Excess Positive Charge Research Articles

A Photothermal Polymeric Platform for Efficient and Safe Gene Transfection: When Polyethylenimine Collaborates with Indocyanine Green.

Gene transfection, defined by the delivery of nucleic acids into cellular compartments, stands as a crucial procedure in gene therapy. While branched polyethylenimine (PEI) is widely regarded as the "gold standard" for nonviral vectors, its cationic nature presents several issues, including nonspecific protein adsorption and notable cytotoxicity. Additionally, it often fails to achieve high transfection efficiency, particularly with hard-to-transfect cell types. To overcome these challenges associated with PEI as a vector for plasmid DNA (pDNA), the photothermal agent indocyanine green (ICG) is integrated with PEI and pDNA to form the PEI/ICG/pDNA (PI/pDNA) complex for more efficient and safer gene transfection. The negatively charged ICG serves a dual purpose: neutralizing PEI's excessive positive charges to reduce cytotoxicity and, under near-infrared irradiation, inducing local heating that enhances cell membrane permeability, thus facilitating the uptake of PI/pDNA complexes to boost transfection efficiency. Using pDNA encoding vascular endothelial growth factor as a model, our system shows enhanced transfection efficiency in vitro for hard-to-transfect endothelial cells, leading to improved cell proliferation and migration. Furthermore, in vivo studies reveal the therapeutic potential of this system in accelerating the healing of infected wounds by promoting angiogenesis and reducing inflammation. This approach offers a straightforward and effective method for gene transfection, showing potentials for tissue engineering and cell-based therapies.

How cations catalyse the hydrogenation of graphene vacancies

In alkaline solutions hydrogen adsorption involves the splitting of a water molecule, which can be catalysed by the presence of cations. We have analysed the adsorption processes from a water molecule approaching the surface of a graphene bilayer containing a vacancy, both in the presence and in the absence of cations (Na+, K+ and Mg2+) by quantum molecular dynamics using DFT based tight-binding. A cation near the interface induces a region with positive excess charge in its solvation shell, which facilitates the orientation of the reacting water molecule with the hydrogen towards the surface. This concerted mechanism catalyses the hydrogenation and stabilizes the resulting hydroxyl. Therefore in the presence of cations the hydrogen evolution reaction occurs spontaneously at less negative charges than in the absence. Thus our investigations suggest a detailed scenario for the catalytic effect of cations both on the spatial and temporal nano-scale.

Probing Metal Ion Adduction in the ESI Charged Residue Mechanism via Gas-Phase Ion/Ion Chemistry.

The final stages of the charged residue mechanism/model (CRM) for ion generation via electrospray ionization (ESI) involves the binding of excess charge onto analyte species. Ions of both polarities can bind to the analyte with an excess of ions of the same polarity as the droplet. For large biomolecule/biocomplex ions, which are commonly the species of interest in native mass spectrometry (MS), the binding of acids and salts onto the analyte can lead to extensive broadening of ion signals due to adduction. Therefore, heating step(s) to facilitate desolvation and salt adduct removal are commonplace. In this work, we describe an approach to study the final stages of CRM using gas-phase ion/ion reactions to generate analyte ion/salt clusters of well-defined composition, followed by gas-phase collision-induced dissociation (CID). While there are many variables that can be studied systematically via this approach, the work described herein is focused on salt clusters of the form [Na10X11]-, where X = acetate (Ac-), chloride (Cl-), or nitrate (NO3-), in reaction with a common charge state of ubiquitin as well as several model peptides. Experiments in which equimolar quantities of each salt (i.e., NaAc, NaCl, and NaNO3) are subjected to ESI with ubiquitin (Ubi) and gas-phase ion/ion reaction studies involving [Na10X11]- and [Ubi + 6H]6+ show similar trends, in terms of the extent of sodium ion incorporation into the protein ions. Ion/ion reaction studies using model peptides show that the acetate-containing salt transfers significantly more Na+ ions into the peptide ions. Exchange of Na+ for H+ is shown to occur at the C-terminus and at up to all of the amide linkages using [Na10X11]-, whereas only the C-terminus engages in Na+/H+ exchange with [Na10Cl11]- and [Na10(NO3)11]-. In the latter cases, an additional Na+ is taken up as the excess positive charge, presumably due to solvation of the charge by multiple sites (e.g., carbonyl oxygens and basic sites).

