Emerging polymeric materials for treatment of oral diseases: design strategy towards a unique oral environment.

Oral diseases are prevalent but challenging diseases owing to the highly movable and wet, microbial and inflammatory environment. Polymeric materials are regarded as one of the most promising biomaterials due to their good compatibility, facile preparation, and flexible design to obtain multifunctionality. Therefore, a variety of strategies have been employed to develop materials with improved therapeutic efficacy by overcoming physicobiological barriers in oral diseases. In this review, we summarize the design strategies of polymeric biomaterials for the treatment of oral diseases. First, we present the unique oral environment including highly movable and wet, microbial and inflammatory environment, which hinders the effective treatment of oral diseases. Second, a series of strategies for designing polymeric materials towards such a unique oral environment are highlighted. For example, multifunctional polymeric materials are armed with wet-adhesive, antimicrobial, and anti-inflammatory functions through advanced chemistry and nanotechnology to effectively treat oral diseases. These are achieved by designing wet-adhesive polymers modified with hydroxy, amine, quinone, and aldehyde groups to provide strong wet-adhesion through hydrogen and covalent bonding, and electrostatic and hydrophobic interactions, by developing antimicrobial polymers including cationic polymers, antimicrobial peptides, and antibiotic-conjugated polymers, and by synthesizing anti-inflammatory polymers with phenolic hydroxy and cysteine groups that function as immunomodulators and electron donors to reactive oxygen species to reduce inflammation. Third, various delivery systems with strong wet-adhesion and enhanced mucosa and biofilm penetration capabilities, such as nanoparticles, hydrogels, patches, and microneedles, are constructed for delivery of antibiotics, immunomodulators, and antioxidants to achieve therapeutic efficacy. Finally, we provide insights into challenges and future development of polymeric materials for oral diseases with promise for clinical translation.

Antioxidant and Immunomodulatory Polymer Vesicles for Effective Diabetic Wound Treatment through ROS Scavenging and Immune Modulating.

Chronic diabetic wound patients usually show high glucose levels and systemic immune disorder, resulting in high reactive oxygen species (ROS) levels and immune cell dysfunction, prolonged inflammation, and delayed wound healing. Herein, we prepared an antioxidant and immunomodulatory polymer vesicle for diabetic wound treatment. This vesicle is self-assembled from poly(ε-caprolactone)36-block-poly[lysine4-stat-(lysine-mannose)22-stat-tyrosine)16] ([PCL36-b-P[Lys4-stat-(Lys-Man)22-stat-Tyr16]). Polytyrosine is an antioxidant polypeptide that can scavenge ROS. d-Mannose was introduced to afford immunomodulatory functions by promoting macrophage transformation and Treg cell activation through inhibitory cytokines. The mice treated with polymer vesicles showed 23.7% higher Treg cell levels and a 91.3% higher M2/M1 ratio than those treated with PBS. Animal tests confirmed this vesicle accelerated healing and achieved complete healing of S. aureus-infected diabetic wounds within 8 days. Overall, this is the first antioxidant and immunomodulatory vesicle for diabetic wound healing by scavenging ROS and regulating immune homeostasis, opening new avenues for effective diabetic wound healing.

Kinetically Controlled Preparation of Worm-like Micelles with Tunable Diameter/Length and Structural Stability.

Anisotropic nanoparticles such as worm-like micelles have aroused much attention due to their promising applications from templates to drug delivery. The fabrication of worm-like micelles with tunable structural stability and control over their diameter and length is of great importance but still challenging. Herein, we report a kinetically controlled ring-opening metathesis polymerization-induced self-assembly (ROMPISA) for the robust preparation of kinetically trapped worm-like micelles with tunable diameter/length at enlarged experimental windows by the rational manipulation of kinetic factors, including solvent property, temperature, and π-π stacking effects. The resultant worm structures were thermodynamically metastable and capable of excellent structural stability at room temperature due to the kinetic trapping effect. At elevated temperatures, these thermodynamically metastable worms could undergo morphology evolution into vesicular structures in a controlled manner. Moreover, the structural stability of worms could also be significantly enhanced by in situ cross-linking. Overall, this kinetically controlled ROMPISA opens a new avenue for PISA chemistry that is expected to prepare "smart" polymer materials by manipulating kinetic factors.

