasmonic Nanocrystals: From Synthetic Approaches to Practical Applications.

Self-assembly of plasmonic nanocrystals (PNCs) and polymers provides access to a variety of functionalized metallic-polymer building blocks and higher-order hybrid plasmonic assemblies, and thus is of considerable fundamental and practical interest. The hybrid assemblies often not only inherit individual characteristics of polymers and PNCs but also exhibit distinct photophysical and catalytic properties compared to that of a single PNC building block. The tailorable plasmonic coupling between PNCs within assemblies enables the precise control over localized surface plasmon resonance, which subsequently affords a series of light-driven or photo-activated applications, such as surface-enhanced Raman scattering detection, photoacoustic imaging, photothermal therapy, and photodynamic therapy. In this review, the synthetic strategies of a library of PNC-polymer hybrid building blocks and corresponding assemblies are summarized along with the mechanisms of polymer-assisted self-assembly of PNCs and the concepts for bridging the intrinsic properties of PNC-polymer assemblies to widespread practical applications.

Synthesis and Antibacterial Study of Sulfobetaine/Quaternary Ammonium-Modified Star-Shaped Poly[2-(dimethylamino)ethyl methacrylate]-Based Copolymers with an Inorganic Core.

Cationic polymethacrylates are interesting candidates for bacterial disinfectants since they can be made in large-scale by various well-established polymerization techniques such as atom transfer radical polymerization (ATRP). However, they are usually toxic or ineffective in serum and various strategies to improve their biocompatibility or nonfouling property have often resulted in compromised bactericidal activity. Also, star-shaped polymers are less explored than linear polymers for application as antibacterial compounds. In this paper, star polymers with poly[2-(dimethylamino)ethyl methacrylate] (PDMA) as the arms and polyhedral oligomeric silsesquioxane (POSS) as the core (POSS-g-PDMA) were successfully synthesized by ATRP. The minimum inhibition concentrations (MICs) of the synthesized POSS-g-PDMA are in the range of 10-20 µg/mL. POSS-g-PDMA was further modified by various hydrophilization strategies in attempting to reduce hemolysis. With quaternization of POSS-g-PDMA, the antibacterial activities of the obtained quaternary polymers are almost unchanged and the copolymers become relatively nonhemolytic. We also copolymerized sulfobetaine (SB) with POSS-g-PDMA to obtain random and block PDMA-co-PSB arm structures, where the PDMA and poly(sulfobetaine) were the cationic and zwitterionic blocks, respectively. The random cationic-zwitterionic POSS-g-(PDMA-r-PSB) copolymers showed poor antibacterial activity, while the block POSS-g-(PDMA-b-PSB) copolymers retained the antibacterial and hemolytic activity of the pristine POSS-g-PDMA. Further, the block copolymers of POSS-g-(PDMA-b-PSB) showed enhanced antifouling property and serum stability as seen by their nanoparticle size stability in the presence of serum and reduced red blood cell aggregation; the POSS-g-(PDMA-b-PSB) also somewhat retained its MIC in blood unlike the quaternized or random zwitterionic copolymers. The antibacterial kinetics study showed that Escherichia coli can be killed within 30 min by both random and block copolymers of POSS-g-(PDMA-co-PSB). Finally, our POSS star polymers showed low toxicity to zebrafish embryo and could be potentially used in aquaculture antibacterial applications.

Dendronized Semiconducting Polymer as Photothermal Nanocarrier for Remote Activation of Gene Expression.

Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near-infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nanocarrier not only to efficiently deliver genes but also to spatiotemporally control gene expression in conjunction with heat-inducible promoter. DSP has a high photothermal conversion efficiency (44.2 %) at 808 nm, permitting fast transduction of NIR light into thermal signals for intracellular activation of transcription. Such a DSP-mediated remote activation can rapidly and safely result in 25- and 4.5-fold increases in the expression levels of proteins in living cells and mice, respectively. This study thus provides a promising approach to optically regulate transgene systems for on-demand therapeutic transgene dosing.

Double-Layered Plasmonic-Magnetic Vesicles by Self-Assembly of Janus Amphiphilic Gold-Iron(II,III) Oxide Nanoparticles.

Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3 O4 NPs grafted with polymer brushes of different hydrophilicity on Au and Fe3 O4 surfaces separately. Like liposomes, the vesicle shell is composed of two layers of Au-Fe3 O4 NPs in opposite direction, and the orientation of Au or Fe3 O4 in the shell can be well controlled by exploiting the amphiphilic property of the two types of polymers.

Robust Nanoparticle-DNA Conjugates Based on Mussel-Inspired Polydopamine Coating for Cell Imaging and Tailored Self-Assembly.

We have demonstrated that mussel-inspired polydopamine can serve as an intermediate coating layer for covalently attaching oligonucleotides on nanostructures of diverse chemical nature, which are made possible by the universal adhesion and spontaneous reactivity of polydopamine. Our results have shown that polydopamine can strongly bond to representative nanoparticles (i.e., Au nanoparticles and magnetic polymer nanobeads) and form a thin layer of coating that allows for attachment of commercially available DNA with thiol or amine end functionality. The resulting DNA-nanoparticle conjugates not only show excellent chemical and thermal stability and high loading density of DNA, but the linked DNA also maintain their biological functions in directing cancer cell targeting and undergo DNA hybridization to form multifunctional magnetic core-plasmonic satellite assemblies. The generally applicable strategy opens new opportunities for easy adoption of DNA-nanoparticle conjugates for broad applications in biosensors and nanomedicine.

SERS-encoded nanogapped plasmonic nanoparticles: growth of metallic nanoshell by templating redox-active polymer brushes.

We report a new strategy to synthesize core-shell metal nanoparticles with an interior, Raman tag-encoded nanogap by taking advantage of nanoparticle-templated self-assembly of amphiphilic block copolymers and localized metal precursor reduction by redox-active polymer brushes. Of particular interest for surface-enhanced Raman scattering (SERS) is that the nanogap size can be tailored flexibly, with the sub-2 nm nanogap leading to the highest SERS enhancement. Our results have further demonstrated that surface functionalization of the nanogapped Au nanoparticles with aptamer targeting ligands allows for specific recognition and ultrasensitive detection of cancer cells. The general applicability of this new synthetic strategy, coupled with recent advances in controlled wet-chemical synthesis of functional nanocrystals, opens new avenues to multifunctional core-shell nanoparticles with integrated optical, electronic, and magnetic properties.

Plasmonic vesicles of amphiphilic gold nanocrystals: self-assembly and external-stimuli-triggered destruction.

We have developed a new class of plasmonic vesicular nanostructures assembled from amphiphilic gold nanocrystals with mixed polymer brush coatings. One major finding is that the integration of gold nanocrystals (nanoparticles and nanorods) with two types of chemically distinct polymer grafts, which are analogous to block copolymers as a whole, creates a new type of hybrid building block inheriting the amphiphilicity-driven self-assembly of block copolymers to form vesicular structures and the plasmonic properties of the nanocrystals. In contrast to other vesicular structures, the disruption of the plasmonic vesicles can be triggered by stimulus mechanisms inherent to either the polymer or the nanocrystal. Recent advances in nanocrystal synthesis and controlled surface-initiated polymerization have opened a wealth of possibilities for expanding this concept to other types of nanocrystals and integrating different types of nanocrystals into multifunctional vesicles. The development of multifunctional vesicles containing stimuli-responsive polymers could enable their broader applications in biosensing, multimodality imaging, and theragnostic nanomedicine.

Janus Nanoparticles: From Fabrication to (Bio)Applications.

Janus nanoparticles (JNPs) refer to the integration of two or more chemically discrepant composites into one structure system. Studies into JNPs have been of significant interest due to their interesting characteristics stemming from their asymmetric structures, which can integrate different functional properties and perform more synergetic functions simultaneously. Herein, we present recent progress of Janus particles, comprehensively detailing fabrication strategies and applications. First, the classification of JNPs is divided into three blocks, consisting of polymeric composites, inorganic composites, and hybrid polymeric/inorganic JNPs composites. Then, the fabrication strategies are alternately summarized, examining self-assembly strategy, phase separation strategy, seed-mediated polymerization, microfluidic preparation strategy, nucleation growth methods, and masking methods. Finally, various intriguing applications of JNPs are presented, including solid surfactants agents, micro/nanomotors, and biomedical applications such as biosensing, controlled drug delivery, bioimaging, cancer therapy, and combined theranostics. Furthermore, challenges and future works in this field are provided.

