Multifunctional Gene Delivery System Research Articles

Tea polyphenol nanoparticles enable targeted siRNA delivery and multi-bioactive therapy for abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier’s intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy.Graphical

PH-Responsive hyaluronic acid-cloaked polycation/gold nanohybrids for tumor-targeted synergistic photothermal/gene therapy.

The combination of photothermal therapy (PTT) and gene therapy (GT) has attracted intense interest in cancer treatment. However, the lack of long circulation and active tumor targeting reduces the therapeutic efficacy of complementary PTT/GT. In this work, hyaluronic acid (HA)-cloaked gold nanorods-PGED (prepared by ring-opening of polyglycidyl methacrylate (PGMA) with ethylenediamine (ED))/pDNA (AP/pDNA-HA) complexes were prepared to achieve long circulation and tumor targeting for photoacoustic imaging (PAI)-guided synergistic PTT/GT. Gold nanorods endow the complexes with photothermal effect and PAI function. Benefiting from the HA cloak, the AP/pDNA-HA complexes exhibit excellent stability, biocompatibility, long circulation behavior and active targeting. In addition, the pH-responsive characteristic of the Schiff base bonds helps the AP/pDNA-HA complexes to effectively escape from the endosome/lysosome. The antioncogene p53 was employed to investigate the gene transfection efficiency of the delivery system both in vitro and in vivo. The superiority of synergistic PTT/GT is established in a mouse 4T1 breast tumor model. The current study provides a facile strategy for constructing multifunctional gene delivery systems with long circulation and tumor targeting features, which can achieve effective imaging-guided synergistic tumor treatment.

GFP Plasmid and Chemoreagent Conjugated with Graphene Quantum Dots as a Novel Gene Delivery Platform for Colon Cancer Inhibition In Vitro and In Vivo.

Scientists have studied intensively the gene delivery carriers for treating genetic diseases. However, there are challenges that impede the application of naked gene-based therapy at the clinical level, such as quick elimination of the circulation, lack of membrane penetrability, and poor endosome trapping. Herein, we develop graphene quantum dots (GQDs)-derivative nanocarriers and introduce polyethylenimine (PEI) to equip the system with enhanced biocompatibility and abundant functional groups for modification. In addition to carrying green fluorescent protein (GFP) as an example of gene delivery, this system covalently binds colon cancer cells targeted antibody and epidermal growth factor receptor (EGFR) to enhance cell membrane penetrability and cell uptake of nanocarriers. To achieve multistrategy cancer therapy, the anticancer drug doxorubicin (Dox) is noncovalently encapsulated to achieve pH-induced drug release at tumor sites and leaves space for further functional gene modification. This nanoparticle serves as a multifunctional gene delivery system, which facilitates improved cytotoxicity and longer-sustained inhibition capacity compared to free Dox treatments in colon cancer cells. Moreover, our GQD composites display compatible tumor suppression ability compared with the free Dox treatment group in xenograft mice experiment with significantly less toxicity. This GQD nanoplatform was demonstrated as a multifunctional gene delivery system that could contribute to treating other genetic diseases in the future.

Construction of traceable cucurbit[7]uril-based virus-mimicking quaternary complexes with aggregation-induced emission for efficient gene transfection.

Construction of an efficient cationic gene delivery system with low cytotoxicity, high transfection efficacy, as well as gene tracking function remains a major challenge in gene therapy. Fabrication of simple and reversible nanocomplexes based on host-guest interaction provides an opportunity to construct stimuli-responsive intelligent supramolecular systems. Inspired by the hierarchical structure of viruses, a novel virus-mimicking PG/CB/TPE/DNA gene delivery system is developed via a multistep noncovalent self-assembly process between pDNA and the preformed PG/CB/TPE complexes based on the host-guest interaction between cucurbit[7]uril (CB[7]) and the protonated diamine group in the poly(glycidyl methacrylate)s derivative (PG), as well as the electrostatic interaction between para-carboxyl functionalized tetraphenylethylene (TPE) and cationic PG. The developed efficient multifunctional gene delivery system exhibits stimuli responsive characteristics and aggregation-induced emission phenomena, thereby enabling gene delivery pH responsiveness and traceability. Moreover, the introduction of TPE and CB[7] endows the self-assembled PG/CB/TPE/DNA complexes with virus-mimicking architecture and properties such as low cytotoxicity, high stability, excellent endosomal escape, and efficient transfection, which are expected to be used as a promising gene delivery system.

