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The development of safe and efficient gene carriers is the key to the clinical success of gene therapy. The present study was designed to develop and evaluate the chitosan-graft-polyethylenimine (CP)/DNA nanoparticles as novel non-viral gene vectors for gene therapy of osteoarthritis. The CP/DNA nanoparticles were produced through a complex coacervation of the cationic polymers with pEGFP after grafting chitosan (CS) with a low molecular weight (Mw) PEI (Mw = 1.8 kDa). Particle size and zeta potential were related to the weight ratio of CP:DNA, where decreases in nanoparticle size and increases in surface charge were observed as CP content increased. The buffering capacity of CP was significantly greater than that of CS. The transfection efficiency of CP/DNA nanoparticles was similar with that of the Lipofectamine™ 2000, and significantly higher than that of CS/DNA and PEI (25 kDa)/DNA nanoparticles. The transfection efficiency of the CP/DNA nanoparticles was dependent on the weight ratio of CP:DNA (w/w). The average cell viability after the treatment with CP/DNA nanoparticles was over 90% in both chondrocytes and synoviocytes, which was much higher than that of PEI (25 kDa)/DNA nanoparticles. The CP copolymers efficiently carried the pDNA inside chondrocytes and synoviocytes, and the pDNA was detected entering into nucleus. These results suggest that CP/DNA nanoparticles with improved transfection efficiency and low cytotoxicity might be a safe and efficient non-viral vector for gene delivery to both chondrocytes and synoviocytes.

The cellular transport process of DNA is hampered by cell membrane barriers, and hence, a delivery vehicle is essential for realizing the potential benefits of gene therapy to combat a variety of genetic diseases. Virus-based vehicles are effective, although immunogenicity, toxicity and cancer formation are among the major limitations of this approach. Cationic polymers, such as polyethyleneimine are capable of condensing DNA to nanoparticles and facilitate gene delivery. Lack of biodegradation of polymeric gene delivery vehicles poses significant toxicity because of the accumulation of polymers in the tissue. Many attempts have been made to develop biodegradable polymers for gene delivery by modifying existing polymers and/or using natural biodegradable polymers. This review summarizes mechanistic aspects of gene delivery and the development of biodegradable polymers for gene delivery.

Stimuli-responsive biomaterials that contain logic gates hold great potential for detecting and responding to pathological markers as part of clinical therapies. However, a major barrier is the lack of a generalized system that can be used to easily assemble different ligand-responsive units to form programmable nanodevices for advanced biocomputation. Here we develop a programmable polymer library by including responsive units in building blocks with similar structure and reactivity. Using these polymers, we have developed a series of smart nanocarriers with hierarchical structures containing logic gates linked to self-immolative motifs. Designed with disease biomarkers as inputs, our logic devices showed site-specific release of multiple therapeutics (including kinase inhibitors, drugs and short interfering RNA) in vitro and in vivo. We expect that this ‘plug and play’ platform will be expanded towards smart biomaterial engineering for therapeutic delivery, precision medicine, tissue engineering and stem cell therapy.A programmable polymer library that responds to external and internal stimuli has been developed and used to fabricate a series of nanocarriers for drug release. The carriers respond to disease biomarkers, triggering self-immolative motifs and leading to the site-specific release of therapeutics both in vitro and in vivo.

Objectives Carbon dots (CDs), as a fascinating class of fluorescent carbon nanomaterials, have been proven to be powerful tools in the field of bioimaging and biosensing due to their small size, suitable photostability and favourable biocompatibility. However, the cellular uptake of free CDs lacks selectivity and the same negative charges as cell membranes may cause inefficient cell internalization. In this study, an efficient detecting and targeting nanosystem was developed based on the DNA aptamer AS1411 modified CDs with polyethyleneimine (PEI) as connecting bridge. Materials and methods Hydrothermally prepared CDs were assembled with positive‐charged PEI, followed by conjugation with AS1411 through electrostatic interaction to form CDs‐PEI‐AS1411 nanocomplexes. The CDs, CDs‐PEI and CDs‐PEI‐AS1411 were characterized by transmission electron microscopy (TEM), fourier transform infrared (FTIR) spectra, UV–vis spectra, zeta potential measurements and capillary electrophoresis characterizations. The cytotoxicity investigation of the CDs‐PEI‐AS1411 and CDs‐PEI in both MCF‐7 and L929 cells was carried out by the CCK‐8 assay. The cellular uptake of the CDs‐PEI‐AS1411 was studied with confocal microscopy and flow cytometry. Results The as‐prepared nanosystem possessed good photostability and no obvious cytotoxicity. On the basis of the confocal laser scanning microscope observation and the flow cytometry studies, the cellular uptake of CDs‐PEI‐AS1411 nanosystem in MCF‐7 cells was significantly higher than that of L929 cells, which revealed the highly selective detection ability of nucleolin‐positive cells. Conclusions The results of this study indicated that the CDs‐PEI‐AS1411 nanosystem had a potential value in cancer cell targeted imaging.