A Self-Assembled Plasmonic Substrate for Enhanced Fluorescence Resonance Energy Transfer.

Fluorescence resonance energy transfer (FRET) has found widespread uses in biosensing, molecular imaging, and light harvesting. Plasmonic metal nanostructures offer the possibility of engineering photonic environment of specific fluorophores to enhance the FRET efficiency. However, the potential of plasmonic nanostructures to enable tailored FRET enhancement on planar substrates remains largely unrealized, which are of considerable interest for high-performance on-surface bioassays and photovoltaics. The main challenge lies in the necessitated concurrent control over the spectral properties of plasmonic substrates to match that of fluorophores and the fluorophore-substrate spacing. Here, a self-assembled plasmonic substrate based on polydopamine (PDA)-coated plasmonic nanocrystals is developed to effectively address this challenge. The PDA coating not only drives interfacial self-assembly of the nanocrystals to form closely packed arrays with customized optical properties, but also can serve as a tailored nanoscale spacer between the fluorophores and plasmonic nanocrystals, which collectively lead to optimized fluorescence enhancement. The biocompatible plasmonic substrate that allows convenient bioconjugation imparted by PDA has afforded improved FRET efficiency in DNA microarray assay and FRET imaging of live cells. It is envisioned that the self-assembled plasmonic substrates can be readily integrated into fluorescence-based platforms for diverse biomedical and photoconversion applications.

Transformable hybrid semiconducting polymer nanozyme for second near-infrared photothermal ferrotherapy.

Despite its growing promise in cancer treatment, ferrotherapy has low therapeutic efficacy due to compromised Fenton catalytic efficiency in tumor milieu. We herein report a hybrid semiconducting nanozyme (HSN) with high photothermal conversion efficiency for photoacoustic (PA) imaging-guided second near-infrared photothermal ferrotherapy. HSN comprises an amphiphilic semiconducting polymer as photothermal converter, PA emitter and iron-chelating Fenton catalyst. Upon photoirradiation, HSN generates heat not only to induce cytotoxicity but also to enhance Fenton reaction. The increased ·OH generation promotes both ferroptosis and apoptosis, oxidizes HSN (42 nm) and transforms it into tiny segments (1.7 nm) with elevated intratumoral permeability. The non-invasive seamless synergism leads to amplified therapeutic effects including a deep ablation depth (9 mm), reduced expression of metastasis-related proteins and inhibition of metastasis from primary tumor to distant organs. Thereby, our study provides a generalized nanozyme strategy to compensate both ferrotherapy and phototherapeutics for complete tumor regression.

Mesoporous polydopamine with built-in plasmonic core: Traceable and NIR triggered delivery of functional proteins.

Functional proteins are essential for the regulation of cellular behaviors and have found growing therapeutic uses. However, low bioavailability of active proteins to their intracellular targets has been a long-standing challenge to achieve their full potential for cell reprogramming and disease treatment. Here we report mesoporous polydopamine (mPDA) with a built-in plasmonic nanoparticle core as a multifunctional protein delivery system. The mPDA with a unique combination of large surface area, metal-chelating property, and broad-spectrum photothermal transduction allows efficient loading and near-infrared light-triggered release of functional proteins, while the plasmonic core serves as a photostable tracer and fluorescence quencher, collectively leading to real-time monitoring and active cytosolic release of model proteins. In particular, controlled delivery of cytotoxic ribonuclease A has shown excellent performance in invivo cancer therapy. The possibility of coating mPDA on a broad range of functional cores, thanks to its universal adhesion, provides opportunities for developing tailored delivery carriers of biologics to overcome intrinsic biological barriers.

Polydopamine-mediated synthesis of core-shell gold@calcium phosphate nanoparticles for enzyme immobilization.

