Easy Access to Diverse Multiblock Copolymers with On-Demand Blocks via Thioester-Relayed In-Chain Cascade Copolymerization.

Multiblock copolymers are envisioned as promising materials with enhanced properties and functionality compared with their diblock/triblock counterparts. However, the current approaches can construct multiblock copolymers with a limited number of blocks but tedious procedures. Here, we report a thioester-relayed in-chain cascade copolymerization strategy for the easy preparation of multiblock copolymers with on-demand blocks, in which thioester groups with on-demand numbers are built in the polymer backbone by controlled/living polymerizations. These thioester groups further serve as the in-chain initiating centers to trigger the acyl group transfer ring-opening polymerization of episulfides independently and concurrently to extend the polymer backbone into multiblock structures. The compositions, number of blocks, and block degree of polymerization can be easily regulated. This strategy can offer easy access to a library of multiblock copolymers with ≈100 blocks in only 2 to 4 steps.

Synthesis of Poly(thioester sulfonamide)s via the Ring-Opening Copolymerization of Cyclic Thioanhydride with N-Sulfonyl Aziridine Using Mild Phosphazene Base.

Providing access to diverse polymer structures is highly desirable, which helps to explore new polymer materials. Poly(thioester sulfonamide)s, combining both the advantages of thioesters and amides, however, are rarely available in polymer chemistry. Here, the ring-opening copolymerization (ROCOP) of cyclic thioanhydride with N-sulfonyl aziridine using mild phosphazene base, resulting in well-defined poly(thioester sulfonamide)s with highly alternative structures, high yields, and controlled molecular weights, is reported. Additionally, benefiting from the mild catalytic process, this ROCOP can be combined with ROCOP of N-sulfonyl aziridines with cyclic anhydrides to produce novel block copolymers.

Modulating Local Charge Distribution of Carbon Nitride for Promoting Exciton Dissociation and Charge-Induced Reactions.

The sustainable light can generate reduction and oxidation centers in situ through the generation of photoexcited electrons and holes in the presence of photocatalyst. However, the photoexcited electrons and holes have huge Coulombic attraction and high exciton binding energy due to the weak screening effect and dielectric properties in many low-dimensional conjugated polymers, such as carbon nitride. Reducing the exciton binding energy of carbon nitride and promoting the conversion of excitons into free charge carriers are necessary for improving the activity of photocatalytic reactions but still very challenging. Here, by introducing amino-cyano functional groups into carbon nitride, it is demonstrated that excitons can be effectively dissociated into electrons and holes by finely controlling the charge distribution of heptazine ring. It is found that carbon nitride with heptazine rings of positive charge distribution can greatly reduce the exciton binding energy to 24 from 71 meV. Compared with heptazine ring having negative charge distribution, heptazine ring with positive charge distribution can increase photocatalytic hydrogen production of carbon nitride by up to ten times. This work provides an easy way to promote the dissociation of excitons in carbon nitride by regulating the charge distribution.

Silica Aerogels with Self-Reinforced Microstructure for Bioinspired Hydrogels.

Aerogel is a kind of high-performance lightweight open-porous solids with ultralow density, high specific surface area, and broad application in many emerging fields including biotechnology, energy, environment, aerospace, etc. A giant challenge remains in preventing of the hydrophilic aerogel framework shrinkage when replacing of solvent with air in its extremely abundant nanosized pores during its fabrication process in ambient conditions. In this work, started from a linear polymeric precursor with further condensation reaction, superhydrophilic silica aerogels with self-reinforced microstructure and the least volume shrinkage have been successfully obtained via ambient pressure drying process without use of any additives in the presence of a low surface tension solvent. The resulting superhydrophilic silica aerogels possess specific surface area up to 1065 m2/g, pore volume up to 2.17 cm3/g and density down to 84 mg/cm3, and these values are comparable to those of their counterparts obtained by supercritical CO2 drying process. Moreover, as an application demonstration, the bioinspired hydrogels with desirable mechanical flexibility and adhesive performance at extremely harsh environment (e.g., below -50 °C) have been successfully synthesized by mimicking carrier of a functional bioagent with the resulting superhydrophilic silica aerogel microparticles. Our work has made a significant step forward for future high-performance hydrophilic aerogels with self-enhanced microstructures and the resulting superhydrophilic aerogels have shown great potentials in making functional hydrogels with bionic properties.

