Sodium Alginate- and Cationic Cellulose-Functionalized Polycaprolactone Nanofibers for In Vitro and Antibacterial Applications.

The use of polyelectrolytes is emerging as a fascinating strategy for the functionalization of biomedical membranes, due to their ability to enhance biological responses using the interaction effect of charged groups on multiple interface properties. Herein, two different polyelectrolytes were used to improve the antibacterial properties of polycaprolactone (PCL) nanofibers fabricated via electrospinning. First, a new cationic cellulose derivative, cellulose-bearing imidazolium tosylate (CIMD), was prepared via the nucleophilic substitution of the tosyl group using 1-methylimidazole, as confirmed by NMR analyses, and loaded into the PCL nanofibers. Secondly, sodium alginate (SA) was used to uniformly coat the fibers' surface via self-assembly, as remarked through SEM-EDX analyses. Polyelectrolyte interactions between the CIMD and the SA, initially detected using a FTIR analysis, were confirmed via Z potential measurements: the formation of a CMID/SA complex promoted a substantial charge neutralization of the fibers' surfaces with effects on the physical properties of the membrane in terms of water adsorption and in vitro degradation. Moreover, the presence of SA contributed to the in vitro response of human mesenchymal stem cells (hMSCs), as confirmed by a significant increase in the cells' viability after 7 days in the case of the PCL/CMID/SA complex with respect to the PCL and PCL/CMID membranes. Contrariwise, SA did not nullify the antibacterial effect of CMID, as confirmed by the comparable resistance exhibited by S. mutans, S. aureus, and E. coli to the PCL/CIMD and PCL/CIMD/SA membranes. All the reported results corroborate the idea that the CIMD/SA functionalization of PCL nanofibers has a great potential for the fabrication of efficient antimicrobial membranes for wound healing.

Capsule Shedding and Membrane Binding Enhanced Photodynamic Killing of Gram-Negative Bacteria by a Unimolecular Conjugated Polyelectrolyte.

The development of new antimicrobial agents to treat infections caused by Gram-negative bacteria is of paramount importance due to increased antibiotic resistance worldwide. Herein, we show that a water-soluble porphyrin-cored hyperbranched conjugated polyelectrolyte (PorHP) exhibits high photodynamic bactericidal activity against the Gram-negative bacteria tested, including a multidrug-resistant (MDR) pathogen, while demonstrating low cytotoxicity toward mammalian cells. Comprehensive analyses reveal that the antimicrobial activity of PorHP proceeds via a multimodal mechanism by effective bacterial capsule shedding, strong bacterial outer membrane binding, and singlet oxygen generation. Through this multimodal antimicrobial mechanism, PorHP displays significant performance for Gram-negative bacteria with >99.9% photodynamic killing efficacy. Overall, PorHP shows great potential as an antimicrobial agent in fighting the growing threat of Gram-negative bacteria.

Titanium surface-grafted zwitterionic polymers with an anti-polyelectrolyte effect enhances osteogenesis.

Zwitterionic polymers have attracted considerable attention because of their anti-adsorption and unique anti-polyelectrolyte effects and was widely used in surface modification. In this study, zwitterionic copolymers (poly (sulfobetaine methacrylate-co-butyl acrylate) (pSB) coating on the surface of a hydroxylated titanium sheet using surface-initiated atom transfer radical polymerization (SI-ATRP) was successfully constructed. X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR) and Water contact angle (WCA) analysis proved the successful preparation of the coating. The swelling effect caused by the anti-polyelectrolyte effect was reflected in the simulation experiment in vitro, and this coating can promote the proliferation and osteogenesis of MC3T3-E1. Therefore, this study provides a new strategy for designing multifunctional biomaterials for implant surface modifications.

Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes - Then and Now.

Cartilages are unique in the family of connective tissues in that they contain a high concentration of the glycosaminoglycans, chondroitin sulfate and keratan sulfate attached to the core protein of the proteoglycan, aggrecan. Multiple aggrecan molecules are organized in the extracellular matrix via a domain-specific molecular interaction with hyaluronan and a link protein, and these high molecular weight aggregates are immobilized within the collagen and glycoprotein network. The high negative charge density of glycosaminoglycans provides hydrophilicity, high osmotic swelling pressure and conformational flexibility, which together function to absorb fluctuations in biomechanical stresses on cartilage during movement of an articular joint. We have summarized information on the history and current knowledge obtained by biochemical and genetic approaches, on cell-mediated regulation of aggrecan metabolism and its role in skeletal development, growth as well as during the development of joint disease. In addition, we describe the pathways for hyaluronan metabolism, with particular focus on the role as a "metabolic rheostat" during chondrocyte responses in cartilage remodeling in growth and disease.Future advances in effective therapeutic targeting of cartilage loss during osteoarthritic diseases of the joint as an organ as well as in cartilage tissue engineering would benefit from 'big data' approaches and bioinformatics, to uncover novel feed-forward and feed-back mechanisms for regulating transcription and translation of genes and their integration into cell-specific pathways.

pH-sensitive nano-polyelectrolyte complexes with arthritic macrophage-targeting delivery of triptolide.