Advancing Artificial Cells with Functional Compartmentalized Polymeric Systems - In Honor of Wolfgang Meier.

The fundamental building block of living organisms is the cell, which is the universal biological base of all living entities. This micrometric mass of cytoplasm and the membrane border have fascinated scientists due to the highly complex and multicompartmentalized structure. This specific organization enables numerous metabolic reactions to occur simultaneously and in segregated spaces, without disturbing each other, but with a promotion of inter- and intracellular communication of biomolecules. At present, artificial nano- and microcompartments, whether as single components or self-organized in multicompartment architectures, hold significant value in the study of life development and advanced functional materials and in the fabrication of molecular devices for medical applications. These artificial compartments also possess the properties to encapsulate, protect, and control the release of bio(macro)molecules through selective transport processes, and they are capable of embedding or being connected with other types of compartments. The self-assembly mechanism of specific synthetic compartments and thus the fabrication of a simulated organelle membrane are some of the major aspects to gain insight. Considerable efforts have now been devoted to design various nano- and microcompartments and understand their functionality for precise control over properties. Of particular interest is the use of polymeric vesicles for communication in synthetic cells and colloidal systems to reinitiate chemical and biological communication and thus close the gap toward biological functions. Multicompartment systems can now be effectively created with a high level of hierarchical control. In this way, these structures can not only be explored to deepen our understanding of the functional organization of living cells, but also pave the way for many more exciting developments in the biomedical field.

Physically and Chemically Compartmentalized Polymersomes for Programmed Delivery and Biological Applications.

Multicompartment polymersomes (MCPs) refer to polymersomes that not only contain one single compartment, either in the membrane or in the internal cavity, but also mimic the compartmentalized structure of living cells, attracting much attention in programmed delivery and biological applications. The investigation of MCPs may promote the application of soft nanomaterials in biomedicine. This Review seeks to highlight the recent advances of the design principles, synthetic strategies, and biomedical applications of MCPs. The compartmentalization types including chemical, physical, and hybrid compartmentalization are discussed. Subsequently, the design and controlled synthesis of MCPs by the self-assembly of amphiphilic polymers, double emulsification, coprecipitation, microfluidics and particle assembly, etc. are summarized. Furthermore, the diverse applications of MCPs in programmed delivery of various cargoes and biological applications including cancer therapy, antimicrobials, and regulation of blood glucose levels are highlighted. Finally, future perspectives of MCPs from the aspects of controlled synthesis and applications are proposed.

Membrane and Lumen-Compartmentalized Polymersomes for Biocatalysis and Cell Mimics.

Compartmentalization is a crucial feature of a natural cell, manifested in cell membrane and inner lumen. Inspired by the cellular structure, multicompartment polymersomes (MCPs), including membrane-compartmentalized polymersomes and lumen-compartmentalized polymersomes (polymersomes-in-polymersomes), have aroused great expectations for biological applications such as biocatalysis and cell mimics in the past decades. Compared with traditional polymersomes, MCPs have advantages in encapsulating multiple enzymes separately for multistep enzymatic cascade reactions. In this review, first, the design principles and preparation methods of membrane-compartmentalized and lumen-compartmentalized polymersomes are summarized. Next, recent advances of MCPs as nanoreactors and cell mimics to mimic subcellular organelles or artificial cells are discussed. Finally, the future research directions of MCPs are prospected.

Polymeric Bowl-Shaped Nanoparticles: Hollow Structures with a Large Opening on the Surface.