Considerable efforts have been made to develop reliable immobilization approaches to improve enzyme stability and reusability. However, relatively complicated preparation often leads to compromised enzyme activity. This study reports a facile method of retaining full enzymatic activity by immobilizing glucose oxidase (GOx) into core-shell nanoparticles with polydopamine (PDA) sandwiched between a gold nanoparticle (Au NP) core and a calcium phosphate (CaP) shell (Au@PDA@CaP). The strong adhesion of PDA on Au NPs and its metal chelating properties directed the preferential growth of the CaP shell on the Au NPs, leading to well-dispersed and uniform nanohybrids. Concurrent loading of GOx during the growth of CaP held the key to the successful immobilization of GOx. As a result, Au@PDA@CaP-immobilized GOx had similar activity but better resistance against heating, long-term storage and repeated uses compared to free GOx. This work provides a green strategy for constructing nanobiocatalysts with high enzyme activity and stability.

Lateral Flow Immunoassay Based on Polydopamine-Coated Gold Nanoparticles for the Sensitive Detection of Zearalenone in Maize.

In this work, polydopamine-coated gold nanoparticles (Au@PDAs) were synthesized by the oxidative self-polymerization of dopamine (DA) on the surface of AuNPs and applied for the first time as a signal-amplification label in lateral flow immunoassays (LFIAs) for the sensitive detection of zearalenone (ZEN) in maize. The PDA layer functioned as a linker between AuNPs and anti-ZEN monoclonal antibody (mAb) to form a probe (Au@PDA-mAb). Compared with AuNPs, Au@PDA had excellent color intensity, colloidal stability, and mAb coupling efficiency. The limit of detection of the Au@PDA-based LFIA (Au@PDA-LFIA) was 7.4 pg/mL, which was 10-fold lower than that of the traditional AuNP-based LFIA (AuNP-LFIA) (76.1 pg/mL). The recoveries of Au@PDA-LFIA were 93.80-111.82%, with the coefficient of variation of 1.08-9.04%. In addition, the reliability of Au@PDA-LFIA was further confirmed by the high-performance liquid chromatography method. Overall, our study showed that PDA coating can chemically modify the surface of AuNPs through a simple method and can thus significantly improve the detection sensitivity of LFIA.

Bioconjugated quantum dots for in vivo molecular and cellular imaging.

Semiconductor quantum dots (QDs) are tiny light-emitting particles on the nanometer scale, and are emerging as a new class of fluorescent labels for biology and medicine. In comparison with organic dyes and fluorescent proteins, they have unique optical and electronic properties, with size-tunable light emission, superior signal brightness, resistance to photobleaching, and broad absorption spectra for simultaneous excitation of multiple fluorescence colors. QDs also provide a versatile nanoscale scaffold for designing multifunctional nanoparticles with both imaging and therapeutic functions. When linked with targeting ligands such as antibodies, peptides or small molecules, QDs can be used to target tumor biomarkers as well as tumor vasculatures with high affinity and specificity. Here we discuss the synthesis and development of state-of-the-art QD probes and their use for molecular and cellular imaging. We also examine key issues for in vivo imaging and therapy, such as nanoparticle biodistribution, pharmacokinetics, and toxicology.

Raman-encoded, multivalent glycan-nanoconjugates for traceable specific binding and killing of bacteria.

Glycan recognition plays key roles in cell-cell and host-pathogen interactions, stimulating widespread interest in developing multivalent glycoconjugates with superior binding affinity for biological and medical uses. Here, we explore the use of Raman-encoded silver coated gold nanorods (GNRs) as scaffolds to form multivalent glycoconjugates. The plasmonic scaffolds afford high-loading of glycan density and their optical properties offer the possibilities of monitoring and quantitative analysis of glycan recognition. Using E. coli strains with tailored on/off of the FimH receptors, we have demonstrated that Raman-encoded GNRs not only allow for real-time imaging and spectroscopic detection of specific binding of the glycan-GNR conjugates with bacteria of interest, but also cause rapid eradication of the bacteria due to the efficient photothermal conversion of GNRs in the near-infrared spectral window. We envision that optically active plasmonic glycoconjugates hold great potential for screening multivalent glycan ligands for therapeutic and diagnostic applications.