Since pro-inflammatory macrophages take on a critical significance in the pathophysiology of rheumatoid arthritis (RA), the therapeutics to affect macrophages may receive distinct anti-RA effects. However, the therapeutic outcomes are still significantly impeded, which is primarily due to the insufficient drug delivery at the arthritic site. In this study, the macrophage-targeting and pH stimuli-responsive nano-polyelectrolyte complexes were designed for the efficient targeted delivery of triptolide (TP/PNPs) on the arthritic site. The anionic and cationic amphiphilic copolymers, i.e., hyaluronic acid-g-vitamin E succinate (HA-VE) and the quaternized poly (ß-amino ester) (QPBAE-C18), were prepared and then characterized. The result indicated that TP/PNPs with the uniform particle size of âˆ¼ 175 nm exhibited the high drug loading capacity and storage stability based on the polymeric charge interaction, in which DLC and DEE of TP/PNPs were obtained as 11.27 ± 0.44 % and 95.23 ± 2.34 %, respectively. Mediated by the "ELVIS" effect of NPs, CD44 receptor-mediated macrophage targeting, and pH-sensitive endo/lysosomal escape under the "proton sponge" effect, TP/PNPs exhibited the enhanced cellular internalization and cytotoxicity while mitigating the inflammation of LPS-activated RAW 264.7 cells. Even after 96-hour after administration, PNPs were preferentially accumulated in the inflammatory joints in a long term. It is noteworthy that after treatment for 14 days with 100 µg/kg of TP, TP/PNPs significantly facilitated arthritic symptom remission, protected cartilage, and mitigated inflammation of antigen-induced arthritis (AIA) rats, whereas the systematic side-effects of TP were reduced. In this study, an effective drug delivery strategy was proposed for the treatment of RA.

Development of chitosan-polygalacturonic acid polyelectrolyte complex fibrous scaffolds using the hydrothermal treatment for bone tissue engineering.

An ideal bone regeneration scaffold system needs to meet the high compressive properties of the bone. The stiffness of the scaffold extracellular matrix determines the cell's fate via cell adhesion migration and differentiation in-vitro and in-vivo. This study aims to investigate the effect of hydrothermal treatment on polyelectrolyte complex (PEC) fibrous biomaterials and its effect on scaffold morphology, cell viability, and function in-vitro. FTIR analysis revealed the ability of the thermal treatment to set the interaction of HAp with polymeric PEC fibers. FESEM analysis showed that with an increase in temperature, the interconnectivity and pore size increased (control-82.38 ± 12.92 µm; at 120°C-335.48 ± 85.10 µm). Mechanical tests showed that the scaffolds heated at 90°C showed the highest stiffness in both dry and wet states (dry state: 1.82 ± 0.07 MPa, wet state: 122 ± 1.78 kPa). Additionally, the hydrothermal treatment also improved the aqueous stability as well as swelling capacity. According to the experimental findings, hydrothermal treatment is a useful technique for crosslinker-free gelation with improved mechanical strength and nanofibrous structure. Furthermore, the cell adhesion, proliferation, and osteogenic differentiation of the MG63 cells on the hydrogel scaffolds in-vitro were evaluated by MTT assay, confocal imaging, alkaline phosphatase assay, and collagen estimation. The in-vitro study showed that scaffolds fabricated at 90°C promoted better MG63 cell attachment, proliferation, and differentiation. These results suggest the potential use of hydrothermal treated chitosan-polygalacturonic acid (PgA) fibrous scaffolds in bone tissue engineering.

Metal Ion Doping of Alginate-Based Surface Coatings Induces Adipogenesis of Stem Cells.