Organic/inorganic nanohybrids as multifunctional gene delivery systems.

In this review, we summarize the rational design and versatile application of organic/inorganic hybrid gene carriers as multifunctional delivery systems. Organic/inorganic nanohybrids with both organic and inorganic components in one nanoparticle have attracted intense attention because of their favorable properties. Particularly, nanohybrids comprising cationic polymers and inorganic nanoparticles are considered to be promising candidates as multifunctional gene delivery systems. In this review, we begin with an introduction of gene delivery and gene carriers to demonstrate the incentive for fabricating nanohybrids as multifunctional carriers. Next, the construction strategies and morphology effects of organic/inorganic hybrid gene carriers are summarized and discussed. Both sections provide valuable information for the design and synthesis of hybrid gene carriers with superior properties. Finally, an overview is provided of the application of nanohybrids as multifunctional gene carriers. Diverse therapies and versatile imaging-guided therapies have been achieved via the rational design of nanohybrids. In addition to a simple combination of the functions of organic and inorganic components, the performances arising from the synergistic effects of both components are considered to be more intriguing. In summary, this review might offer guidance for the understanding of organic/inorganic nanohybrids as multifunctional gene delivery systems.

Multifunctional gene delivery systems with targeting ligand CAGW and charge reversal function for enhanced angiogenesis.

Gene delivery systems with good biocompatibility and high transfection efficiency play a major role in the clinical application of gene therapy. It is of great interest to develop a functional anionic polymer to modify polycationic carriers for the purpose of improving their biocompatibility and gene delivery ability. Herein, we prepared three kinds of anionic polymers, i.e., cis-aconitic anhydride grafted poly(l-lysine) (PLCA), cis-aconitic anhydride and CAGW functional peptide grafted poly(l-lysine) (PLCA-CAGW), and succinic anhydride and CAGW peptide grafted poly(l-lysine) (PLSA-CAGW), and coated them onto binary gene complexes to obtain three ternary complexes, i.e., TCP-CA, TCP-CA-CAGW and TCP-SA-CAGW, respectively. These gene delivery systems were integrated with a specific functional peptide and smart polyplexes that enabled them to perform a desired function in response to pH changes in biological microenvironments. The results of the cell viability assay showed that the prepared anionic polymers could improve the biocompatibility of gene complexes. Gene expression at the mRNA and protein levels demonstrated that TCP-CA-CAGW enhanced the gene delivery efficiency, benefiting from the targeting CAGW peptide and charge reversal moiety (cis-aconitic amide), while TCP-SA-CAGW showed a relatively low transfection efficiency because of negatively charged PLSA-CAGW and its non-reversal function. The PLCA-CAGW shell in TCP-CA-CAGW possessed an aconitic acid group, EC targeting ligand and charge reversal cis-aconitic amide, which enabled the gene delivery systems to be neutral in blood circulation, but once in the acidic lysosomes, they became positively charged for improving lysosomal escape and nuclear localization. Importantly, the in vitro/vivo angiogenesis assay demonstrated that human umbilical vein endothelial cells transfected with TCP-CA-CAGW functionalized ternary complexes could obviously enhance vascularization. These multifunctional ternary complexes with functional smart anionic polymer shells possessed low cytotoxicity and high gene delivery efficiency, and this strategy may be a promising platform for cardiovascular gene therapy.

A multifunctional polymeric gene delivery system for circumventing biological barriers.

