A glycopolymersome strategy for 'drug-free' treatment of diabetic nephropathy.

Diabetic nephropathy is a severe complication of diabetes. Treatment of diabetic nephropathy is an important challenge due to persistent hyperglycemia and elevated levels of reactive oxygen species (ROS) in the kidney. Herein, we designed a glycopolymersome that can treat type 2 diabetic nephropathy by effectively inhibiting hyperglycemia and ROS-associated diabetic nephropathy pathogenesis. The glycopolymersome is self-assembled from phenylboronic acid derivative-containing copolymer, poly(ethylene oxide)45-block-poly[(aspartic acid)13-stat-glucosamine24-stat-(phenylboronic acid)18-stat-(phenylboronic acid pinacol ester)3] [PEO45-b-P(Asp13-stat-GA24-stat-PBA18-stat-PAPE3)]. PBA segment can reversibly bind blood glucose or GA segment for long-term regulation of blood glucose levels; PAPE segment can scavenge excessive ROS for renoprotection. In vitro studies confirmed that the glycopolymersomes exhibit efficient blood glucose responsiveness within 2 h and satisfactory ROS-scavenging ability with 500 µM H2O2. Moreover, the glycopolymersomes display long-acting regulation of blood glucose levels in type 2 diabetic nephropathy mice within 32 h. Dihydroethidium staining revealed that these glycopolymersomes reduced ROS to normal levels in the kidney, which led to 61.7% and 76.6% reduction in creatinine and urea levels, respectively, along with suppressing renal apoptosis, collagen accumulation, and glycogen deposition in type 2 diabetic nephropathy mice. Notably, the polypeptide-based glycopolymersome was synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides (NCAs), thereby exhibiting favorable biodegradability. Overall, we proposed a new glycopolymersome strategy for 'drug-free' treatment of diabetic nephropathy, which could be extended to encompass the design of various multifunctional nanoparticles targeting diabetes and its associated complications.

Lung-selective nucleic acid vectors generated by in vivo lung-targeting-protein decoration of polyplexes.

Nucleic acid drugs show immense therapeutic potential, but achieving selective organ targeting (SORT) for pulmonary disease therapy remains a formidable challenge due to the high mortality rate caused by pulmonary embolism via intravenous administration or the mucus barrier in the respiratory tract via nebulized delivery. To meet this important challenge, we propose a new strategy to prepare lung-selective nucleic-acid vectors generated by in vivo decoration of lung-targeting proteins on bioreducible polyplexes. First, we synthesized polyamidoamines, named pabol and polylipo, to encapsulate and protect nucleic acids, forming polyamidoamines/mRNA polyplexes. Second, bovine serum albumin (BSA) was coated on the surface of these polyplexes, called BSA@polyplexes, including BSA@pabol polyplexes and BSA@polylipo polyplexes, to neutralize excess positive charge, thereby enhancing biosafety. Finally, after subcutaneous injection, proteins, especially vitronectin and fibronectins, attached to the polyplexes, resulting in the formation of lung-selective nucleic-acid vectors that achieve efficient lung targeting.

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.

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.

Ultrafast Monomer Emulsified Aqueous Ring-Opening Metathesis Polymerization for the Synthesis of Water-Soluble Polynorbornenes with Precise Structure.

Ring-opening metathesis polymerization (ROMP) in an aqueous medium provides an important environmentally friendly platform for the preparation of water-soluble polymeric materials. However, it is challenging to keep high synthetic efficacy and good control over molecular weight and distribution due to the inevitable catalyst decomposition in an aqueous medium. To meet this challenge, we propose a facile monomer emulsified aqueous ROMP (ME-ROMP) by injecting a tiny amount of a CH2Cl2 solution of the Grubbs' third-generation catalyst (G3) into the aqueous solution of norbornene (NB) monomers without deoxygenation. Driven by the minimization of interfacial tension, the water-soluble monomers could serve as surfactants with hydrophobic NB moieties inserted into the CH2Cl2 droplets of G3, leading to the significantly suppressed catalyst decomposition and accelerated polymerization. The ME-ROMP is confirmed to be living with an ultrafast polymerization rate, near quantitative initiation and monomer conversion, for the highly efficient and ultrafast synthesis of well-defined water-soluble polynorbornenes with various compositions and architectures.