Polymeric vectors are safer alternatives for gene delivery owing to their advantages as compared to viral vectors. To improve the stability and transfection efficiency of poly(lactic-co-glycolic acid) (PLGA)- and poly(ethylenimine) (PEI)-based vectors, poly(ethylene glycol) (PEG), folic acid (FA), arginylglycylaspartic acid (RGD) peptides and isoleucine-lysine-valine-alanine-valine (IKVAV) peptides were employed and PLGA–PEI–PEG–FA and PLGA–PEI–PEG–RGD copolymers were synthesized. PLGA–PEI–PEG–FA/DNA, PLGA–PEI–PEG–RGD/DNA and PLGA–PEI–PEG–RGD/IKVAV/DNA nanocomplexes (NCs) were formed through bulk mixing. The structure and properties, including morphology, particle size, surface charge and DNA encapsulation, of NCs were studied. Robust NCs with spherical shape, uniform size distribution and slightly positive charge were able to completely bind DNA above their respective N/P ratios. The critical N/P ratio for PLGA–PEI–PEG–FA/DNA, PLGA–PEI–PEG–RGD/DNA and PLGA–PEI–PEG–RGD/IKVAV/DNA NCs was identified to be 12:1, 8:1 and 10:1, respectively. The covalent modification of PEI through a combination of biodegradable PLGA, hydrophilic PEG and targeting motifs significantly decreased the cytotoxicity of PEI. The developed NCs showed both N/P ratio and cell type-dependent transfection efficiency. An increase in N/P ratio resulted in increased transfection efficiency, and much improved transfection efficiency of NCs was observed above their respective critical N/P ratios. This study provides a promising means to produce polymeric vectors for gene delivery.

Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio. This review addresses these perspectives and discusses molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity, including membrane destabilization, mitochondrial dysfunction, and perturbations of glycolytic flux and redox homeostasis as well as chemical strategies for the generation of better tolerated polycations. We further examine the effect of PEI and its derivatives on complement activation and interaction with Toll-like receptors. These perspectives are intended to lay the foundation for an improved understanding of interlinked mechanisms controlling transfection and toxicity and their translation for improved engineering of polycation-based transfectants. [Display omitted] Polycations such as polyethylenimines (PEIs) are widely used as non-viral transfectants, but they often induce cytotoxicity and may trigger immune reactions. Here we examine and discuss molecular events pertaining to dynamic and multifaceted PEI-mediated cytotoxicity and immune system modulation and their translation for improved and safer engineering of polycation-based transfectants.

Modifying chitosan (CS) with polyethylenimine (PEI) grafts is an effective way to improve its gene transfection performance. However, it is still a challenge to conduct the grafting with fine control and high efficiency, particularly for the modification of water-insoluble CS. Herein, a novel method to graft CS with PEI (1.8 kDa, PEI-1.8) was developed by using ionic liquid 1-butyl-3-methyl imidazolium acetate ([BMIM]Ac) as a reaction solvent, water-insoluble CS as a reaction substrate and 1,1-carbonyldiimidazole (CDI) as a linking agent. The grafting reaction was greatly accelerated and the reaction time was largely shortened to 4 h by taking advantages of the good solubility of CS, the enhanced nucleophilicity of amino groups and the preferential stability of the activated complexes in the ionic liquid. The chitosan-graft-polyethylenimine (CS-g-PEI) products were characterized by 1H NMR, FTIR and GPC. PEI-1.8 was quantitatively grafted to CS through urea linkages, and the grafting degree (GD) was conveniently tuned by varying the molar ratios of PEI-1.8 to D-glucosamine units of CS in the range of 9.0 × 10(-3) to 9.0 × 10(-2). Compared with CS, the synthesized CS-g-PEI copolymers showed higher pDNA-binding affinity, which increased with the GD as shown in Agarose gel electrophoresis. The dynamic light scattering (DLS) experiment demonstrated that the CS-g-PEI/pDNA polyplexes had suitable particle sizes and proper ζ-potentials for cell transfection. The CS-g-PEI copolymer with a medium GD of 4.5% conferred the best gene transfection, with the efficiency 44 times of CS and 38 times of PEI-1.8 in HEp-2 cells. The cytotoxicity of CS-g-PEI was tested and found nearly as low as that of CS and much lower than that of PEI.