PySupercharge: a python algorithm for enabling ABC transporter bacterial secretion of all proteins through amino acid mutation.

The process of producing proteins in bacterial systems and secreting them through ATP-binding cassette (ABC) transporters is an area that has been actively researched and used due to its high protein production capacity and efficiency. However, some proteins are unable to pass through the ABC transporter after synthesis, a phenomenon we previously determined to be caused by an excessive positive charge in certain regions of their amino acid sequence. If such an excessive charge is removed, the secretion of any protein through ABC transporters becomes possible. In this study, we introduce 'linear charge density' as the criteria for possibility of protein secretion through ABC transporters and confirm that this criterion can be applied to various non-secretable proteins, such as SARS-CoV-2 spike proteins, botulinum toxin light chain, and human growth factors. Additionally, we develop a new algorithm, PySupercharge, that enables the secretion of proteins containing regions with high linear charge density. It selectively converts positively charged amino acids into negatively charged or neutral amino acids after linear charge density analysis to enable protein secretion through ABC transporters. PySupercharge, which also minimizes functional/structural stability loss of the pre-mutation proteins through the use of sequence conservation data, is currently being operated on an accessible web server. We verified the efficacy of PySupercharge-driven protein supercharging by secreting various previously non-secretable proteins commonly used in research, and so suggest this tool for use in future research requiring effective protein production.

Polyelectrolyte-protein synergism: pH-responsive polyelectrolyte/insulin complexes as versatile carriers for targeted protein and drug delivery

The co-assembly of polyelectrolytes (PE) with proteins offers a promising approach for designing complex structures with customizable morphologies, charge distribution, and stability for targeted cargo delivery. However, the complexity of protein structure limits our ability to predict the properties of the formed nanoparticles, and our goal is to identify the key triggers of the morphological transition in protein/PE complexes and evaluate their ability to encapsulate multivalent ionic drugs. A positively charged PE can assemble with a protein at pH above isoelectric point due to the electrostatic attraction and disassemble at pH below isoelectric point due to the repulsion. The additional hydrophilic block of the polymer should stabilize the particles in solution and enable them to encapsulate a negatively charged drug in the presence of PE excess. We demonstrated that diblock copolymers, poly(ethylene oxide)-block-poly(N,N-dimethylaminoethyl methacrylate) and poly(ethylene oxide)-block-poly(N,N,N-trimethylammonioethyl methacrylate), consisting of a polycation block and a neutral hydrophilic block, reversibly co-assemble with insulin in pH range between 5 and 8. Using small-angle neutron and X-ray scattering (SANS, SAXS), we showed that insulin arrangement within formed particles is controlled by intermolecular electrostatic forces between protein molecules, and can be tuned by varying ionic strength. For the first time, we observed by fluorescence that formed protein/PE complexes with excess of positive charges exhibited potential for encapsulating and controlled release of negatively charged bivalent drugs, protoporphyrin-IX and zinc(II) protoporphyrin-IX, enabling the development of nanocarriers for combination therapies with adjustable charge, stability, internal structure, and size.

Enhancing the safety and effectiveness of polyethylenimine gene delivery through cell membrane encapsulation

Due to the powerful DNA loading capacity and excellent proton sponge effect, the cationic polymer polyethyleneimine (PEI) has been demonstrated as a versatile, efficient DNA delivery tool both in vitro and in vivo. However, the excess surface positive charge of PEI and the common capture/clearance of PEI/DNA complex by the immune system limit its further clinical applications. To reduce the cytotoxicity resulting from surface charge and avoid the clearance of nanoparticles interacting with proteins and circulating immune cells in the blood, a bionic gene delivery system was developed by coating PEI/DNA complexes with natural cell membranes. The obtained RAW Cell membrane-coated PEI/DNA capsules (RAWm-PDc) and Red blood Cell membrane-coated PEI/DNA capsules (RBCm-PDc) complex showed excellent dispersibility and stability with an average particle size of 200–300 nm. Moreover, the RAWm-PDc/RBCm-PDc complex had great DNA loading capacity and protected the bound DNA effectively from nuclease hydrolysis. Most importantly, the RAWm-PDc/RBCm-PDc complex exhibited low protein adsorption, reduced cytotoxicity and high gene delivery efficiency. All the results demonstrated the potential of RAWm-PDc/RBCm-PDc as a promising non-viral gene delivery vector.

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.