Metal ions are important effectors of protein and cell functions. Here, polyelectrolyte multilayers (PEMs) made of chitosan (Chi) and alginate (Alg) were doped with different metal ions (Ca2+, Co2+, Cu2+, and Fe3+), which can form bonds with their functional groups. Ca2+ and Fe3+ ions can be deposited in PEM at higher quantities resulting in more positive ζ potentials and also higher water contact angles in the case of Fe3+. An interesting finding was that the exposure of PEM to metal ions decreases the elastic modulus of PEM. Fourier transformed infrared (FTIR) spectroscopy of multilayers provides evidence of interaction of metal ions with the carboxylic groups of Alg but not for hydroxyl and amino groups. The observed changes in wetting and surface potential are partly related to the increased adhesion and proliferation of multipotent C3H10T1/2 fibroblasts in contrast to plain nonadhesive [Chi/Alg] multilayers. Specifically, PEMs doped with Cu2+ and Fe3+ ions greatly promote cell attachment and adipogenic differentiation, which indicates that changes in not only surface properties but also the bioactivity of metal ions play an important role. In conclusion, metal ion-doped multilayer coatings made of alginate and chitosan can promote the differentiation of multipotent cells on implants without the use of other morphogens like growth factors.

Polyelectrolyte Complex Hydrogels with Controlled Mechanics Affect Mesenchymal Stem Cell Differentiation Relevant to Growth Plate Injuries.

The growth plate is a complex cartilage structure in long bones that mediates growth in children. When injured, the formation of a "bony bar" can occur which impedes normal growth and can cause angular deformities or growth arrest. Current treatments for growth plate injuries are limited and result in poor patient outcomes, necessitating research toward novel treatments that can prevent bony bar formation and stimulate cartilage regeneration. This study investigates alginate-chitosan polyelectrolyte complex (PEC) hydrogels as an injectable biomaterial system to prevent bony bar formation. Biomaterial properties including stiffness and degradation are quantified, and the effect that material properties have on mesenchymal stem cell (MSC) fate is quantified in vitro. Specifically, this study aims to elucidate the effectiveness of biomaterial-based control over the differentiation behavior of MSCs toward osteogenic or chondrogenic lineages using biochemical metabolite assays and quantitative real time PCR. Further, the PEC hydrogels are employed in a rat growth plate injury model to determine their effectiveness in preventing bony bar formation in vivo. Results indicate that hydrogel composition and material properties affect the differentiation tendency of MSCs in vitro, and the PEC hydrogels show promise as an injectable biomaterial for growth plate injuries.

Direct-Contact Co-culture of Astrocytes and Glioblastoma Cells Patterned using Polyelectrolyte Multilayer Templates.

Glioblastoma Multiforme (GBM) is the most abundant and fatal malignant brain cancer. There are more than 13,000 cases projected in the United States in 2020 and 2021. GBM tumors most often arise from astrocytes and are characterized by their invasive nature, often recruiting healthy tissues into tumor tissue. Understanding communication between astrocytes and glioblastoma cells is vital for the molecular understanding of tumor progression. This protocol demonstrates a novel patterned co-culture method to investigate contact-mediated effects of astrocytes on GBM employing layer-by-layer assembly and micro-capillary-force driven patterning. Advantages include a protein-free cell culture environment and precise control of cellular interaction dictated by the pattern dimensions. This technique provides a versatile, economical, reproducible protocol for mimicking cellular interaction between glioma and astrocytes in glioma tumors. This model can further be used to tease apart changes in GBM molecular biology due to physical contact with astrocytes or with non-contact mediated soluble cofactor communication.

Combined Modification of Fiber Materials by Enzymes and Metal Nanoparticles for Chemical and Biological Protection.

To obtain fiber materials with pronounced chemical-biological protection, metal (Zn or Ta) nanoparticles were jointly applied with polyelectrolyte complexes of enzymes and polypeptides being their stabilizers. Computer modeling revealed the preferences between certain polyelectrolyte partners for N-acyl-homoserine lactone acylase and hexahistidine-tagged organophosphorus hydrolase (His6-OPH) possessing the quorum quenching (QQ) behavior with bacterial cells. The combinations of metal nanoparticles and enzymes appeared to function better as compared to the combinations of the same QQ-enzymes with antibiotics (polymyxins), making it possible to decrease the applied quantities by orders of magnitude while giving the same effect. The elimination of Gram-positive and Gram-negative bacterial cells from doubly modified fiber materials notably increased (up to 2.9-fold), whereas His6-OPH retained its hydrolytic activity in reaction with organophosphorus compounds (up to 74% of initially applied activity). Materials with the certain enzyme and Zn nanoparticles were more efficient against Bacillus subtilis cells (up to 2.1-fold), and Ta nanoparticles acted preferentially against Escherichia coli (up to 1.5-fold). Some materials were proved to be more suitable for combined modification by metal nanoparticles and His6-OPH complexes as antimicrobial protectants.

Keggin-type polyoxometalates as Cu(II) chelators in the context of Alzheimer's disease.

