Highly Efficient Multifunctional Supramolecular Gene Carrier System Self‐Assembled from Redox‐Sensitive and Zwitterionic Polymer Blocks

It has been a challenge to incorporate multiple features into a single gene carrier system to overcome numerous hurdles during the gene delivery. Herein, a supramolecular approach for building a multifunctional gene carrier system is demonstrated with the functions of disulfide bond based reduction‐responsive degradation and zwitterionic phosphorylcholine based extracellular stabilization and favorable cellular uptake. The gene carrier system is self‐assembled from two molecular building blocks: one host polymer, which is a redox‐sensitive β‐cyclodextrin based cationic star polymer, and one guest polymer, which is adamantyl end capped zwitterionic phosphorylcholine based polymer. The host and guest polymers self‐assemble to integrate multiple functions into one system, based on the host‐guest interaction between β‐cyclodextrin and adamantyl moieties. With the rational designs of both building blocks, the supramolecular gene carrier system possesses excellent protein stability, serum tolerance, cellular uptake and intracellular DNA release properties, and also low cytotoxicity. These features work simultaneously to achieve exceptionally high gene transfection efficiency, which is proven in MCF‐7 cell cultures using luciferase and green fluorescence protein reporter genes. Finally, the supramolecular gene carrier is applied to deliver the therapeutic p53 anti‐cancer gene in MCF‐7 cells, showing great potential for cancer gene therapy application.     

Tumor Intracellular‐Environment Responsive Materials Shielded Nano‐Complexes for Highly Efficient Light‐Triggered Gene Delivery without Cargo Gene Damage

Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochemical internalization (PCI) has provided the opportunity to overcome endo‐lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo‐oxidation of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light‐triggered gene delivery system is demonstrated based on endo‐lysosomal pH‐responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo‐lysosomal pH‐sensitive de‐shielding ability of the pH‐responsive shielding material incorporated in the ternary gene complexes (pH‐TCs), a more significant photo‐triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH‐insensitive material‐shielded nanocarriers cause photo‐oxidation of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light‐triggered gene delivery system using pH‐TCs is applied to deliver the therapeutic p53 gene in melanoma K‐1735 bearing mice, showing excellent therapeutic potential for cancer.     

Structure‐Invertible Nanoparticles for Triggered Co‐Delivery of Nucleic Acids and Hydrophobic Drugs for Combination Cancer Therapy

Here, a new type of structure‐invertible, redox‐responsive polymeric nanoparticle for the efficient co‐delivery of nucleic acids and hydrophobic drugs in vitro and in vivo is reported for the first time, to combat the major challenges facing combination cancer therapy. The co‐delivery vector, which is prepared by conjugating branched poly(ethylene glycol) with dendrimers of two generations (G2) through disulfide linkages, is able to complex nucleic acids and load hydrophobic drugs with high loading capacity through structure inversion. The cleavage of disulfide linkages at intracellular glutathione‐rich reduction environment significantly decreases the cytotoxicity, and promotes more efficient drug release and gene transfection in vitro and in vivo. The co‐delivery carrier also displays enhanced endosomal escape capability and improved serum stability in vitro as compared with G2, and exhibits prolonged residence time and stronger transfection activity in vivo. Most importantly, co‐delivery of doxorubicin (DOX) and B‐cell lymphoma 2 (Bcl‐2) small interfering RNA (siRNA) exerts a combinational effect against tumor growth in murine tumor models in vivo, which is much more effective than either DOX or Bcl‐2 siRNA‐based monotherapy. The structure‐invertible nanoparticles may constitute a promising stimuli‐responsive system for the efficacious co‐delivery of multiple cargoes in future clinical applications of combination cancer therapies.     

pH‐Triggered Pinpointed Cascading Charge‐Conversion and Redox‐Controlled Gene Release Design: Modularized Fabrication for Nonviral Gene Transfection

Although pH and reduction responses are widely applied on gene and drug delivery system, the undefined molecule and disconnected response to corresponding transfection barriers still hamper their further application. Here, a multistage‐responsive lipopeptides polycation‐DNA nanoparticles (namely KR‐DC) as gene vector is designed, consisting of three functional modules. It provides the following outstanding “smart” characteristics: i) facile manufacture and ease to adjust ingredients for different conditions, ii) negatively charged surface to remain stable and increase biocompatibility in physiological environment, iii) pH‐triggered cascading charge‐conversion corresponding to tumor extracellular pH and endo/lysosomal pH, iv) the first stage of charge reversal for uptake enhancement at tumor site, v) the second stage of charge conversion for rapid endosomal escape, vi) the third stage of redox degradation aiming at DNA controlled release and nuclear entry, vii) cell‐penetrating peptides mimicking arginine‐rich periphery targeting to membrane penetration capacity improvement, and viii) lipid forming hydrophobic cavity for potential fat‐soluble drug encapsulation. Finally, KR‐DC nanoparticles achieve significantly enhanced in vitro transfection efficiency by almost four orders of magnitude in manual tumor environment with reduced side effects and satisfying gene expression in Hela xenograft tumor model in vivo.     