An Overview on (LDHs)

Layered Double Hydroxides are inorganic solid minerals with brucite-like structures. They are non-silicate minerals seen in the soil very rare in amount [1]. LDHs have brucite-like layers with an excess positive charge on their surface. The excess charges are balanced by anions that are present in the interlayer. Generally, LDHs are also known as Hydrotalcite-like compounds because Hydrotalcite is one of the LDHs seen commonly in soil. Due to their higher anion exchange capacity, they are also known by the name anionic clay. In nature, they generally occur as a clay mineral, but sometimes as the metabolic by-product of micro-organisms. Even humans can manufacture it at a low cost of production.

Electrocatalytic Mechanisms for an Oxygen Evolution Reaction at a Rhombohedral Boron Monosulfide Electrode/Alkaline Medium Interface.

Rhombohedral boron monosulfide (r-BS) with a layer stacking structure is a promising electrocatalyst for an oxygen evolution reaction (OER) within an alkaline solution. We investigated the catalytic mechanisms at the r-BS electrode/alkaline medium interface for an OER using hybrid solvation theory based on the first-principles method combined with classical solution theory. In this study, we elucidate the activities of the OER at the outermost r-BS sheet with and without various surface defects. The Gibbs free energies along the OER path indicate that the boron vacancies at the first and second layers of the r-BS surface (VB1 and VB2) can promote the OER. However, we found that the VB1 is easily occupied by the oxygen atom during the OER, degrading its electrocatalytic performance. In contrast, VB2 is suitable for the active site of the OER due to its structure stability. Next, we applied a bias voltage with the OER potential to the r-BS electrode. The bias voltage incorporates the positive excess surface charge into pristine r-BS and VB2, which can be understood by the relationship between the OER potential and potentials of zero charge at the r-BS electrode. Because the OH- ions are the starting point of the OER, the positively charged surface is kinetically favorable for the electrocatalyst owing to the attractive interaction with the OH- ions. Finally, we qualitatively discuss the flat-band potential at a semiconductor/alkaline solution interface. It suggests that p-type carrier doping could promote the catalytic performance of r-BS. These results explain the previous measurement of the OER performance with the r-BS-based electrode and provide valuable insights into developing a semiconductor electrode/water interface.

Layered Double Hydroxides as the Unique Product of Target Ionic Construction for Energy, Chemical, Foods, Cosmetics, Medicine and Ecology Applications.

Layered Double Hydroxide (LDH) is an α-modification of the M-host (M2+ ) hydroxide, in which some part of the M-host cations is replaced by M-guest cations (M3+ or M4+ ). The emerging excess positive charge is compensated by the intercalation of anions into the interlayer space, which also contains water molecules. LDHs exhibit anion exchange properties. Targeted ionic design of LDHs via combining three components (M-host, M-guest cations, intercalated anions) allows the creation of a very wide range of highly efficient electrochemical, electrocatalytic, electrochromic substances, catalysts, ion exchangers, sorbents, color pigments, pharmacological drugs, food, and cosmetic additives. In this review, the structure and areas of application of LDHs are considered from the perspective of the targeted ionic design of a substance for a specific application.

Thin La doped CaMnO3 ceramics for attenuation−impedance balance to facilitate excellent microwave absorption

The perovskite structure oxide, CaMnO3, has been extensively investigated and applied as a potential microwave absorption material due to its versatile dielectric and spontaneous polarization. However, the low conductivity of pure CaMnO3 material limits its further application. Herein, to increase dielectric loss and achieve better microwave absorption properties, lanthanum (La)-doped CaMnO3 (Ca1-xLaxMnO3) ceramics were fabricated by a high temperature solid state reaction. The results of XRD and XPS show that the La atom was efficiently doped at the Ca site in CaMnO3, which carries excess positive charges and affects the valence state of Mn ions and the concentration of oxygen vacancies. Therefore, the conductivity and imaginary permittivity of Ca1-xLaxMnO3 ceramics increased dramatically with La-doped content. Benefiting from the tunable dielectric and impedance properties, Ca1-xLaxMnO3 ceramics can be utilized in a highly efficient way to absorb microwave radiation with a thin thickness. The sample with x = 0.04 shows the best microwave absorption property, with an RLmin value of -52.63 dB (d = 1.41 mm) and effective absorption bandwidth coves full X band in the thickness range from 1.315 mm to 1.395 mm.