Aiming to circumvent the pre-defined obstacles in the journey of gene transportation, we attempt to compile a number of functional components into a tandem tri-copolymeric material. Herein, a β-cyclodextrin-functionalized poly(glycerol methacrylate) (PG) segment and a quaternary amine-functionalized poly[(2-acryloyl)-ethyl-(p-boronic acid pinacol ester benzyl)diethylammonium bromide] (BP) segment are attached to complex DNA to formulate a nanoscaled delivery system based on electrostatic interactions. The formulated polyplex is strengthened by a hydrophobic poly[2-(5,5-dimethyl-1,3-dioxan-2-yloxy)ethyl acrylate] (PDM) segment, affording improved complex stability. To retrieve the polyplex from entrapment by acidic and digestive endo/lysosomes, light-stimulated ROS-producing 4,4'-(1,2-diphenylethene-1,2-diyl)bis(1,4-phenylene)diboronic acid (TPE) is installed in the cavities of cyclodextrin. Upon light irradiation, TPE is triggered to produce abundant ROS, not only committing disruption of the endo/lysosome membrane for polyplex escape from the entrapment but also inducing the transformation of the positively charged BP to become negatively charged. This charge conversion behavior, together with the transformation of PDM to be hydrophilic and responsive to an acidic endosome pH gradient (pH 5.0) is envisioned to induce the dissociation of the electrostatically-assembled polyplex, thereby facilitating the release of the DNA payload for the subsequent transcription machinery. This strategically-tailored and easily synthesized tandem tri-copolymer exhibits excellent gene expression activity and provides a facile response to endogenous and exogenous stimuli for active gene expression.

A flexible bowl-shaped magnetic assembly for multifunctional gene delivery systems.

Magnetic assemblies with special morphologies are promising for versatile biomedical applications due to their intriguing properties and performances. In this work, a polycation-functionalized bowl-shaped magnetic assembly (b-MNP-PGEA) was constructed for magnetic resonance imaging (MRI)-guided synergistic cancer therapy. Taking advantage of distinct properties of Fe3O4 nanoparticles, self-assembly concept, morphology control, and appropriate surface functionalization, the as-prepared magnetic assembly with special morphology was expected to work as a multifunctional carrier to realize the combination of magnetofection and photothermal therapy (PTT). The morphology effect of the magnetic assembly on cellular uptake and the subsequent gene transfection were investigated. The feasibility of the magnetic and photothermal carriers for MRI and complementary PTT/gene therapy was also studied. In addition, the excellent in vivo performance of the proposed bowl-shaped multifunctional carriers was demonstrated using a mouse breast cancer model. Interestingly, synergistic effects based on PTT-enhanced gene therapy were achieved. The facile assembly strategy for the development of special bowl-shaped magnetic carriers for synergistic PTT/gene therapy provides a new avenue for the versatile construction of efficient theranostic platforms.

A multi-functional macrophage and tumor targeting gene delivery system for the regulation of macrophage polarity and reversal of cancer immunoresistance.

To achieve effective tumor eradication using anti-tumor immunotherapies, a fusion peptide functionalized gene delivery system for macrophage and tumor targeting delivery of the plasmid DNA encoding the IL-12 gene (pDNA IL-12) was prepared for macrophage re-polarization as well as reversal of cancer immunosuppression. A fusion peptide containing the tuftsin sequence that can interact with Fc receptors and neuropilin-1, and hyaluronic acid (HA) that can interact with CD44 were introduced into the delivery system by self-assembly to form peptide/hyaluronic acid/protamine/CaCO3/DNA nanoparticles (PHNP) with both macrophage targeting and tumor targeting capabilities. PHNP provides an efficient immunoregulation on J774A.1 cells to shift the anti-inflammatory M2 phenotype to the anti-tumor M1 phenotype with enhanced secretion of pro-inflammatory cytokines and increased expression of M1 markers. Owing to the improved delivery efficiency caused by the fusion peptide and HA, the transfection mediated by multi-functional PHNP can up-regulate IL-12 as well as down-regulate IL-10 and IL-4 more effectively as compared with the nanoparticles without HA and/or peptide decoration. More importantly, the gene delivery system can also deliver pDNA IL-12 to targeted cancerous HeLa cells to realize the secretion of IL-12. PHNP not only enables tumorous cells to produce pDNA IL-12, but also down-regulates CD47 and up-regulate CD80 and HLA-1 in the malignant cells, indicating that the gene delivery system can effectively reverse tumor induced immunosuppression.