Polymeric bowl-shaped nanoparticles (BNPs) are anisotropic hollow structures with large openings on the surface, which have shown advantages such as high specific area and efficient encapsulation, delivery and release of large-sized cargoes on demand compared to solid nanoparticles or closed hollow structures. Several strategies have been developed to prepare BNPs based on either template or template-free methods. For instance, despite the widely used self-assembly strategy, alternative methods including emulsion polymerization, swelling and freeze-drying of polymeric spheres, and template-assisted approaches have also been developed. It is attractive but still challenging to fabricate BNPs due to their unique structural features. However, there is still no comprehensive summary of BNPs up to now, which significantly hinders the further development of this field. In this review, the recent progress of BNPs will be highlighted from the perspectives of design strategies, preparation methods, formation mechanisms, and emerging applications. Moreover, the future perspectives of BNPs will also be proposed.

Tryptophan-Modulated Nanoscale Metal-Organic Framework for Coordinated Loading of Biomolecules for Cascade Production of Reactive Oxygen and Nitrogen Species.

Owing to the high surface area and porosity, metal-organic frameworks (MOFs) could be utilized as both nanocarriers of biopharmaceuticals and nanoreactors to organize cascade biological reactions with great potential in cancer treatment. However, nanoscale MOFs suitable for biomedical applications rely on harsh preparation conditions. Here, we utilized tryptophan to modulate the morphology and optical properties of zeolitic imidazolate framework-8 (ZIF-8) as nanocarrier to efficiently encapsulate the enzyme and mRNA. Under room temperature in an aqueous solution, tryptophan would coordinate with zinc ions to form ZIF-8:Trp with a decreased size from the µm range to sub-200 nm. In addition, cargo release could be monitored in real time via fluorescence red-shift effects. Besides being used as nanocarriers of biomolecules, ZIF-8:Trp could also be utilized as nanoreactors to induce cascade reactions to produce reactive oxygen and nitrogen species. Overall, this nanosized ZIF-8:Trp could provide a new strategy for preparation of cascade bioreactions and provide new insight for gas therapy.

Intracellular Self-Assembly of Peptides to Induce Apoptosis against Drug-Resistant Melanoma.

Biosynthesis has been a diverse toolbox to develop bioactive molecules and materials, especially for fabricating modified peptides and their assemblies induced by enzymes. Although desired chemical structures and nanoarchitectures have been achieved, the subsequent interferences of peptide assemblies with organelles and the cellular pathways still remain unsolved important challenges. Herein, we developed a new tripeptide, phenylalanine-phenylalanine-tyrosine (Phe-Phe-Tyr, or FFY), which can be intracellularly oxidized and in situ self-assemble into nanoparticles with excellent interference capability with microtubules and ultimately reverse the drug resistance of melanoma. With the catalysis of tyrosinase, FFY was first oxidized to a melanin-like FFY dimer (mFFY) with a diquinone structure for further self-assembling into mFFY assemblies, which could inhibit the self-polymerization of tubulin to induce severe G2/M arrest (13.9% higher than control). Afterward, mitochondrial dysfunction was also induced for overproduction of cleaved caspase 3 (3.1 times higher than control) and cleaved PARP (6.3 times higher), achieving a high level of resistant reversing without chemotherapeutic drugs. In vivo studies showed that the resistant melanoma tumor volumes were reduced by 87.4% compared to control groups after FFY treatment by peritumoral injections. Overall, this tyrosinase-induced tripeptide assembly has been demonstrated with effective intrinsic apoptosis against drug-resistant melanoma, providing a new insight into utilizing biomolecules to interfere with organelles to activate certain apoptosis pathways for treatment of drug-resistant cancer.

Transformation of Amorphous Nanobowls to Crystalline Ellipsoids Induced by Trans-Cis Isomerization of Azobenzene.