An Antibacterial Polypeptide Coating Prepared by In Situ Enzymatic Polymerization for Preventing Delayed Infection of Implants.

Delayed implant-associated infection is an important challenge, as the treatment involves a high risk of implant replacement. Mussel-inspired antimicrobial coatings can be applied to coat a variety of implants in a facile way, but the adhesive 3,4-dihydroxyphenylalanine (DOPA) group is prone to oxidation. Therefore, an antibacterial polypeptide copolymer poly(Phe7-stat-Lys10)-b-polyTyr3 was designed to prepare the implant coating upon tyrosinase-induced enzymatic polymerization for preventing implant-associated infections. Both poly(Phe7-stat-Lys10) and polyTyr3 blocks have specific functions: the former provides intrinsic antibacterial activity with a low risk to induce antimicrobial resistance, and the latter is attachable to the surface of implants to rapidly generate an antibacterial coating by in situ injection of polypeptide copolymer since tyrosine could be oxidized to DOPA under catalyzation of skin tyrosinase. This polypeptide coating with excellent antibacterial effect and desirable biofilm inhibition activity is promising for broad applications in a multitude of biomedical materials to combat delayed infections.

Quantifiable Relationship Between Antibacterial Efficacy and Electro-Mechanical Intervention on Nanowire Arrays.

Physical disruption is an important antibacterial means as it is lethal to bacteria without spurring antimicrobial resistance. However, it is very challenging to establish a quantifiable relationship between antibacterial efficacy and physical interactions such as mechanical and electrical forces. Herein, titanium nitride (TN) nanowires with adjustable orientations and capacitances are prepared to exert gradient electro-mechanical forces on bacteria. While vertical nanowires show the strongest mechanical force resulting in an antibacterial efficiency of 0.62 log reduction (vs 0.22 for tiled and 0.36 for inclined nanowires, respectively), the addition of electrical charges maximizes the electro-mechanical interactions and elevates the antibacterial efficacy to more than 3 log reduction. Biophysical and biochemical analyses indicate that electrostatic attraction by electrical charge narrows the interface. The electro-mechanical intervention more easily stiffens and rips the bacteria membrane, disturbing the electron balance and generating intracellular oxidative stress. The antibacterial ability is maintained in vivo and bacteria-challenged rats are protected from serious infection. The physical bacteria-killing process demonstrated here can be controlled by adjusting the electro-mechanical interactions. Overall, these results revealed important principles for rationally designing high-performance antibacterial interfaces for clinical applications.

Drug delivery approaches for enhanced antibiofilm therapy.

Biofilms have attracted increasing attention in recent years. Many bacterial infections are associated with biofilm formation. A bacterial biofilm is an aggregated membrane-like substance that is composed of a large number of bacteria and their secreted extracellular polymeric substances. The traditional antibiofilm approaches, such as chemotherapy based on antibiotics, are often ineffective in eradicating biofilms owing to the limited diffusion ability of antibiotics within biofilms and inactivation of antibiotics by biofilms. Moreover, a larger dosage of antibiotics could be effective, but leads to an increased tolerance. Smart drug delivery systems that deliver antibiotics into the biofilm interior is a promising strategy to meet this challenge. In this review, we focus on the methods to improve drug delivery efficiency for enhanced chemotherapy of biofilms. Furthermore, we have summarized chemical approaches for enhanced drug delivery, such as chemical shields, charge reversal, and dual corona enhanced delivery strategies; these methods focus on physicochemical biofilm properties and specific biofilm features. Afterwards, physical approaches are discussed, such as magnetism-mediated drug delivery, electricity-mediated drug delivery, ultrasound-mediated drug delivery, and shock wave-mediated drug delivery. Finally, a perspective on the development of next-generation antibiofilm drug delivery systems is given.