Multifunctional Nucleus-targeting Nanoparticles with Ultra-high Gene Transfection Efficiency for In Vivo Gene Therapy.

Cancer stem cell-like cells (CSCL) are responsible for tumor recurrence associated with conventional therapy (e.g. surgery, radiation, and chemotherapy). Here, we developed a novel multifunctional nucleus-targeting nanoparticle-based gene delivery system which is capable of targeting and eradicating CSCL. These nanoparticles can facilitate efficient endosomal escape and spontaneously penetrate into nucleus without additional nuclear localization signal. They also induced extremely high gene transfection efficiency (>95%) even in culture medium containing 30% serum, which significantly surpassed that of some commercial transfection reagents, such as Lipofectamine 2000 and Lipofectamine 3000 etc. Especially, when loaded with the TRAIL gene, this system mediated remarkable depletion of CSCL. Upon systemic administration, the nanoparticles accumulated in tumor sites while sparing the non-cancer tissues and significantly inhibited the growth of tumors with no evident systemic toxicity. Taken together, our results suggest that these novel multifunctional, nucleus-targeting nanoparticles are a very promising in vivo gene delivery system capable of targeting CSCL and represent a new treatment candidate for improving the survival of cancer patients.

PGMA-Based Cationic Nanoparticles with Polyhydric Iodine Units for Advanced Gene Vectors.

It is crucial for successful gene delivery to develop safe, effective, and multifunctional polycations. Iodine-based small molecules are widely used as contrast agents for CT imaging. Herein, a series of star-like poly(glycidyl methacrylate) (PGMA)-based cationic vectors (II-PGEA/II) with abundant flanking polyhydric iodine units are prepared for multifunctional gene delivery systems. The proposed II-PGEA/II star vector is composed of one iohexol intermediate (II) core and five ethanolamine (EA) and II-difunctionalized PGMA arms. The amphipathic II-PGEA/II vectors readily self-assemble into well-defined cationic nanoparticles, where massive hydroxyl groups can establish a hydration shell to stabilize the nanoparticles. The II introduction improves cell viabilities of polycations. Moreover, by controlling the suitable amount of introduced II units, the resultant II-PGEA/II nanoparticles can produce fairly good transfection performances in different cell lines. Particularly, the II-PGEA/II nanoparticles induce much better in vitro CT imaging abilities in tumor cells than iohexol (one commonly used commercial CT contrast agent). The present design of amphipathic PGMA-based nanoparticles with CT contrast agents would provide useful information for the development of new multifunctional gene delivery systems.

Cell-Targeting Cationic Gene Delivery System Based on a Modular Design Rationale.

En route to target cells, a gene carrier faces multiple extra- and intracellular hurdles that would affect delivery efficacy. Although diverse strategies have been proposed to functionalize gene carriers for individually overcoming these barriers, it is challenging to generate a single multifunctional gene carrier capable of surmounting all these barriers. Aiming at this challenge, we have developed a supramolecular modular approach to fabricate a multifunctional cationic gene delivery system. It consists of two prefunctionalized modules: (1) a host module: a polymer (PCD-SS-PDMAEMA) composed of poly(β-cyclodextrin) backbone and disulfide-linked PDMAEMA arms, expectedly acting to compact DNA and release DNA upon cleavage of disulfide linkers in reductive microenvironment; and (2) a guest module: adamantyl and folate terminated PEG (Ad-PEG-FA), expectedly functioning to reduce nonspecific interactions, improve biocompatibility, and provide folate-mediated cellular targeting specificity. Through the host-guest interaction between β-cyclodextrin units of the "host" module and adamantyl groups of the "guest" module, the PCD-SS-PDMAEMA-1 (host) and Ad-PEG-FA (guest) self-assemble forming a supramolecular pseudocopolymer (PCD-SS-PDMAEMA-1/PEG-FA). Our comprehensive analyses demonstrate that the functions preassigned to the two building modules are well realized. The gene carrier effectively compacts DNA into stable nanosized polyplexes resistant to enzymatic digestion, triggers DNA release in reducing environment, possesses significantly improved hemocompatibility, and specifically targets folate-receptor positive cells. Most importantly, endowed with these predesigned functions, the PCD-SS-PDMAEMA-1/PEG-FA supramolecular gene carrier exhibits excellent transfection efficacy for both pDNA and siRNA. Thus, this work represents a proof-of-concept example showing the efficiency and convenience of an adaptable, modular approach for conferring multiple functions to a single supramolecular gene carrier toward effective in vivo delivery of therapeutic nucleic acids.

