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.

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.

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.

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.

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.

Ultrasound-Responsive Peptide Nanogels to Balance Conflicting Requirements for Deep Tumor Penetration and Prolonged Blood Circulation.

A series of biological barriers need to be overcome for therapeutic nanocarriers accumulating at the tumor site and uptaken by cancer cells. One strategy is to construct switchable nanocarriers to meet the conflicting requirements for various physiology environments. In this work, besides widely studied endogenous stimuli-responsiveness, an exogenous ultrasound responsiveness was additionally embedded into nanocarriers to balance the conflicting needs of prolonged blood circulation and deep tumor penetration. Polylysine and Pluronic F127 were first coassembled and then cross-linked by genipin to form stable nanogel structure. Subsequently, ICAM-1 antibody was grafted onto the nanogel (designated as GenPLPFT) for active tumor targeting. Upon external sonication, the F127 was shed from GenPLPFT to induce swelling of nanogel with reduced stability and accelerated drug release. In detail, sonication leads to GenPLPF swelling from 329 to 516 nm, while its Young's modulus significantly decreased from 336.78 to 3.93 kPa. Through intravenous injection, relatively rigid GenPLPFT was able to achieve a high level of accumulation at tumor site by active targeting and long-term blood circulation. Moreover, under sonication at the tumor site, GenPLPFT became softer with enhanced deformability to achieve deep tumor penetration. In addition, in vivo studies revealed that GenPLPFT was able to penetrate into the deep area of xenografted tumor with enhanced antitumor efficacy and reduced toxicity. Overall, this peptide nanogel with ultrasound-responsive stiffness demonstrates an effective approach to overcome a series of biological barriers for enhanced deep tumor 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.

Mitochondrial-targeting nanoprodrugs to mutually reinforce metabolic inhibition and autophagy for combating resistant cancer.

Abnormal energy metabolism is one of the hallmarks of cancer and closely linked to therapy resistance. However, existing metabolic inhibitors suffer from inefficient cell enrichment and therapeutic effects. In this work, we developed an effective strategy to mutually reinforce the metabolic inhibition and autophagy for enhanced tumor killing efficacy and combating resistant cancer. First, mitochondrial homing moiety triphenylphosphonium and metabolic inhibitor lonidamine were grafted onto polylysine. After self-assembly of this functionalized polylysine, ferrocene and glucose oxidase were immobilized to afford additional chemotherapy functions, and the final product was named as FG/T-Nanoprodrug. Effective mitochondrial targeting and metabolic inhibition were observed in resistant cancer cells. In addition, owing to the inhibited metabolism, less glucose is consumed to allow FG/T-Nanoprodrug to produce excess reactive oxygen species (ROS) by glucose oxidase and ferrocene. The enhanced chemodynamic therapy increases the mitochondrial permeability to promote the release of cytochrome c from mitochondria, ultimately induces high levels of autophagy. The FG/T-Nanoprodrug demonstrated superior mutually reinforcing of metabolic inhibition (up to 3.7-fold compared to free lonidamine) and autophagy (up to 125.3-fold compared to free lonidamine) to effectively kill resistant cancer cell both in vitro and in vivo. Overall, this strategy could pave a new way to efficient treatment of resistant cancer and other metabolically abnormal diseases.

Bioreducible, arginine-rich polydisulfide-based siRNA nanocomplexes with excellent tumor penetration for efficient gene silencing.

RNA interference (RNAi) technology has great potential in cancer therapy, e.g., small interfering RNA (siRNA) can be exploited to silence specific oncogenes related to tumor growth and progression. However, it is critical to achieve high transfection efficiency while reducing cytotoxicity. In this paper, we report an siRNA delivery strategy targeting the oncogene KRAS based on arginine-modified poly(disulfide amine)/siRNA nanocomplexes. The poly(disulfide amine) is synthesized via aza-Michael polyaddition followed by the introduction of arginine groups onto its backbone to afford poly((N,N'-bis(acryloyl)cystamine-co-ethylenediamine)-g-Nω-p-tosyl-l-arginine) (PBR) polycations. Thus multiple interactions including electrostatic interaction, hydrogen bonding and a hydrophobic effect are introduced simultaneously between PBR and siRNA or cell membranes to improve transfection efficiency. By optimizing the grafting density of arginine groups, PBR/siRNA nanocomplexes achieve high cellular uptake efficiency, successful endosomal/lysosomal escape, and rapid biodegradation in the presence of high GSH concentration in the cytoplasm, and finally release siRNA to activate the RNAi mechanism. Additionally, compared to commercially available PEI 25K, PBR/siRNA nanocomplexes possess a significantly increased gene silencing effect on human pancreatic cancer cells (PANC-1) with decreased cytotoxicity and enhanced tumor penetration ability in PANC-1 multicellular spheroids in vitro. Overall, with both GSH-responsiveness and excellent tumor penetration, this safe and efficient poly(disulfide amine)-based siRNA delivery system is expected to provide a new strategy for gene therapy of pancreatic cancer and other stromal-rich tumors.

Recent progress on charge-reversal polymeric nanocarriers for cancer treatments.