Light‐Triggered Self‐Assembly of a Spiropyran‐Functionalized Dendron into Nano‐/Micrometer‐Sized Particles and Photoresponsive Organogel with Switchable Fluorescence

The synthesis, self‐assembly, and spectroscopic investigations of spiropyran (SP)‐functionalized dendron 1 are reported. Under UV light irradiation, assembly of 1 into nano‐/microparticles occurs due to the transformation of the closed form of SP into the open merocyanine (MC) form. The formation of these nano‐/microparticles is confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) experiments in addition to the confocal laser scanning microscopy (CLSM) measurements. These nano‐/microparticles exhibit relatively strong red emission. It is interesting to note that the direct cooling of the toluene/benzene solution of 1 to 0 °C leads to gel formation. Multivalent π–π interactions due to the dendron in 1 may be the driving‐force for the gelation. The UV light irradiation cannot destroy the gel phase, and in fact, the gel–gel transition is successfully realized. The purple‐blue gel exhibits relatively strong red fluorescence; moreover, the fluorescence can be reversibly switched by alternating UV and visible light irradiation. The results clearly indicate that the MC form after aggregation becomes more stable and fluorescent.     

Entanglement of Conjugated Polymer Chains Influences Molecular Self‐Assembly and Carrier Transport

The influence of polymer entanglement on the self‐assembly, molecular packing structure, and microstructure of low‐M_w (lightly entangled) and high‐M_w (highly entangled) poly (3‐hexylthiophene) (P3HT), and the carrier transport in thin‐film transistors, are investigated. The polymer chains are gradually disentangled in a marginal solvent via ultrasonication of the polymer solution, and demonstrate improved diffusivity of precursor species (coils, aggregates, and microcrystallites), enhanced nucleation and crystallization of P3HT in solution, and self‐assembly of well‐ordered and highly textured fibrils at the solid–liquid interface. In low‐M_w P3HT, reducing chain entanglement enhances interchain and intrachain ordering, but reduces the interconnectivity of ordered domains (tie molecules) due to the presence of short chains, thus deteriorating carrier transport even in the face of improving crystallinity. Reducing chain entanglement in high‐M_w P3HT solutions increases carrier mobility up to ≈20‐fold, by enhancing interchain and intrachain ordering while maintaining a sufficiently large number of tie molecules between ordered domains. These results indicate that charge carrier mobility is strongly governed by the balancing of intrachain and interchain ordering, on the one hand, and interconnectivity of ordered domains, on the other hand. In high‐M_w P3HT, intrachain and interchain ordering appear to be the key bottlenecks to charge transport, whereas in low‐M_w P3HT, the limited interconnectivity of the ordered domains acts as the primary bottleneck to charge transport.     

Tumor‐Microenvironment‐Activated In Situ Self‐Assembly of Sequentially Responsive Biopolymer for Targeted Photodynamic Therapy

A sequentially responsive photosensitizer‐integrated biopolymer is developed for tumor‐specific photodynamic therapy, which is capable of forming long‐retained aggregates in situ inside tumor tissues. Specifically, the photosensitizer zinc phthalocyanine (ZnPc) is conjugated with polyethylene glycol (PEG) via pH‐labile maleic acid amide linker and then immobilized onto the hyaluronic acid (HA) chain using a redox‐cleavable disulfide linker. The PEG segment can enhance blood circulation of the molecular carrier after intravenous administration and be shed after reaching the acidic tumor microenvironment, allowing the remaining fragment to self‐assemble into large clusters in situ to avoid backward diffusion and improve tumor retention. This process is driven by hydrophobic interactions and does not require additional external actuation. The aggregates are then internalized by the tumor cells via HA‐facilitated endocytosis, and the high glutathione level in tumor cells eventually leads to the intracellular release of ZnPc to facilitate its interaction with the subcellular lipid structures. This tumor‐triggered morphology‐based delivery platform is constructed with clinically tested components and could potentially be applied to other hydrophobic therapeutics.     