Expanding the Conjugate Structure of Polymeric Carbon Nitride for Enhanced Light Absorption and Photothermal Conversion.

The development of efficient and inexpensive materials for light energy conversion is very important for achieving sustainable energy supply and carbon neutrality. Polymeric carbon nitride has become a promising material for light energy conversion due to its advantages of simple preparation and high physical and chemical stability. However, the pristine polymeric carbon nitride only absorbs light with a wavelength of less than 450 nm, and the energy conversion for low-energy photons is very limited. Here, by introducing the pyromellitic dianhydride component to construct an in-plane heterostructure, the conjugated structure of polymeric carbon nitride is successfully expanded. This in-plane carbon nitride-carbon nanoribbon (C3 N4 -C) heterostructure has an ultrawide absorption range from 200 to 2000 nm. Compared with the original material, the photothermal conversion performance of C3 N4 -C is significantly improved under the irradiation of Xe lamp or infrared laser. Furthermore, C3 N4 -C exhibits good potential for synergistic photothermal and chemotherapy. This work provides a simple strategy to construct expanded conjugate structure for improved light absorption and energy conversion materials based on polymeric carbon nitride.

Facile Multicomponent Polymerization and Postpolymerization Modification via an Effective Meldrum's Acid-Based Three-Component Reaction.

Providing access to highly diverse polymer structures by multicomponent reactions is highly desirable; efficient Meldrum's acid-based multicomponent reactions, however, have been rarely highlighted in polymer chemistry. Here, the three-component reaction of Meldrum's acid, indole, and aldehyde is introduced into polymer synthesis. Direct multicomponent polymerization of Meldrum's acid, dialdehyde, and diindole can perform under mild conditions, resulting in complex Meldrum's acid-containing polymers with well-defined structures, and high molecular weights. Additionally, nearly quantitative postpolymerization modification can also perform via this Meldrum's acid-based multicomponent reaction. These results indicate that Meldrum's acid-based multicomponent reaction will be a potential tool to prepare novel polymers.

Polymerization-Induced Self-Assembly to Produce Prodrug Nanoparticles with Reduction-Responsive Camptothecin Release and pH-Responsive Charge-Reversible Property.

Polymerization-induced self-assembly has been demonstrated to be a powerful strategy for fabricating polymeric nanoparticles in the last two decades. However, the stringent requirements for the monomers greatly limit the chemical versatility of PISA-based functional nanoparticles and expanding the monomer family of PISA is still highly desirable. Herein, a camptothecin analogue (CPTM) is first used as the monomer in PISA. Prodrug nanoparticles with reduction-responsive camptothecin release behavior are fabricated at 10% solid concentration (100 mg g-1 ). Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) and poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) are used as the macro RAFT agents to comediate the RAFT dispersion polymerization of CPTM in ethanol to produce the PHPMA/PDEAEMA-stabilized nanoparticles. The PDEAEMA chains become hydrophobic and are in the collapsed state at physiological pH values. In contrast, in the vicinity of an acidic tumor, the tertiary amine groups of PDEAEMA chains are rapidly protonated, leading to fast hydrophobic-hydrophilic transitions and charge reversal. Such fast charge-reversal results in enhanced cancer cell internalization of the prodrug nanoparticles, thus achieving superior anticancer efficacy.

Cationic micelle: A promising nanocarrier for gene delivery with high transfection efficiency.