A polypeptide coating for preventing biofilm on implants by inhibiting antibiotic resistance genes.

Aging population has been boosting the need for orthopedic implants. However, biofilm has been a major obstacle for orthopedic implants due to its insensitivity to antibiotics and tendency to drive antimicrobial resistance. Herein, an antibacterial polypeptide coating with excellent in vivo adhesive capacity was prepared to prevent implants from forming biofilms and inducing acquired antibiotic resistance. A peptide-based copolymer, poly[phenylalanine10-stat-lysine12]-block-3,4-dihydroxy-l-phenylalanine [Poly(Phe10-stat-Lys12)-DOPA] was modularly designed, where poly(Phe10-stat-Lys12) is antibacterial polypeptide with high antibacterial activity, and DOPA provides strong adhesion in both wet and dry microenvironments. Meanwhile, compared to traditional "graft-onto" methods, this antibacterial coating can be facilely achieved by immersing Titanium substrates into antibacterial polypeptide solution for 5 min at room temperature. The poly(Phe10-stat-Lys12)-DOPA polymer showed good antibacterial activity with minimum inhibitory concentrations against S. aureus and E. coli of 32 and 400 µg/mL, respectively. Compared to obvious antimicrobial resistance of S. aureus after continuous treatment with vancomycin, this antibacterial coating doesn't drive antimicrobial resistance upon long-term utilization. Transcriptome sequencing and qPCR tests further confirmed that the antibacterial coating was able to inhibit the expression of multiple peptide resistance factor (mprF) and lipoteichoic acid modification D-alanylation genes (dltB and dltC) that can increase the net positive charge of bacterial cell wall to induce the resistance to cationic antimicrobial peptides. In vivo experiments confirmed that this poly(Phe10-stat-Lys12)-DOPA coating can both effectively prevent biofilm formation through surface contact sterilization and avoid local and systemic infections. Overall, we proposed a facile method for preparing antibacterial orthopedic implants with longer indwelling time and without inducing antimicrobial resistance by coating a polypeptide-based polymer on the implants.

Oxygen-generating polymer vesicles for enhanced sonodynamic tumor therapy.

The efficacy of sonodynamic therapy (SDT) is often limited by the insolubility of sonosensitizers and unfavorable hypoxia tumor microenvironment. To meet this challenge, an oxygen-generating polymer vesicle is developed to achieve enhanced SDT. The hydrophilic coronas and the hydrophobic membrane of polymer vesicles can function as different modules for the simultaneous delivery of manganese dioxide and chlorine e6 (designated as Ce6-MnO2-PVs). These Ce6-MnO2-PVs exhibited high catalase mimetic activity and could efficiently generate reactive oxygen species upon ultrasound activation. In vivo results showed that Ce6-MnO2-PVs almost completely eradicated the subcutaneous tumors (94% volume reduction) without any obvious systemic toxicity. Moreover, these Ce6-MnO2-PVs showed effective behavior for the attenuation of crucial tumor progression-releated factors. Specially, the expression levels of both hypoxia-inducible factor-1α and vascular endothelial growth factor at 4 h post-injection detected by immunofluorescence were reduced by 66% and 52%, respectively. These findings suggest that Ce6-MnO2-PVs may serve as an effective and safe platform for enahnced SDT in hypoxic tumors.

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.

Chirality-controlled polymerization-induced self-assembly.