Chondroitin Sulfate‐Coated DNA‐Nanoplexes Enhance Transfection Efficiency by Controlling Plasmid Release from Endosomes: A New Insight into Modulating Nonviral Gene Transfection

Degradation of plasmid DNA (pDNA) in the endosome compartment and its release to the cytosol are the major hurdles for efficient gene transfection. This is generally addressed by using transfection reagents that can overcome these limitations. In this article, the first report is presented which suggests that controlling the release of pDNA from endosome is the key for achieving efficient transfection. In this study, chondroitin sulfate (CS)‐coated DNA‐nanoplexes are developed using a modular approach where CS is coated post‐pDNA/PEI nanoplex formation. To ensure good stability of the nanoplexes, imine/enamine chemistry is exploited by reacting aldehyde‐modified chondroitin sulfate (CS‐CHO) with free amines of pDNA/PEI complex. This supramolecular nanocarrier system displays efficient cellular uptake, and controlled endosomal pDNA release without eliciting any cytotoxicity. On the contrary, burst release of pDNA from endosome (using chloroqine) results in significant reduction in gene expression. Unlike pDNA/PEI‐based transfection, the nanoparticle design presented here shows exceptional stability and gene transfection efficiency in different cell lines such as human colorectal cancer cells (HCT116), human embryonic kidney cells (HEK293), and mouse skin‐derived mesenchymal stem cells (MSCs) using luciferase protein as a reporter gene. This new insight will be valuable in designing next generation of transfection reagents.     

Hierarchical Self‐Assembly of Peptide‐Coated Carbon Nanotubes

Numerous applications, from molecular electronics to super‐strong composites, have been suggested for carbon nanotubes. Despite this promise, difficulty in assembling raw carbon nanotubes into functional structures is a deterrent for applications. In contrast, biological materials have evolved to self‐assemble, and the lessons of their self‐assembly can be applied to synthetic materials such as carbon nanotubes. Here we show that single‐walled carbon nanotubes, coated with a designed amphiphilic peptide, can be assembled into ordered hierarchical structures. This novel methodology offers a new route for controlling the physical properties of nanotube systems at all length scales from the nano‐ to the macroscale. Moreover, this technique is not limited to assembling carbon nanotubes, and could be modified to serve as a general procedure for controllably assembling other nanostructures into functional materials.     

Self‐Assembly Mechanism of Spiky Magnetoplasmonic Supraparticles

Concave nanoparticles (NPs) with complex angled and non‐Platonic geometries have unique optical, magnetic, catalytic, and biological properties originating from the singularities of the electrical field in apexes and craters. Preparation of such particles with a uniform size/shape and core–shell morphology represents a significant challenge, largely because of the poor knowledge of their formation mechanism. Here, this challenge is addressed and a study of the mechanism of their formation is presented for a case of complex spiky morphologies that led us to the conclusion that NPs with concave geometries can be, in fact, supraparticles (SPs) produced via the self‐assembly of smaller convex integrants. This mechanism is exemplified by the vivid case of spiky SPs formed via the attachment of small and faceted Au NPs on smooth Au‐coated iron oxide (Fe₃O₄@Au) seeds. The theoretical calculations of energies of primary interactions—electrostatic repulsion and van‐der Waals repulsion, elaborated for this complex case—confirm experimental observation and the self‐limiting mechanism of SP formation. Besides demonstrating the mechanistic aspects of synthesis of NPs with complex geometries, this work also uncovers a facile approach for preparation of concave magnetoplasmonic particles. When combined with a spiky geometry, such bi‐functional magnetoplasmonic SPs can serve as a unique platform for optoelectronic devices and biomedical applications.     

Kirigami‐Inspired Self‐Assembly of 3D Structures

Self‐assembly of 3D structures presents an attractive and scalable route to realize reconfigurable and functionally capable mesoscale devices without human intervention. A common approach for achieving this is to utilize stimuli‐responsive folding of hinged structures, which requires the integration of different materials and/or geometric arrangements along the hinges. It is demonstrated that the inclusion of Kirigami cuts in planar, hingeless bilayer thin sheets can be used to produce complex 3D shapes in an on‐demand manner. Nonlinear finite element models are developed to elucidate the mechanics of shape morphing in bilayer thin sheets and verify the predictions through swelling experiments of planar, millimeter‐scaled PDMS (polydimethylsiloxane) bilayers in organic solvents. Building upon the mechanistic understandings, The transformation of Kirigami‐cut simple bilayers into 3D shapes such as letters from the Roman alphabet (to make “ADVANCED FUNCTIONAL MATERIALS”) and open/closed polyhedral architectures is experimentally demonstrated. A possible application of the bilayers as tether‐less optical metamaterials with dynamically tunable light transmission and reflection behaviors is also shown. As the proposed mechanistic design principles could be applied to a variety of materials, this research broadly contributes toward the development of smart, tetherless, and reconfigurable multifunctional systems.     