Versatile Types of MRI-Visible Cationic Nanoparticles Involving Pullulan Polysaccharides for Multifunctional Gene Carriers.

Owing to the low cytotoxicity and excellent biocompatibility, polysaccharides are good candidates for the development of promising biomaterials. In this paper, a series of magnetic resonance imaging (MRI)-visible cationic polymeric nanoparticles involving liver cell-targeting polysaccharides were flexibly designed for multifunctional gene delivery systems. The pullulan-based vector (PuPGEA) consisting of one liver cell-targeting pullulan backbone and ethanolamine-functionalized poly(glycidyl methacrylate) (denoted by BUCT-PGEA) side chains with abundant hydroxyl units and secondary amine was first prepared by atom transfer radical polymerization. The resultant cationic nanoparticles (PuPGEA-GdL or PuPGEA-GdW) with MRI functions were produced accordingly by assembling PuPGEA with aminophenylboronic acid-modified Gd-DTPA (GdL) or GdW10O36(9-) (GdW) via the corresponding etherification or electrostatic interaction. The properties of the PuPGEA-GdL and PuPGEA-GdW nanoparticles including pDNA condensation ability, cytotoxicity, gene transfection, cellular uptake, and in vitro and in vivo MRI were characterized in details. Such kinds of cationic nanoparticles exhibited good performances in gene transfection in liver cells. PuPGEA-GdW demonstrated much better MRI abilities. The present design of PuPGEA-based cationic nanoparticles with the liver cell-targeting polysaccharides and MRI contrast agents would shed light on the exploration of tumor-targetable multifunctional gene delivery systems.

A facile modular approach toward multifunctional supramolecular polyplexes for targeting gene delivery.

Extensive efforts and numerous methodologies have been explored to develop safe and efficient gene carriers that are capable of overcoming multiple extra- and intracellular barriers during the transfection process. However, it is a great challenge to fabricate a gene carrier system containing multiple functional components. In this work, we propose a facile modular approach to design targeted multifunctional gene delivery systems, which are based on building blocks with pre-defined functions to tackle specific barriers. These building blocks can be rationally combined and self-assemble into an integrated gene delivery system via host-guest interactions. As a proof of concept, three adamantyl-terminated targeting guest modules, adamantyl terminated RGD peptide (Ad-RGD), folate and lactobionic acid terminated PEGs (FA-PEG-Ad and LA-PEG-Ad), were synthesized, characterized, and utilized for post-functionalizing of adamantyl decorated cationic PEI based supramolecular polyplexes (PEI-Ad4/PCD/DNA) through the free CD units of the poly(β-cyclodextran) (PCD) host module. These multifunctional targeting supramolecular polyplexes exhibited enhanced cellular uptake and excellent transfection activity in receptor-positive cells. By modulating the functional components of the supramolecular platform, we can customize the gene carriers for further research on different tissues or cells in vitro or in vivo.