Əyləc sürtünmə cütlərində ifratkeçiricilik effekti Ə.X. Canəhmədov, D.A. Volçenko, M.Ya. Cavadov, N.N. Fidrovskaya, N.A. Volçenko, D.Yu. Juravlev, V.N. Lunin

The article addresses the following issues: general principles of the state of superconductivity in brake friction pairs; isotropic and Josephson effects; paired electron and its role in superconductivity; vibrations of the crystal lattice and vortices in the metal friction element; the discussion of the results. The exciting factor for particles of various kinds in metal friction elements is pulsed normal forces in the mating of friction pairs. Conduction electrons in a metal at a low ambient temperature and its thermally stabilized state are capable of forming pairs that unite particles with equal, oppositely directed impulses. For this to happen, there must be an attraction between the electrons. Behavior and connections of pairs of electrons and the interaction of their energy levels with the nodes of the crystal lattice of a metal friction element. The presence of positive ions in the crystal lattice ensures that a moving electron attracts nearby ions, they shift towards it and create a local excess of positive charge. A locally polarized region attracts another electron, which moves towards the first one. Elastic vibrations of the crystal lattice are the movement of phonons-quanta of sound waves. In this case, electrons are attracted, emitting and absorbing phonons. Between electrons and vibrations of the crystal lattice occurring directly by the attraction of the lattice of electrons prevailing over the Coulomb collision. The emergence of mechanical and magnetic vortices, when the transport current fields exceed the minimum limit of its intensity, magnetic vortices are born near the surface and migrate deep into the metal friction element. Keywords: braking device, friction pairs, metal friction element, superconductivity, electric, magnetic field.

Lattice-charge imbalance and redox catalysis over perovskite-type ferrite- and manganite-based mixed oxides as studied by XRD, FTIR, UV–Vis DRS, and XPS

In the present investigation, two sets of pure and substituted ferrite- and manganite-based mixed oxides were prepared within the stoichiometric formulaA_{1 - x} A^{prime}_{x} B_{1 - x} B^{prime}_{x} O_{3}, where A = Bi or La, A′ = Sr, B = Fe or Mn, B′ = Co, x = 0 or 0.2, by calcination at 700 °C (for 1 h) of corresponding metal citrate xerogels. Materials thus obtained were examined for bulk and surface characteristics using X-ray diffractometry, ex situ Fourier transform infrared spectroscopy, UV–Vis diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, and N2 sorptiometry. Their redox catalytic activity was evaluated towards a 2-propanol dehydrogenation reaction in the gas phase by employing in situ Fourier transform infrared spectroscopy. The results obtained could help reveal that (1) the presence of Bi (versus La) and Mn (versus Fe) facilitated the formation of polymeric crystalline phases assuming lattice-charge imbalance (due to excess positive charge), (2) the surface exposure of the excess positive charge was manifested in the generation of Mn sites having various oxidation states ≥ 3+, (3) the consequent development of visible light absorptions at 498–555 nm suggested occurrence of electron double-exchange facilitated by the formation of Mnn+–O2−–Mn(n+1)+ Zener-type linkages, and (4) the exposure of such linkages at the surface warrants the establishment of the electron-mobile environment necessitated by the redox catalytic activity. Moreover, the relationship between the alcohol dehydrogenation activity and the magnitude of the lattice-charge imbalance (i.e., the net excess positive charge) of the catalysts was highlighted.

MECHANISMS AFFECTING THE SPEED AND DIRECTION OF VACUUM ARC CATHODE SPOTS MOVEMENT IN A MAGNETIC FIELD

Based on the known experimental and theoretical data, a new model of the plasma jet, which emit by cathode spot (СS) along the magnetic field proposed. According to this model, the plasma jet contains an oppositely directed current of accelerated ions of the cathode material with an excess positive charge and a current of accelerated electrons with an excess negative charge, between which an electric field of polarization of the plasma jet formed. Based on this model, the basic parameters of the plasma jet from the external parameters of the magnetic field, the arc current, and the average charge state of the ions calculated. The main mechanisms affecting the speed and direction of movement of the arc CS on the cathode end surface clarified for the first time.