Two Keggin polyoxometalates were used as new copper ligands to counteract the effects of CuII(Amyloid-ß) interaction. Their ability to remove CuII from CuII(Amyloid-ß), to stop CuII(Amyloid-ß) induced formation of reactive oxygen species and to restore apo-like self-assembly of CuII(Amyloid-ß) was shown.

Polyoxometalate Modified by Zeolite Imidazole Framework for the pH-Responsive Electrodynamic/Chemodynamic Therapy.

Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS) via a catalytic reaction on the surface of POM NPs induced by an electric field (E). At the same time, POM@ZIF-8 NPs can catalyze the intracellular H2O2 into ROS via a Fenton-like reaction, thereby achieving the combination of EDT and CDT. Besides, since ZIF-8 is acid-responsive, it can protect normal tissues and avoid side effects. Of great note is that the cytotoxicity and the apoptosis rate of the POM@ZIF-8+E group (80%) were found to be significantly higher than that of the E group (55%). As a result, a high tumor inhibition phenomenon can be observed both in vitro and in vivo. The present study thus provides an alternative concept for combinational therapeutic modality with exceptional efficacy.

Polycationic Silver Nanoclusters Comprising Nanoreservoirs of Ag+ Ions with High Antimicrobial and Antibiofilm Activity.

Silver-based nano-antibiotics are rapidly developing as promising alternatives to conventional antibiotics. Ideally, to remain potent against a wide range of drug-resistant and anaerobic bacteria, silver-based nano-antibiotics should easily penetrate through the bacterial cell walls and actively release silver ions. In this study, highly monodispersed, ultrasmall (<3 nm), polycationic silver nanoclusters (pAgNCs) are designed and synthesized for the elimination of a range of common Gram-negative and Gram-positive pathogens and their corresponding established and matured biofilms, including those composed of multiple species. The pAgNCs also show greatly enhanced antibacterial efficacy against anaerobic bacteria such as Fusobacterium nucleatum and Streptococcus sanguinis. These results demonstrate that the cationic nature facilitates better penetration to the bacterial cell membrane while the presence of a high percentage (>50%) of silver ions (i.e., Ag+ nanoreservoirs) on the cluster surface maintains their efficiency in both aerobic and anaerobic conditions. Significantly, the pAgNCs showed a strong capacity to significantly delay the development of bacterial resistance when compared to similar-sized negatively charged silver nanoparticles or conventional antibiotics. This study demonstrates a novel design strategy that can lay the foundation for the development of future highly potent nano-antibiotics effective against a broad spectrum of pathogens and biofilms needed in many everyday life applications and industries.

Self-assembled nanoparticles containing photosensitizer and polycationic brush for synergistic photothermal and photodynamic therapy against periodontitis.

BACKGROUND: Periodontitis is a chronic inflammatory disease in oral cavity owing to bacterial infection. Photothermal therapy (PTT) and photodynamic therapy (PDT) have many advantages for antibacterial treatment. As an excellent photosensitizer, indocyanine green (ICG) shows prominent photothermal and photodynamic performances. However, it is difficult to pass through the negatively charged bacterial cell membrane, thus limiting its antibacterial application for periodontitis treatment. RESULTS: In this work, self-assembled nanoparticles containing ICG and polycationic brush were prepared for synergistic PTT and PDT against periodontitis. First, a star-shaped polycationic brush poly(2-(dimethylamino)ethyl methacrylate) (sPDMA) was synthesized via atom transfer radical polymerization (ATRP) of DMA monomer from bromo-substituted ß-cyclodextrin initiator (CD-Br). Next, ICG was assembled with sPDMA to prepare ICG-loaded sPDMA (sPDMA@ICG) nanoparticles (NPs) and the physicochemical properties of these NPs were characterized systematically. In vitro antibacterial effects of sPDMA@ICG NPs were investigated in porphyromonas gingivalis (Pg), one of the recognized periodontitis pathogens. A ligature-induced periodontitis model was established in Sprague-Dawley rats for in vivo evaluation of anti-periodontitis effects of sPDMA@ICG NPs. Benefiting from the unique brush-shaped architecture of sPDMA polycation, sPDMA@ICG NPs significantly promoted the adsorption and penetration of ICG into the bacterial cells and showed excellent PTT and PDT performances. Both in vitro and in vivo, sPDMA@ICG NPs exerted antibacterial and anti-periodontitis actions via synergistic PTT and PDT. CONCLUSIONS: A self-assembled nanosystem containing ICG and polycationic brush has shown promising clinical application for synergistic PTT and PDT against periodontitis.