Prussian blue nanoparticle-loaded microbubbles for photothermally enhanced gene delivery through ultrasound-targeted microbubble destruction

By adsorbing chitosan (CS)-functionalized Prussian blue (PB) nanoparticles (CS/PB NPs) complexing DNA onto the surface of gas encapsulated microbubbles (MBs), a multifunctional gene delivery system of MBs@CS/PB/DNA was fabricated for photothermally enhanced gene transfection through ultrasound-targeted microbubble destruction. CS/PB NPs of (2.69 ± 0.49)nm could complex DNA effectively when the mass ratio was 2:1. It was found that MBs@CS/PB/DNA could enhance ultrasound imaging greatly both in vitro and in vivo. In addition, MBs@CS/PB/DNA could be disrupted by applying a higher-intensity ultrasound irradiation to release CS/PB/DNA, which could effectively transform the near-infrared (NIR) light into heat to assist the uptake of CS/PB/DNA by cells. With the aid of ultrasound irradiation and NIR light irradiation, the gene transfection efficiency was significantly enhanced to (43.08 ± 1.13)%, much higher than polyethylenimine. Moreover, MBs@CS/PB/DNA showed excellent biocompatibility, encouraging the further exploration of MBs@CS/PB/DNA to be a platform for combined ultrasound image, photothermal therapy, drug delivery, and gene therapy.

Functionalized PGMA nanoparticles with aggregation-induced emission characteristics for gene delivery systems

AIE fluorogen conjugated cationic nanoparticles with excellent bioimaging abilities and stable morphologies were designed for multifunctional gene delivery systems.

Multifunctional cationic polyurethanes designed for non-viral cancer gene therapy

Nano-polyplexes from bioreducible cationic polymers have a massive promise for cancer gene therapy. However, the feasibility of cationic polyurethanes for non-viral gene therapy is so far not well studied. In this work, a linear cationic polyurethane containing disulfide bonds, urethane linkages and protonable tertiary amino groups was successfully generated by stepwise polycondensation reaction between 2,2′-dithiodiethanol bis(p-nitrophenyl carbonate) and 1,4-bis(3-aminopropyl)piperazine (BAP). We confirmed that the cationic polyurethane (denoted as PUBAP) displayed superior gene delivery properties to its cationic polyamide analogue, thus causing higher in vitro transfection efficiency in MCF-7 and SKOV-3 cells. Besides, further folate-PEGylation and hydrophobic deoxycholic acid (DCA) conjugation to amino-containing PUBAP can be conducted to afford multifunctional polyurethane gene delivery system. After optimization, folate-decorated nano-polyplexes from the PUBAP conjugated with 8 folate-PEG chains and 12 DCA residues exhibited superb colloidal stability under physiological conditions, and performed rapid uptake via folate receptor-mediated endocytosis, efficient intracellular gene release and nucleus translocation into SKOV-3 cells in vitro and in vivo. Importantly, PUBAP based polyplexes possess low cytotoxicity as a result of PUBAP biodegradability. Therefore, marked growth inhibition of SKOV-3 tumor xenografted in Balb/c nude mice was achieved with negligible side effects on the mouse health after intravenous administration of PUBAP based polyplexes with a therapeutic plasmid encoding for TNF-related apoptosis-inducing ligand. This work provides a new insight into biomedical application of bio-responsive polyurethanes for cancer therapy. Statement of significanceIn this study, we have confirmed that disulfide-based cationic polyurethane presents a new non-viral vector for gene transfer and cancer gene therapy. The significance of this work includes: (1) design and synthesis of a group of novel disulfide-based cationic polyurethane by non-isocyanate chemistry; (2) comparative study of transfection activity between cationic polyurethanes and cationic polyamides; (3) feasibility of bioreducible cationic polyurethanes for in vivo cancer gene therapy.