FORMATION FEATURES AND ELECTROCHROMIC PROPERTIES OF POLYPORPHYRIN FILMS BASED ON Zn-TETRAKIS(3-(HYDROXYPHENYL)PORPHYRIN

This paper presents the results of electrochemical deposition and the redox behavior of polyporphyrin films based on Zn(II) tetrakis(3–(hydroxyphenyl)porphyrin (ZnT(3–OHPh)P). It has been shown that electrochemical deposition initiated by superoxide anion–radical can be used to form films based on ZnT(3–OHPh)P. The potential ranges at which the electrochemical deposition of poly–ZnT(3–OHPh)P occurs on ITO electrodes were determined. The thickness of the obtained films based on ZnT(3–OHPh)P was determined by atomic force microscopy (AFM) and is about 90 nm. The presented results of studying the electronic absorption spectra of films based on ZnT(3–OHPh)P showed that the tetrapyrrole macrocycle is not destroyed during electrochemical deposition. The paper presents the results of Raman spectroscopy, which confirm that the main reason for the binding of hydroxyphenylporphyrin molecules in a polyporphyrin film is the formation of C–O–C bridges between side substituents. The redox processes in poly–ZnT(3–OHPh)P were studied by the spectroelectrochemical method. Electrochromic responses of films based on ZnT(3–OHPh)P have been determined in a wide range of potentials. Process of electroreduction leads to a decrease and a shift to the short–wavelength region of the Soret band. Electrooxidation of films based on ZnT(3–OHPh)P leads to a decrease in the intensity of the Soret band and the disappearance of the Q bands. It is shown that the observed spectral changes are in good agreement with the known literature data and indicate the localization of excess negative or positive charges on the macrocycle. Due to the change in their optical properties depending on the applied voltage, films based on ZnT(3–OHPh)P can be recommended as a promising electrochromic coating.

Low-cost triboelectric nanogenerator based on aseptic carton package

Triboelectric nanogenerators (TENGs) are efficient systems that convert mechanical energy to electrical energy. Based on contact electrification, an emerging powerful tool in energy harvesting technologies, most TENGs are constructed using expensive materials (e.g. gold and platinum) and costly processes. Aseptic carton packages (ACP) are plastic-laminated materials basically composed of paperboard, polyethylene and aluminum, but having all parts required for a TENG device: dielectric inductor and metal. Using the concept implicit in the triboelectric series where hydrophilic materials acquire a positive net charge while hydrophobic ones develop negative net charge upon contact, ACP was used as the main component of a sandwich-type triboelectric nanogenerator (ACP-TENG). Electrostatic potential mapping confirmed that pristine polyethylene is a negative charge inductor while after its oxidation develops an excess positive charge. Potentials as high as 200 V are reached with ACP-TENG during mechanical loads, charging a 10 μF capacitor to 3.5 V in less than 10 min. Continuous open-circuit voltage of roughly 80 V is developed under pressure-relaxation cycles at 1.8 Hz, reaching an output peak current of ∼400 nA. The efficiency of ACP-TENG is comparable to nanoengineered devices, but costing only a fraction of them. We believe that the ACP-TENG reported here is a reliable way to construct low-cost energy harvesting devices and it can be used as an environmentally friendly destination/solution for food packaging.

Abnormal Sub‐Auroral Ion Drifts (ASAID) Developed in Various Inner‐Magnetosphere Configurations at Geomagnetically Quiet Times

AbstractUtilizing multi‐point observations, we investigate a series of inner‐magnetosphere configurations formed at Kp ≤ 3+ when the magnetosphere‐ionosphere (M‐I) conjugate Abnormal Sub‐Auroral Ion Drifts (ASAID) developed near the plasmapause. We analyze the development of ASAID by adopting the recent theories of (1) fast‐time short‐circuiting explaining SAID development and (2) Larmor radius effects explaining ASAID development. The earthward ASAID electric field developed (1) by short‐circuiting when the reconnection‐related earthbound hot ring current (RC) electrons became stopped and ions kept moving earthward and started their usual Larmor rotations, and (2) because of the larger Larmor radius of the hot RC ions creating excess positive charges in the nearby cold‐inner‐edge plasmasheet plasma and deficit negative charges inside the hot RC region. Respective new findings include the observations of (1a) earthward hot RC ion injections across and near the ASAID channel in the inner magnetosphere and (1b) the localized increase of energetic proton differential fluxes (good proxy for hot RC ions) in the topside ionosphere within the ASAID channel, and (2a) M‐I conjugate ASAID and ASAID‐SAID series created by their respective single intrusion and repeated intrusions of hot RC ions into the cold plasmasheet plasma. New findings also include (3) the specifications of plasma waves such as Kelvin‐Helmholtz surface waves and electromagnetic ion cyclotron (EMIC) waves developed in the inner‐magnetosphere during plasmasheet rippling, and (4) the development of multiple ASAID channels in the hot zone impacted by EMIC waves.