Recent studies have shown that biodegradable nanoparticles can be efficiently prepared with polymerization of N-carboxyanhydrides-induced self-assembly (NCA-PISA). However, thus far, the effect of chiral monomer ratio on such NCA-PISA formulations and the resulting nanoparticles has not yet been fully explored. Herein, we show, for the first time, that the morphology, secondary structure, and biodegradation rate of PISA nanoparticles can be controlled by altering the chiral ratio of the core-forming monomers. This chirality-controlled PISA (CC-PISA) method allowed the preparation of nanoparticles that are more adjustable and applicable for future biomedical applications. Additionally, the complex secondary peptide structure (ratio of α-helix to ß-sheet) and π-π stacking affect the polymer self-assembly process. More specifically, a PEG45 macro-initiator was chain-extended with l- and d-phenylalanine (l- and d-Phe-NCA) in various molar ratios in dry THF at 15 wt%. This ring-opening polymerization (ROP) allowed the preparation of homo- and hetero-chiral Phe-peptide block copolymers that self-assembled in situ into nanoparticles. For homo-chiral formulations, polymers self-assembled into vesicles once a sufficiently high phenylalanine degree of polymerization (DP) was obtained. Hetero-chiral formulations formed larger nanoparticles with various morphologies and, much to our surprise, using an equal enantiomer ratio inhibited PISA and led to a polymer solution instead. Finally, it was shown that the enzymatic biodegradation rate of such PISA particles is greatly affected by the polymer chirality. This PISA approach could be of great value to fabricate nanoparticles that exploit chirality in disease treatment.

Hydrogels for the treatment of oral and maxillofacial diseases: current research, challenges, and future directions.

Oral and maxillofacial diseases such as infection and trauma often involve various organs and tissues, resulting in structural defects, dysfunctions and/or adverse effects on facial appearance. Hydrogels have been applied in the treatment of oral diseases and defect repair due to their three-dimensional network structure. With their biocompatible structure and unique stimulus-responsive property, hydrogels have been applied as an excellent drug-delivery system for treatments that mainly include oral mucosal diseases, wounds, periodontitis and cancer therapy. Hydrogels are also ideal scaffolds in regenerative engineering of dentin-pulp complex, periodontal tissue, bone and cartilage. This review discusses the fundamental structure of hydrogels in brief and then focuses on the characteristics and limitations in current research and applications of hydrogels. Finally, potential future directions are proposed.

Highly porous nitrogen-doped carbon superstructures derived from the intramolecular cyclization-induced crystallization-driven self-assembly of poly(amic acid).

Hierarchically porous carbon nanomaterials have shown significant potential in electrochemical energy storage due to the promoted charge and mass transfer. Herein, a facile template-free method is proposed to prepare nitrogen-doped carbon superstructures (N-CSs) with multi-level pores by pyrolysis of polymeric precursors derived from the intramolecular cyclization-induced crystallization-driven self-assembly (ICI-CDSA) of poly(amic acid) (PAA). The excellent thermal stability of PAA enables the N-CSs to inherit the hierarchical structure of the precursors during pyrolysis, which facilitates the formation of meso- and macropores while the decomposition of the precursors promotes the creation of micropores. Electrochemical tests demonstrate the ultrahigh surface-area-normalized capacitance (76.5 µF cm-2) of the N-CSs facilitated by the hierarchically porous structure, promoting the charge and mass transfer, as well as the high utilization of pyridinic and pyrrolic nitrogen (12.9%) to provide significant pseudocapacitance contribution up to 40.6%. Considering the diversity of monomers of PAA, this ICI-CDSA strategy could be extended to prepare carbon nanomaterials with various morphologies, pore structures and chemical compositions.

Intelligent design of polymersomes for antibacterial and anticancer applications.

Polymersomes (or polymer vesicles) have attracted much attention for biomedical applications in recent years because their lumen can be used for drug delivery and their coronas and membrane can be modified with a variety of functional groups. Thus, polymersomes are very suitable for improved antibacterial and anticancer therapy. This review mainly highlighted recent advances in the synthetic protocols and design principles of intelligent antibacterial and anticancer polymersomes. Antibacterial polymersomes are divided into three categories: polymersomes as antibiotic nanocarriers, intrinsically antibacterial polymersomes, and antibacterial polymersomes with supplementary means including photothermal and photodynamic therapy. Similarly, the anticancer polymersomes are divided into two categories: polymersomes-based delivery systems and anticancer polymersomes with supplementary means. In addition, the bilateral relationship between bacteria and cancer is addressed, since more and more evidences show that bacteria may cause cancer or promote cancer progression. Finally, prospective on next-generation antibacterial and anticancer polymersomes are discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.