Nanocarriers (NCs) for delivery anticancer therapeutics have been under development for decades. Although great progress has been achieved, the clinic translation is still in the infancy. The key challenge lies in the biological barriers which lie between the NCs and the target spots, including blood circulation, tumor penetration, cellular uptake, endo-/lysosomal escape, intracellular therapeutics release and organelle targeting. Each barrier has its own distinctive microenvironment and requires different surface charge. To address this challenge, charge-reversal polymeric NCs have been a hot topic, which are capable of overcoming each delivery barrier, by reversing their charges in response to certain biological stimuli in the tumor microenvironment. In this review, the triggering mechanisms of charge reversal, including pH, enzyme and redox approaches are summarized. Then the corresponding design principles of charge-reversal NCs for each delivery barrier are discussed. More importantly, the limitations and future prospects of charge-reversal NCs in clinical applications are proposed.

Ultrasound-responsive polymer-based drug delivery systems.

Ultrasound-responsive polymeric materials have received a tremendous amount of attention from scientists for several decades. Compared to other stimuli-responsive materials (such as UV-, thermal-, and pH-responsive materials), these smart materials are more applicable since they allow more efficient drug delivery and targeted treatment by fairly non-invasive means. This review describes the recent advances of such ultrasound-responsive polymer-based drug delivery systems and illustrates various applications. More specifically, the mechanism of ultrasound-induced drug delivery, typical formulations, and biomedical applications (tumor therapy, disruption of blood-brain barrier, fighting infectious diseases, transdermal drug delivery, and enhanced thrombolysis) are summarized. Finally, a perspective on the future research directions for the development of ultrasound-responsive polymeric materials to facilitate a clinical translation is given.

Bone-targeting polymer vesicles for simultaneous imaging and effective malignant bone tumor treatment.

We present a bone-targeting polymer vesicle with excellent single photon emission computed tomography/computed tomography (SPECT/CT) imaging capability and high antitumor drug delivery efficiency as an integrated platform for the simultaneous diagnosing and treatment of malignant bone tumors. This polymer vesicle can be self-assembled from poly(ε-caprolactone)67-b-poly[(L-glutamic acid)6-stat-(L-glutamic acid-alendronic acid)16] (PCL67-b-P[Glu6-stat-(Glu-ADA)16]), directly in water without the aid of a cosolvent. SPECT/CT dynamically tracked the drug distribution in the bone tumor rabbit models, and the tumor size was significantly reduced from >2.0 cm3 to <0.6 cm3 over 11 days. The pathological analysis demonstrated obvious necrosis and apoptosis of the tumor cells. Overall, this bone-targeting polymer vesicle provides us with a new platform for the combination of real-time diagnosis and therapy of malignant bone tumors.

Effective treatment of drug-resistant lung cancer via a nanogel capable of reactivating cisplatin and enhancing early apoptosis.

Cisplatin resistance is a daunting obstacle in cancer therapy and one of the major causes for treatment failure due to the inadequate drug activity and apoptosis induction. To overcome cisplatin resistance, we proposed a multifunctional nanogel (designated as Valproate-D-Nanogel) capable of reactivating cisplatin and enhancing early apoptosis. This Valproate-D-Nanogel was prepared through copolymerizing carboxymethyl chitosan with diallyl disulfide and subsequent grafting with valproate to reverse the drug-resistance in cisplatin-resistant human lung adenocarcinoma cancer. It can significantly increase the proportion of G2/M phase (up to 3.2-fold enhancement) to reactivate cisplatin via high level of G2/M arrest induced by valproate. Meanwhile, the intracellular ROS-P53 crosstalk can be upregulated by diallyl disulfide (up to 8-fold increase of ROS) and valproate (up to 18-fold increase of P53) to enhance early apoptosis. The synchronization of enhanced G2/M arrest and ROS-P53 crosstalk devotes to reverse the cisplatin resistance with a high level of resistance reversion index (50.22). As a result, improved in vivo tumor inhibition (up to 15-fold higher compared to free cisplatin) and decreased systemic toxicity was observed after treatment with Valproate-D-Nanogels. Overall, this nanogel can effectively inhibit cisplatin-resistance cancer through combined pathways and provides an effective approach for overcoming cisplatin-resistance in cancer treatment.

Design principles, synthesis and biomedical applications of polymer vesicles with inhomogeneous membranes.

Inspired by cell membrane structures, synthetic polymer vesicles caused great expectations for the preparation of biomedicine for decades. However, in contrast to bio-membranes, which consist of inhomogeneous features, conventional synthetic polymer vesicles usually consist of a homogeneous membrane which is purely made out of hydrophobic components. This significantly limited the versatility of synthetic polymer vesicle membranes. Fortunately, polymer vesicles with inhomogeneous membranes were recently developed to address this limitation. These new inhomogeneous membrane features introduced secondary functions to the vesicle membrane. Indeed, the membrane of polymer vesicles no longer only serves as a simple barrier that separates the interior from the exterior environment. Introduced membrane features can act as a versatile platform for tailorable nanoparticle functionalities, which allow functions such as biomacromolecule transportation, diabetes treatment, and cancer theranostics. This review highlights recent advances made with polymer vesicles with inhomogeneous membrane structures. More specifically, design principles, biomedical applications, and the future perspectives of such vesicles are summarized.