The stimuli-responsive transition of nanostructures from amorphous to crystalline state is of high interest in polymer science, but is still challenging. Herein, the transformation of amorphous nanobowls to crystalline ellipsoids triggered by UV induced trans-cis isomerization is demonstrated, using an azobenzene-containing amphiphilic homopolymer (PAzoAA) as a building block. The amide bond and azobenzene pendants are introduced to the side chain of PAzoAA to afford hydrogen bonding and π-π interactions, which promote the formation of nanobowls rather than spherical nanostructures. Upon exposure to UV irradiation, trans-cis isomerization of azobenzene pendants occurs, leading to the increase of hydrophilicity and destruction of π-π interaction, further resulting in the disassembly of the nanobowls. Then the PAzoAA re-assembles to form crystalline ellipsoids instead of amorphous nanostructures when recovered at 70 °C without UV light. Further, it is confirmed that the high incubation temperature after UV irradiation is critical for the cis-trans transformation and the high mobility of the polymer chains to facilitate the regular rearrangement of azobenzene pendants. Overall, a facile method to achieve the transformation of amorphous nanobowls to crystalline ellipsoids is proposed, which may bring new insight into preparation of crystalline nanoparticles using amorphous precursors.

Bone-Targeting Polymer Vesicles for Effective Therapy of Osteoporosis.

With the aging of the population, postmenopausal osteoporosis becomes increasingly widespread and severe as fractures caused by osteoporosis may lead to permanent disabilities and even death. Inspired by extracellular vesicles that participate in bone remodeling, we present a biomimicking polymer vesicle for bone-targeted ß-estradiol (E2) delivery. This vesicle is self-assembled from a poly(ε-caprolactone)28-block-poly[(l-glutamic acid)7-stat-(l-glutamic acid-alendronic acid)4] (PCL28-b-P[Glu7-stat-(Glu-ADA)4]) diblock copolymer. The alendronic acid (ADA) on the coronas endows the polymer vesicles with a high bone affinity and acts synergistically with E2 to achieve an enhanced therapeutic effect. As confirmed with ovariectomized osteoporosis rat models, bone loss was significantly reversed as the recovery rates of total BMD (bone mineral density) and trabecular BMD were 70.4% and 99.3%, respectively. Overall, this work provides fresh insight into the treatment of osteoporosis.

Tetrapod Polymersomes.

Hollow nanoparticles such as polymersomes have promising potentials in many fields. However, the design and construction of higher-order polymersomes with precisely controlled spatial compartments is still very challenging. Herein, we report a unique tetrapod polymersome that is assembled by the controlled fusion of four traditional spherical polymersomes. This original species was prepared from poly(ethylene oxide)113-b-poly[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl methacrylate61-stat-2-(diethylamino)ethyl methacrylate23] [PEO113-b-P(TBA61-stat-DEA23)] in DMF/water at lower water content (Cw), where PEO acts as corona forming block. To unravel the secret behind the tetrapod polymersomes, a series of block copolymers with various comonomer types and degrees of polymerization were synthesized and self-assembled. PEO113-b-PTBA80 self-assembles into spherical micelles in DMF/water, and the subsequent evolution into tripod and multipod micelles and finally micelle clusters was achieved by increasing Cw. This suggests that relatively rigid TBA is a "pro-fusion" component that facilitates particle-particle fusion due to its providential hydrophobicity and chain mobility. When one-fourth of TBA of PEO113-b-PTBA80 is substituted by DEA, spherical polymersomes of PEO113-b-P(TBA61-stat-DEA23) are born in DMF/water and then fused into dipod, tripod (Cw = 95%), and finally tetrapod polymersomes (Cw = 100%) upon increasing Cw, suggesting that flexible DEA is not only a promoter for hollow pods but also an "anti-fusion" component that can compromise with pro-fusion force for its high chain mobility. The formation of either tetrapod polymersomes or micelle clusters is a matter of balance between pro-fusion and anti-fusion forces. Overall, we provide a fresh insight for the preparation of tetrapod polymersomes as well as other higher-order structures with precisely defined spatial compartments by fusion-induced particle assembly (FIPA).

Dually Gated Polymersomes for Gene Delivery.