Micelles have demonstrated an excellent ability to deliver several different types of therapeutic agents, including chemotherapy drugs, proteins, small-interfering RNA and DNA, into tumor cells. Cationic micelles, comprising self-assemblies of amphiphilic cationic polymers, have exhibited tremendous promise with respect to the delivery of therapy genes and gene transfection. To date, research in the field has focused on achieving an enhanced stability of the micellar assembly, prolonged circulation times and controlled release of the gene. This review focuses on the micelles as a nanosized carrier system for gene delivery, the system-related modifications for cytoplasm release, stability and biocompatibility, and clinic trials. In accordance with the development of synthetic chemistry and self-assembly technology, the structures and functionalities of micelles can be precisely controlled, and hence the synthetic micelles not only efficiently condense DNA, but also facilitate DNA endocytosis, endosomal escape, DNA uptake and nuclear transport, resulting in a comparable gene transfection of virus.

Interactions in DNA Condensation: An Important Factor for Improving the Efficacy of Gene Transfection.

The rapid developments of gene therapy are benefit from the construction of efficient gene vectors, which help therapy genes efficiently overcome the barriers in the transport and transfection. Condensing DNA into nanoparticles is a crucial role in gene transfection, and the electrostatic interactions of synthetic cationic liposomes and cationic polymers with DNA are generally used for condensing DNA. Recent research has shown that the introduction of the hydrophobic interaction, hydrogen bonding, and coordinative interactions to the gene delivery vectors is also very important for DNA condensation, delivery, and transfection. This review focuses on the four types of interactions in condensed DNA nanoparticles, which could provide a new perspective for improving gene transfection efficacy.

Multicomponent Reactions and Multicomponent Cascade Reactions for the Synthesis of Sequence-Controlled Polymers.

Control over the monomer sequence during polymerization has attracted great attention in polymer science, but it remains a serious challenge. Recently, multicomponent reactions have been playing a significant role in the synthesis of sequence-controlled polymers due to their inherent advantage of combining three or more starting materials in time-saving, one-pot operations to afford complex microstructures. In this feature article, the recent representative developments in the synthesis of sequence-controlled polymers by multicomponent reactions are highlighted to give insight on the design of novel sequence-controlled polymers with sufficient molecular diversity and complexity. The main part of this article is divided into three sections according to the different polymerization strategies using multicomponent reactions: direct multicomponent polymerization, multicomponent cascade polymerization, and iterative multicomponent reaction, respectively. It is anticipated that this feature article may provide some guidance for the fabrication of sequence-controlled polymers by multicomponent reactions.

High DNA-Binding Affinity and Gene-Transfection Efficacy of Bioreducible Cationic Nanomicelles with a Fluorinated Core.

During the last two decades, cationic polymers have become one of the most promising synthetic vectors for gene transfection. However, the weak interactions formed between DNA and cationic polymers result in low transfection efficacy. Furthermore, the polyplexes formed between cationic polymers and DNA generally exhibit poor stability and toxicity because of the large excess of cationic polymer typically required for complete DNA condensation. Herein, we report the preparation of a novel class of bioreducible cationic nanomicelles by the use of disulfide bonds to connect the cationic shell to the fluorocarbon core. These bioreducible nanomicelles form strong interactions with DNA and completely condense DNA at an N/P ratio of 1. The resulting nanomicelle/DNA polyplexes exhibited high biocompatibility and performed very effectively as a gene-delivery system.

Effect of Topological Structures on the Self-Assembly Behavior of Supramolecular Amphiphiles.

Three types of azobenzene-based telechelic guest polymers, PEG-azo, azo-PEG-azo, and PEG-azo4, were synthesized by a facile method. Subsequently, a series supramolecular amphiphiles with three distinct topological structures (hemitelechelic, ditelechelic, and quadritelechelic) were constructed through coupling with host polymer ß-cyclodextrin-poly(l-lactide) (ß-CD-PLLA) by combined host-guest complexation. Research on the self-assembly behavior of these amphiphiles demonstrated that the variation in self-assembly was tuned by the synergistic interaction of hydrophilicity and the curvature of the polymer chains, and very importantly, the topological structure of amphiphiles demonstrated effective control of the self-assembly behavior.