Highly Improved Rate Capability for a Lithium‐Ion Battery Nano‐Li4Ti5O12 Negative Electrode via Carbon‐Coated Mesoporous Uniform Pores with a Simple Self‐Assembly Method

A mesostructured spinel Li₄Ti₅O₁₂ (LTO)‐carbon nanocomposite (denoted as Meso‐LTO‐C) with large (>15 nm) and uniform pores is simply synthesized via block copolymer self‐assembly. Exceptionally high rate capability is then demonstrated for Li‐ion battery (LIB) negative electrodes. Polyisoprene‐block‐poly(ethylene oxide) (PI‐b‐PEO) with a sp²‐hybridized carbon‐containing hydrophobic block is employed as a structure‐directing agent. Then the assembled composite material is crystallized at 700 °C enabling conversion to the spinel LTO structure without loss of structural integrity. Part of the PI is converted to a conductive carbon that coats the pores of the Meso‐LTO‐C. The in situ pyrolyzed carbon not only maintains the porous mesostructure as the LTO is crystallized, but also improves the electronic conductivity. A Meso‐LTO‐C/Li cell then cycles stably at 10 C‐rate, corresponding to only 6 min for complete charge and discharge, with a reversible capacity of 115 mA h g^?1 with 90% capacity retention after 500 cycles. In sharp contrast, a Bulk‐LTO/Li cell exhibits only 69 mA h g^?1 at 10 C‐rate. Electrochemical impedance spectroscopy (EIS) with symmetric LTO/LTO cells prepared from Bulk‐LTO and Meso‐LTO‐C cycled in different potential ranges reveals the factors contributing to the vast difference between the rate‐capabilities. The carbon‐coated mesoporous structure enables highly improved electronic conductivity and significantly reduced charge transfer resistance, and a much smaller overall resistance is observed compared to Bulk‐LTO. Also, the solid electrolyte interphase (SEI)‐free surface due to the limited voltage window (>1 V versus Li/Li⁺) contributes to dramatically reduced resistance.     

Development of Degradable,pH‐Sensitive Star Vectors for Enhancing the Cytoplasmic Delivery of Nucleic Acids

The report describes the synthesis of degradable, pH‐sensitive, membrane‐destabilizing, star‐shaped polymers where copolymers of hydrophobic hexyl methacrylate (HMA) and 2‐(dimethylamino)ethyl methacrylate (DMAEMA) monomers are grafted from the secondary face of a beta‐cyclodextrin (β‐CD) core via acid‐labile hydrazone linkages using atom transfer radical polymerization. The effect of the graft's molecular weight, HMA/DMAEMA molar ratio, and the fraction of DMAEMA converted to cationic N,N,N‐trimethylaminoethyl methacrylate (TMAEMA) monomers on polymer's transfection capacity is systematically investigated. Results show that all star‐shaped polymers condense anti‐GAPDH silencing RNA (siRNA) into nanosized particles at +/‐ ratio ≤ 4:1. Star polymers with shorter (25kDa) P(HMA‐co‐DMAEMA‐co‐TMAEMA) grafts are more efficient and less cytotoxic than carriers with longer (40kDa) grafts. The results show that increasing the ratio of hydrophobic HMA monomers in graft's composition higher than 50 mole% dramatically reduces polymer's aqueous solubility and abolishes their transfection capacity. Further, retention of DMAEMA monomers in graft's composition provide a buffering capacity that enhanced the endosomal escape and transfection capacity of the polymers. These systematic studies show that β‐CD‐P(HMA‐co‐DMAEMA‐co‐TMAEMA)_4.8 polymer with a 25 kDa average graft's molecular weight and a 50/25/25 ratio of HMA/DMAEMA/TMAEMA monomers is the most efficient carrier in delivering the siRNA cargo into the cytoplasm of epithelial cancer cells.     