An ideal gene carrier requires an excellent gating system to efficiently load, protect, deliver, and release environmentally sensitive nucleic acids on demand. Presented in this communication is a polymersome with a "boarding gate" and a "debarkation gate" in the membrane to complete the above important missions. This dually gated polymersome is self-assembled from a block copolymer, poly(ethylene oxide)- block-poly[ N-isopropylacrylamide- stat-7-(2-methacryloyloxyethoxy)-4-methylcoumarin- stat-2-(diethylamino)ethyl methacrylate] [PEO- b-P(NIPAM- stat-CMA- stat-DEA)]. The hydrophilic PEO chains form the coronas of the polymersome, whereas the temperature and pH-sensitive P(NIPAM- stat-CMA- stat-DEA) block forms the dually gated heterogeneous membrane. The temperature-controlled "boarding gate" can be opened at room temperature for facile encapsulation of siRNA and plasmid DNA into polymersomes directly in aqueous solution. The "debarkation gate" can be triggered by proton sponge effect for intracellular release. Biological studies confirmed the successful encapsulation of siRNA and plasmid DNA, efficient in vitro and in vivo gene transfection, and the expression of green fluorescent protein (GFP) from GFP-encoding plasmid, suggesting that this kind of polymersome with a dual gating system can serve as an excellent biomacromolecular shuttle for gene delivery and other biological applications.

Synthesis, Self-Assembly, and Biomedical Applications of Antimicrobial Peptide-Polymer Conjugates.

Antimicrobial peptides (AMPs) have been attracting much attention due to their excellent antimicrobial efficiency and low rate in driving antimicrobial resistance (AMR), which has been increasing globally to alarming levels. Conjugation of AMPs into functional polymers not only preserves excellent antimicrobial activities but reduces the toxicity and offers more functionalities, which brings new insight toward developing multifunctional biomedical materials such as hydrogels, polymer vesicles, polymer micelles, and so forth. These nanomaterials have been exhibiting excellent antimicrobial activity against a broad spectrum of bacteria including multidrug-resistant (MDR) ones, high selectivity, and low cytotoxicity, suggesting promising potentials in wound dressing, implant coating, antibiofilm, tissue engineering, and so forth. This Perspective seeks to highlight the state-of-the-art strategy for the synthesis, self-assembly, and biomedical applications of AMP-polymer conjugates and explore the promising directions for future research ranging from synthetic strategies, multistage and stimuli-responsive antibacterial activities, antifungi applications, and potentials in elimination of inflammation during medical treatment. It also will provide perspectives on how to stem the remaining challenges and unresolved problems in combating bacteria, including MDR ones.

Hydrogel scaffolds for differentiation of adipose-derived stem cells.

Natural extracellular matrices (ECMs) have been widely used as a support for the adhesion, migration, differentiation, and proliferation of adipose-derived stem cells (ADSCs). However, poor mechanical behavior and unpredictable biodegradation properties of natural ECMs considerably limit their potential for bioapplications and raise the need for different, synthetic scaffolds. Hydrogels are regarded as the most promising alternative materials as a consequence of their excellent swelling properties and their resemblance to soft tissues. A variety of strategies have been applied to create synthetic biomimetic hydrogels, and their biophysical and biochemical properties have been modulated to be suitable for cell differentiation. In this review, we first give an overview of common methods for hydrogel preparation with a focus on those strategies that provide potential advantages for ADSC encapsulation, before summarizing the physical properties of hydrogel scaffolds that can act as biological cues. Finally, the challenges in the preparation and application of hydrogels with ADSCs are explored and the perspectives are proposed for the next generation of scaffolds.

Sugar-Breathing Glycopolymersomes for Regulating Glucose Level.