Gd(III) ion-chelated supramolecular assemblies composed of PGMA-based polycations for effective biomedical applications

Ethanolamine (EA) or ethylenediamine (ED)-functionalized poly(glycidyl methacrylate) (PGMA), namely PGEA or PGED, has recently been used as effective gene carriers because of their low cytotoxicity and high transfection efficiency. In this study, a series of PGMA-based supramolecular polycations (PGED-Gd@PGEAs) with magnetic resonance imaging (MRI) functions were readily constructed by assembling multiple adamantine-headed star PGEA (Ad-PGEA) units with a versatile PGED-CD-Gd backbone, which possessed numerous flanking β-cyclodextrin species and Gd3+ ions. The properties of different PGED-Gd@PGEA vectors were systematically characterized, including the plasmid DNA condensation ability, cytotoxicity, gene transfection efficiency, cellular uptake and MRI function. Such supramolecular gene vectors had lower toxicity than ‘gold standard’ polyethylenimine (PEI, 25 kDa). Furthermore, PGED-Gd@PGEAs exhibited significantly higher transfection efficiencies than PEI or the constituent units (PGED-CD-Gd and Ad-PGEA). The chelation of Gd3+ ions imparted the PGED-Gd@PGEA vectors with a good MRI ability without obvious adverse effects. The present design of PGMA-based supramolecular polycations with Gd3+ chelation would provide useful information for the development of low-toxicity and high-efficiency multifunctional gene delivery systems. An intricate polymer complex can carry genes to their cellular targets with high efficiency and low toxicity. Gene therapy has the potential to revolutionize the treatment of diseases such as cancer, but non-viral gene delivery systems are needed to ensure patient safety. Fu-Jian Xu from the Beijing University of Chemical Technology and co-workers have taken steps to reach this goal by assembling cationic polymers and gadolinium (Gd) ions into spherical, supramolecular host-guest complexes. These compounds, based on biocompatible poly(glycidyl methacrylate) and cyclodextrin molecules, can be size adjusted to ensure the nanoparticles have the correct dimensions for optimal cellular uptake. The addition of Gd ions turns the multifunctional delivery device into a magnetic resonance imaging probe for in vivo monitoring of nucleic acid transfer. A series of new poly(glycidyl methacrylate)-based supramolecular polycations with Gd3+ chelation were designed for low-toxicity and high-efficiency multifunctional gene delivery systems.

PGMA-based starlike polycations with flanking phenylboronic acid groups for highly efficient multifunctional gene delivery systems

A simple strategy to prepare starlike PGMA-based vectors with phenylboronic acid groups was proposed for multifunctional gene delivery systems.

Polycation-b-polyzwitterion copolymer grafted luminescent carbon dots as a multifunctional platform for serum-resistant gene delivery and bioimaging.

Nanomaterials that integrate functions of imaging and gene delivery have been of great interest due to their potential use in simultaneous diagnosis and therapy. Herein, polycation-b-polysulfobetaine block copolymer, poly[2-(dimethylamino) ethyl methacrylate]-b-poly[N-(3-(methacryloylamino) propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] (PDMAEMA-b-PMPDSAH) grafted luminescent carbon dots (CDs) were prepared via surface-initiated atom transfer radical polymerization (ATRP) and investigated as a multifunctional gene delivery system (denoted as CD-PDMA-PMPD) in which the CD cores acted as good multicolor cell imaging probes, the cationic PDMAEMA acted as a DNA condensing agent, and the outer shell of zwitterionic PMPDSAH block protected the vector against nonspecific interactions with serum components. As revealed by the fluorescent spectrum study, the photoluminescent attributes, especially the tunable emission property, were well inherited from the parent CDs. The CD-PDMA-PMPD could condense plasmid DNA into nanospheres with sizes of approximate 50 nm at a proper complex ratio, posing little cytotoxicity at higher ratios. It was shown that the hybrid vector exhibited significantly suppressed BSA protein adsorption and superior hemocompatibility compared to those of the widely used PEI25k. In the in vitro transfection assay, an increased serum concentration from 10 to 50% caused a dramatic drop in PEI25k transfection performance, whereas the transfection efficiency of CD-PDMA-PMPD was well maintained; CD-PDMA80-PMPD40 showed 13 and 28 times higher transfection efficiencies than PEI25k at 30 and 50% serum concentration, respectively. Intriguingly, the carbon dots in the transfected cells displayed excitation-dependent fluorescent emissions, portending that this polycation-polyzwitterion modified CD will be a promising theranostic vector with excellent stealth performance.