Sol-Gel Synthesis and Characterization of Yttrium-Doped MgFe2O4 Spinel.

In this study, an environmentally friendly sol-gel synthetic approach was used for the preparation of yttrium-doped MgFe2O4. Two series of compounds with different iron content were synthesized and A-site substitution effects were investigated. In the first series, the iron content was fixed and the charge balance was suggested to be compensated by a partial reduction of Fe3+ to Fe2+ or formation of interstitial O2- ions. For the second series of samples, the iron content was reduced in accordance with the substitution level to compensate for the excess of positive charge, which accumulates due to replacing divalent Mg2+ with trivalent Y3+ ions. Structural, morphological and magnetic properties were inspected. It was observed that single-phase compounds can only form when the substitution level reaches 20 mol% of Y3+ ions and iron content is reduced. The coercivity as well as saturation magnetization decreased with the increase in yttrium content. Mössbauer spectroscopy was used to investigate the iron content in both tetrahedral and octahedral positions.

Micellar nanoparticles inhibit the postoperative inflammation, recurrence and pulmonary metastasis of 4T1 breast cancer by blocking NF-κB pathway and promoting MDSCs depletion

The progression of breast cancer can stimulate the production of myeloid-derived suppressor cells (MDSCs). These cells with significant immunosuppressive activity play a key role in promoting the formation of pulmonary inflammatory and immunosuppressive microenvironment, namely pre-metastatic niche (PMN). Surgical resection of tumors often leads to strong inflammatory reactions, and the produced circulating tumor cells (CTCs) can implant into PMN to promote the recurrence and pulmonary metastasis of breast cancer. Therefore, we developed a hyaluronic acid (HA)-coated chitosan oligosaccharide-all-trans-retinoic-acid (COS-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) (HA@CA/DOX NPs). The hydrophilic segment COS and hydrophobic segment ATRA both blocked NF-κB inflammatory signaling pathway in 4T1 tumor cells and MDSCs and alleviated the inflammation after resection. Besides, ATRA also significantly depleted MDSCs in lungs and tumors, thereby regulating the inflammatory and immunosuppressive microenvironment and inhibiting the formation of PMN. HA coated on the surface of nanoparticles shielded the excessive positive charge and achieved tumor targeting through CD44 on the surface of tumor cells. This drug delivery system combined with anti-inflammation and chemotherapy significantly inhibited the postoperative recurrence and pulmonary metastasis of breast cancer.

Interleukin-10 plasmid delivery by polymeric nanocarrier shows efficient and safe tissue repair in acute muscle damage models in mice

We established a custom-designed nanocarrier for in vivo delivery of an immunomodulatory plasmid capable of facilitating tissue repair in acute muscle damage models in mice. The nanocarrier was constructed by selecting from versatile cationic designs that were used to complex with a negatively charged plasmid, while the excessive positive charge was shielded by the poly (glutamic acid)-polyethylene glycol co-polymer. The best-performing formulation was identified by high throughput screening in macrophages, in which we obtained the hierarchical ranking in terms of reporter gene expression (GFP plasmid, pGFP) and macrophage polarization status (interleukin 10 plasmid, pIL-10). For proof-of-principle, we performed intramuscular (IM) injection of pGFP nanocarrier in a cardiotoxin-induced muscle injury model. After confirming the in vivo GFP transfection, we demonstrated protected delivery of pIL-10 to the injured muscle site, leading to an accelerated tissue repair outcome. Immunophenotyping analysis revealed the increased number of M2 macrophages and regulatory T cells, as well as increased IL-10 production at muscle site. The effectiveness of the pIL-10 carrier was interfered by pharmaceutical macrophage depletion using pre-injected clodronate liposome. When intravenously (IV) injected, our pIL-10 nanocarrier preferentially biodistributed in the injured muscle (owing to transiently decreased blood vessel integrity) and improved tissue repair. Unlike IL-10 protein (that was clinically abandoned), sustained IL-10 production by our nanocarrier dramatically reduced the degree of spleen enlargement and kidney inflammation, suggesting a favorable safety characteristic in vivo.