Self-assembly behavior of a linear-star supramolecular amphiphile based on host-guest complexation.

A star polymer, ß-cyclodextrin-poly(l-lactide) (ß-CD-PLLA), and a linear polymer, azobenzene-poly(ethylene glycol) (Azo-PEG), could self-assemble into a supramolecular amphiphilic copolymer (ß-CD-PLLA@Azo-PEG) based on the host-guest interaction between ß-CD and azobenzene moieties. This linear-star supramolecular amphiphilic copolymer further self-assembled into a variety of morphologies, including sphere-like micelle, carambola-like micelle, naan-like micelle, shuttle-like lamellae, tube-like fiber, and random curled-up lamellae, by tuning the length of hydrophilic or hydrophobic chains. The variation of morphology was closely related to the topological structure and block ratio of the supramolecular amphiphiles. These self-assembly structures could disassemble upon an ultraviolet (UV) light irradiation.

Bioreducible cross-linked nanoshell enhances gene transfection of polycation/DNA polyplex in vivo.

In this study, we have prepared a self-cross-linking PEG-based branched polymer, which easily forms a bioreducible nanoshell around polyplexes of cationic polymer and DNA, simply via heating the polyplex dispersions in the presence of this self-cross-linking branched polymer. This nanoshell can prevent the polyplex from dissociation and aggregation in physiological fluids without inhibiting the electrostatic interactions between the polymer and DNA. Furthermore, glutathione (GSH) can act as a stimulus to open the nanoshell after it has entered the cell. The polyplexes coated with the bioreducible nanoshell show an obvious enhancement in gene transfection in vivo compared with bare polyplexes.

Bioreducible nanocapsules prepared from the self-assembly of branched polymer in nanodroplet.

Though great attention has been paid in constructing well-defined nano-structures via the self-assembly of amphiphilic macromolecules, the self-assembly of non-amphiphilic macromolecules in nanodroplet has drawn less attention up to now. Recently, we prepared a temperature-responsive PEG-based branched polymer with disulfide bonds in its backbone via reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(2-methoxyethoxy) ethyl methacrylate, oligo(ethylene glycol) methacrylate, and N,N'-cystamine bisacrylamide. Subsequently, we loaded the branched polymer into nanodroplets, and have found that the self-assembly behaviors of this branched poly-mer in the nanodroplet are different from those in common solution. Bioreducible nanocapsules with tunable size can easily formed in nanodroplet even at high concentration.

Stimuli-triggered growth and removal of a bioreducible nanoshell on nanoparticles.

A new and easy method of stimuli-triggered growth and removal of a bioreducible nanoshell on nanoparticles is reported. The results show that pH or temperature could induce the aggregation of disulfide-contained branched polymers at the surface of nanoparticles; subsequently, the aggregated polymers could undergo intermolecular disulfide exchange to cross-link the aggregated polymers, forming a bioreducible polymer shell around nanoparticles. When these nanoparticles with a polymer shell are treated with glutathione (GSH) or d,l-dithiothreitol (DTT), the polymer shell could be easily removed from the nanoparticles. The potential application of this method is demonstrated by easily growing and removing a bioreducible shell from liposomes, and improvement of in vivo gene transfection activity of liposomes with a bioreducible PEG shell.

Precise antibiotic delivery to the lung infection microenvironment boosts the treatment of pneumonia with decreased gut dysbiosis.