A series of polyethyleneimine (PEI) incorporated MIL-101 adsorbents with different PEI loadings were reported for the first time in the present work. Although the surface area and pore volume of MIL-101 decreased significantly after loading PEI, all the resulting composites exhibited dramatically enhanced CO 2 adsorption capacity at low pressures. At 100 wt% PEI loading, the CO 2 adsorption capacity at 0.15 bar reached a very competitive value of 4.2 mmol g −1 at 25°C and 3.4 mmol g −1 at 50°C. More importantly, the resulting adsorbents displayed rapid adsorption kinetics and ultrahigh selectivity for CO 2 over N 2 in the designed flue gas with 0.15 bar CO 2 and 0.75 bar N 2 . The CO 2 over N 2 selectivity was up to 770 at 25°C and 1200 at 50°C. We believe that the PEI based metal-organic frameworks is an attractive adsorbent for CO 2 capture.

Cancer metastases and recurrence after surgical resection remain an important cause of treatment failure. Here we demonstrate a general strategy to fabricate personalized nanovaccines based on a cationic fluoropolymer for post-surgical cancer immunotherapy. Nanoparticles formed by mixing the fluoropolymer with a model antigen ovalbumin, induce dendritic cell maturation via the Toll-like receptor 4 (TLR4)-mediated signalling pathway, and promote antigen transportation into the cytosol of dendritic cells, which leads to an effective antigen cross-presentation. Such a nanovaccine inhibits established ovalbumin-expressing B16-OVA melanoma. More importantly, a mix of the fluoropolymer with cell membranes from resected autologous primary tumours synergizes with checkpoint blockade therapy to inhibit post-surgical tumour recurrence and metastases in two subcutaneous tumour models and an orthotopic breast cancer tumour. Furthermore, in the orthotopic tumour model, we observed a strong immune memory against tumour rechallenge. Our work offers a simple and general strategy for the preparation of personalized cancer vaccines to prevent post-operative cancer recurrence and metastasis.A fluoropolymer-based cancer nanovaccine that delivers antigens directly to the cytosol of dendritic cells and elicits strong antitumour immune responses inhibiting tumour growth in animal models can be used to produce personalized treatment for post-surgical immunotherapy.

Hyperbranched polyethyleneimine having 25,000 Da molecular weight was functionalized by a simple sulfopropylation reaction, affording a novel N‐sulfopropylated PEI derivative (PEI‐SO3−). The successful introduction of N‐sulfopropyl and sulfobetaine groups to the amino groups of PEI was spectroscopically confirmed. Furthermore, the antibacterial and anti‐cyanobacterial activity of PEI‐SO3− in comparison to the parent PEI were investigated on two type heterotrophic bacteria, i. e., Gram (−) Escherichia coli and Gram (+) Staphylococcus Aureus bacteria, and one type of autotrophic cyanobacterium, i. e. Synechococcus sp. PCC 7942. Both PEI‐SO3− and PEI showed an enhanced, concentration‐dependent antibacterial and anti‐cyanobacterial activity against the tested bacteria strains, with PEI‐SO3− exhibiting higher activity than the parent PEI, signifying that the introduction of the sulfopropyl and sulfobetaine groups to the PEI amino groups enhanced the antibacterial and the anti‐cyanobacterial properties of PEI. In the case of cyanobacteria, PEI‐SO3− was found to affect the integrity of the photosynthetic system by the inhibition of Photosystem‐II electron transport activity. Cytocompatibility and hemocompatibility studies revealed that PEI‐SO3− exhibits high biocompatibility, suggesting that PEI‐SO3− could be considered as an attractive antibacterial and anti‐cyanobacterial candidate for various applications in the disinfection industry and also against the harmful cyanobacterial blooms. A novel N‐sulfopropylated hyperbranched polyethyleneimine derivative (PEI‐SO3−) was prepared by a simple sulfopropylation reaction. This derivative exhibited high biocompatibility simultaneously with antibacterial and anti‐cyanobacterial activity. Thus, PEI‐SO3− could be considered as an attractive antibacterial and anti‐cyanobacterial candidate for various applications in the disinfection industry or against the harmful cyanobacterial blooms.