Molecular Mimetic Self‐Assembly of Colloidal Particles

This article presents an overview of the current progress in molecular mimetic self‐assembly of colloidal particles. Firstly, the recent study of colloidal particles at interfaces is highlighted, underlining the mesoscopic mimicry of the surface activity of amphiphilic molecules using colloidal particles. Secondly, various strategies developed thus far to impart colloidal particles with anisotropy in terms of chemical composition, surface chemistry and particle morphology, which are regarded as mesoscopic atoms and molecules, are reviewed. Thirdly, an overview of the current theoretical and experimental results of using the rules of molecular synthesis and self‐assembly to direct self‐assembly of colloidal particles is presented. Finally, the experimental challenges associated with molecular mimetic self‐assembly of colloidal particles are outlined, giving a rather conservative conclusion of the status quo of this new research field with a very optimistic outlook.     

Self‐Assembling Peptide as a Potential Carrier for Hydrophobic Anticancer Drug Ellipticine: Complexation,Release and In Vitro Delivery

The self‐assembling peptide EAK16‐II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide‐ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5 h. With different combinations of EAK16‐II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide‐ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF‐7. This work forms the basis for studies of the peptide‐ellipticine suspensions in vitro and in vivo leading to future development of self‐assembling peptide‐based delivery of hydrophobic anticancer drugs.     

Long Minority‐Carrier Diffusion Length and Low Surface‐Recombination Velocity in Inorganic Lead‐Free CsSnI3 Perovskite Crystal for Solar Cells

Sn‐based perovskites are promising Pb‐free photovoltaic materials with an ideal 1.3 eV bandgap. However, to date, Sn‐based thin film perovskite solar cells have yielded relatively low power conversion efficiencies (PCEs). This is traced to their poor photophysical properties (i.e., short diffusion lengths (<30 nm) and two orders of magnitude higher defect densities) than Pb‐based systems. Herein, it is revealed that melt‐synthesized cesium tin iodide (CsSnI₃) ingots containing high‐quality large single crystal (SC) grains transcend these fundamental limitations. Through detailed optical spectroscopy, their inherently superior properties are uncovered, with bulk carrier lifetimes reaching 6.6 ns, doping concentrations of around 4.5 × 10¹⁷ cm^?3, and minority‐carrier diffusion lengths approaching 1 µm, as compared to their polycrystalline counterparts having ≈54 ps, ≈9.2 × 10¹⁸ cm^?3, and ≈16 nm, respectively. CsSnI₃ SCs also exhibit very low surface recombination velocity of ≈2 × 10³ cm s^?1, similar to Pb‐based perovskites. Importantly, these key parameters are comparable to high‐performance p‐type photovoltaic materials (e.g., InP crystals). The findings predict a PCE of ≈23% for optimized CsSnI₃ SCs solar cells, highlighting their great potential.     

Site‐Selective Self‐Assembly of Colloidal Photonic Crystals

A scalable method for site‐selective, directed self‐assembly of colloidal opals on topologically patterned substrates is presented. Here, such substrate contains optical waveguides which couple to the colloidal crystal. The site‐selectivity is achieved by a capillary network, whereas the self‐assembly process is based on controlled solvent evaporation. In the deposition process, a suspension of colloidal microspheres is dispensed on the substrate and driven into the desired crystallization sites by capillary flow. The method has been applied to realize colloidal crystals from monodisperse dielectric spheres with diameters ranging from 290 to 890 nm. The method can be implemented in an industrial wafer‐scale process.     

Non‐Covalent Functionalization of Graphene Using Self‐Assembly of Alkane‐Amines

A simple, versatile method for non‐covalent functionalization of graphene based on solution‐phase assembly of alkane‐amine layers is presented. Second‐order Møller–Plesset (MP2) perturbation theory on a cluster model (methylamine on pyrene) yields a binding energy of ≈220 meV for the amine–graphene interaction, which is strong enough to enable formation of a stable aminodecane layer at room temperature. Atomistic molecular dynamics simulations on an assembly of 1‐aminodecane molecules indicate that a self‐assembled monolayer can form, with the alkane chains oriented perpendicular to the graphene basal plane. The calculated monolayer height (≈1.7 nm) is in good agreement with atomic force microscopy data acquired for graphene functionalized with 1‐aminodecane, which yield a continuous layer with mean thickness ≈1.7 nm, albeit with some island defects. Raman data also confirm that self‐assembly of alkane‐amines is a non‐covalent process, i.e., it does not perturb the sp² hybridization of the graphene. Passivation and adsorbate n‐doping of graphene field‐effect devices using 1‐aminodecane, as well as high‐density binding of plasmonic metal nanoparticles and seeded atomic layer deposition of inorganic dielectrics using 1,10‐diaminodecane are also reported.