Bacterial pneumonia is a common disease with significant health risks. However, the overuse antibiotics in clinics face challenges such as inadequate targeting and limited drug utilization, leading to drug resistance and gut dysbiosis. Herein, a dual-responsive lung inflammatory tissue targeted nanoparticle (LITTN), designed for targeting lung tissue and bacteria, is screened from a series of prepared nanoparticles consisting of permanent cationic lipids, acid-responsive lipids, and reactive oxygen species-responsive and phenylboronic acid-modified lipids with different surface properties. Such nanoparticle is further verified to enhance the adsorption of vitronectin in serum. Additionally, the optimized nanoparticle exhibits more positive charge and coordination of boric acid with cis-diol in the infected microenvironment, facilitating electrostatic interactions with bacteria and biofilm penetration. Importantly, the antibacterial efficiency of dual-responsive rifampicin-loaded LITTN (Rif@LITTN) against methicillin-resistant staphylococcus aureus is 10 times higher than that of free rifampicin. In a mouse model of bacterial pneumonia, the intravenous administration of Rif@LITTN could precisely target the lungs, localize in the lung infection microenvironment, and trigger the responsive release of rifampicin, thereby effectively alleviating lung inflammation and reducing damage. Notably, the targeted delivery of rifampicin helps protect against antibiotic-induced changes in the gut microbiota. This study establishes a new strategy for precise delivery to the lung-infected microenvironment, promoting treatment efficacy while minimizing the impact on gut microbiota. STATEMENT OF SIGNIFICANCE: Intravenous antibiotics play a critical role in clinical care, particularly for severe bacterial pneumonia. However, the inability of antibiotics to reach target tissues causes serious side effects, including liver and kidney damage and intestinal dysbiosis. Therefore, achieving precise delivery of antibiotics is of great significance. In this study, we developed a novel lung inflammatory tissue-targeted nanoparticle that could target lung tissue after intravenous administration and then target the inflammatory microenvironment to trigger dual-responsive antibiotics release to synergistically treat pneumonia while maintaining the balance of gut microbiota and reducing the adverse effects of antibiotics. This study provides new ideas for targeted drug delivery and reference for clinical treatment of pneumonia.

An adhesion-switchable hydrogel dressing for painless dressing removal without secondary damage.

Hydrogels with strong adhesion to wet tissues are considered promising for wound dressings. However, the clinical application of adhesive hydrogel dressing remains a challenge due to the issues of secondary damage during dressing changes. Herein, we fabricated an adhesion-switchable hydrogel formed with poly(acrylamide)-co-poly(N-isopropyl acrylamide), quaternary ammonium chitosan and tannic acid. This hydrogel forms instant and robust adhesion to the skin at body temperature. However, as the temperature rises above the lower critical solution temperature (LCST), the hydrogel loses its adhesion towards the wound area due to the temperature-dependent volume phase transition of the copolymer, occurring around 45 °C. Consequently, the designed hydrogel can be easily detached from adhered tissues upon demand, providing a facile and effective method for painless dressing changes without secondary damage. This hydrogel holds great promise for long-term application in wound dressings.

Nanogalvanic Cells Release Highly Reactive Electrons in Tumors to Effectively Eliminate Tumors.

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, this work presents galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers.

DPA-Zinc around Polyplexes Acts Like PEG to Reduce Protein Binding While Targeting Cancer Cells.

Gene therapy holds great promise as an effective treatment for many diseases of genetic origin. Gene therapy works by employing cationic polymers, liposomes, and nanoparticles to condense DNA into polyplexes via electronic interactions. Then, a therapeutic gene is introduced into target cells, thereby restoring or changing cellular function. However, gene transfection efficiency remains low in vivo due to high protein binding, poor targeting ability, and substantial endosomal entrapment. Artificial sheaths containing PEG, anions, or zwitterions can be introduced onto the surface of gene carriers to prevent interaction with proteins; however, they reduce the cellular uptake efficacy, endosomal escape, targeting ability, thereby, lowering gene transfection. Here, it is reported that linking dipicolylamine-zinc (DPA-Zn) ions onto polyplex nanoparticles can produce a strong hydration water layer around the polyplex, mimicking the function of PEGylation to reduce protein binding while targeting cancer cells, augmenting cellular uptake and endosomal escape. The polyplexes with a strong hydration water layer on the surface can achieve a high gene transfection even in a 50% serum environment. This strategy provides a new solution for preventing protein adsorption while improving cellular uptake and endosomal escape.