Diabetes mellitus is a chronic, life-threatening illness that affects people of every age and ethnicity. It is a long-term pain for those who are affected and must regulate their blood glucose level by frequent subcutaneous injection of insulin every day. Herein, we propose a noninsulin and antidiabetic drug-free strategy for regulating blood glucose level by a nanosized "sugar sponge" which is a lectin-bound glycopolymersome capable of regulating glucose due to the dynamic recognition between the lectin and different carbohydrates. The glycopolymersome is self-assembled from poly(ethylene oxide)-block-poly[(7-(2-methacryloyloxyethoxy)-4-methylcoumarin)-stat-2-(diethylamino)ethyl methacrylate-stat-(α-d-glucopyranosyl)ethyl methacrylate] [PEO-b-P(CMA-stat-DEA-stat-GEMA)]. The lectin bound in the glycopolymersome has different affinity for the glucose in the blood and the glucosyl group in the glycopolymersome. Therefore, this sugar sponge functions as a glucose storage unit by dynamic sugar replacement: The lectin in the sugar sponge will bind and store the glucose from its surrounding solution when the glucose concentration is too high and will release the glucose when the glucose concentration is too low. In vitro, this sugar-breathing behavior is characterized by a remarkable size change of the sugar sponge due to the swelling/shrinkage at high/low glucose levels, which can be used for blood sugar monitoring. In vivo, this sugar sponge showed an excellent antidiabetic effect for type I diabetic mice within 2 days upon one dose, which is much longer than traditional long-acting insulin. Overall, this concept of "controlling sugar levels with sugar" opens new avenues for regulating the blood glucose level without the involvement of insulin or other antidiabetic drugs.

Highly Effective Antibacterial Vesicles Based on Peptide-Mimetic Alternating Copolymers for Bone Repair.

It is an important challenge for bone repair to effectively deliver growth factors and at the same time to prevent and cure inflammation without obvious pathogen resistance. We designed a kind of antibacterial peptide-mimetic alternating copolymers (PMACs) to effectively inhibit and kill both Gram-positive and Gram-negative bacteria. The minimum inhibition concentrations (MICs) of the PMACs against E. coli and S. aureus are 8.0 µg/mL, which are much lower than that of antibacterial peptides synthesized by other methods such as widely used ring-opening polymerization of N-carboxyanhydride. Furthermore, the PMACs can self-assemble into polymer vesicles (polymersomes) in pure water with low cytotoxicity (IC50 > 1000 µg/mL), which can encapsulate growth factors in aqueous solution and release them during long-term antibacterial process for facilitating bone repair. We also find that the alternating structure is essential for the excellent antibacterial activity. The in vivo tests in rabbits confirmed that the growth-factor-encapsulated antibacterial vesicles have better bone repair ability compared with control groups without antibacterial vesicles. Overall, we have provided a novel method for designing PMAC-based highly effective intrinsically antibacterial vesicles that may have promising biomedical applications in the future.

Synthesis and Mechanism Insight of a Peptide-Grafted Hyperbranched Polymer Nanosheet with Weak Positive Charges but Excellent Intrinsically Antibacterial Efficacy.

Antimicrobial resistance is an increasingly problematic issue in the world and there is a present and urgent need to develop new antimicrobial therapies without drug resistance. Antibacterial polymers are less susceptible to drug resistance but they are prone to inducing serious side effects due to high positive charge. Herein we report a peptide-grafted hyperbranched polymer which can self-assemble into unusual nanosheets with highly effective intrinsically antibacterial activity but weak positive charges (+ 6.1 mV). The hyperbranched polymer was synthesized by sequential Michael addition-based thiol-ene and free radical mediated thiol-ene reactions, and followed by ring-opening polymerization of N-carboxyanhydrides (NCAs). The nanosheet structure was confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM) studies. Furthermore, a novel "wrapping and penetrating" antibacterial mechanism of the nanosheets was revealed by TEM and it is the key to significantly decrease the positive charges but have a very low minimum inhibitory concentration (MIC) of 16 µg mL(-1) against typical Gram-positive and Gram-negative bacteria. Overall, our synthetic strategy demonstrates a new insight for synthesizing antibacterial nanomaterials with weak positive charges. Moreover, the unique antibacterial mechanism of our nanosheets may be extended for designing next-generation antibacterial agents without drug resistance.