Understanding the Photochemical Properties of Polythiophene Polyelectrolyte Soft Aggregates with Sodium Dodecyl Sulfate for Antimicrobial Activity.

The threat of antibiotic-resistant bacteria is an ever-increasing problem in public health. In this report, we examine the photochemical properties with a proof-of-principle biocidal assay for a novel series of regio-regular imidazolium derivative poly-(3-hexylthiophene)/sodium dodecyl sulfate (P3HT-Im/SDS) materials from ultrafast sub-ps dynamics to µs generation of reactive oxygen species (ROS) and 30 min biocidal reactivity with Escherichia coli (E. coli). This broad series encompassing pure P3HT-Im to cationic, neutral, and anionic P3HT-Im/SDS materials are all interrogated by a variety of techniques to characterize the physical material structure, electronic structure, and antimicrobial activity. Our results show that SDS complexation with P3HT-Im results in aggregate materials with reduced ROS generation and light-induced anti-microbial activity. However, our characterization reveals that the presence of non-aggregated or lightly SDS-covered polymer segments is still capable of ROS generation. Full encapsulation of the P3HT-Im polymer completely deactivates the light killing pathway. High SDS concentrations, near and above critical micelle concentration, further deactivate all anti-microbial activity (light and dark) even though the P3HT-Im regains its electronic properties to generate ROS.

Altered Proinflammatory Responses to Polyelectrolyte Multilayer Coatings Are Associated with Differences in Protein Adsorption and Wettability.

A full understanding of the relationship between surface properties, protein adsorption, and immune responses is lacking but is of great interest for the design of biomaterials with desired biological profiles. In this study, polyelectrolyte multilayer (PEM) coatings with gradient changes in surface wettability were developed to shed light on how this impacts protein adsorption and immune response in the context of material biocompatibility. The analysis of immune responses by peripheral blood mononuclear cells to PEM coatings revealed an increased expression of proinflammatory cytokines tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1ß, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 and the surface marker CD86 in response to the most hydrophobic coating, whereas the most hydrophilic coating resulted in a comparatively mild immune response. These findings were subsequently confirmed in a cohort of 24 donors. Cytokines were produced predominantly by monocytes with a peak after 24 h. Experiments conducted in the absence of serum indicated a contributing role of the adsorbed protein layer in the observed immune response. Mass spectrometry analysis revealed distinct protein adsorption patterns, with more inflammation-related proteins (e.g., apolipoprotein A-II) present on the most hydrophobic PEM surface, while the most abundant protein on the hydrophilic PEM (apolipoprotein A-I) was related to anti-inflammatory roles. The pathway analysis revealed alterations in the mitogen-activated protein kinase (MAPK)-signaling pathway between the most hydrophilic and the most hydrophobic coating. The results show that the acute proinflammatory response to the more hydrophobic PEM surface is associated with the adsorption of inflammation-related proteins. Thus, this study provides insights into the interplay between material wettability, protein adsorption, and inflammatory response and may act as a basis for the rational design of biomaterials.

G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission.

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

Antibacterial and clusteroluminogenic hypromellose-graft-chitosan-based polyelectrolyte complex films with high functional flexibility for food packaging.

Food packaging can extend the shelf life of food products and enhance the safety and quality of the food. This study reports food-grade polyelectrolyte complex films generated via electrostatic interactions between two cellulose-based agents [viz., hypromellose-graft-chitosan, and carmellose sodium]. At optimal conditions, our films show good barrier properties, high transparency, and high efficiency in post-production agent loading. They also demonstrate intrinsic antibacterial effects against both Gram-negative and Gram-positive bacteria. By using frozen chicken breasts as a model, the films enable real-time monitoring of the status of the frozen food due to the property of clusterisation-triggered emission. Along with their negligible toxicity, our films warrant further development as multi-functional films for effective and self-indicating food packaging.

Hyaluronan/colistin polyelectrolyte complexes: Promising antiinfective drug delivery systems.

Nanotechnology-based modification of known antimicrobial agents is a rational and straightforward way to improve their safety and effectiveness. The aim of this study was to develop colistin (CT)-loaded polymeric carriers based on hyaluronic acid (HA) for potential application as antimicrobial agents against multi-resistant gram-negative microorganisms (including ESKAPE pathogens). CT-containing particles were obtained via a polyelectrolyte interaction between protonated CT amino groups and HA carboxyl groups (the CT-HA complex formation constant [logKCT-HA] was about 5.0). The resulting polyelectrolyte complexes had a size of 210-250 nm and a negative charge (ζ-potential -19 mV), with encapsulation and loading efficiencies of 100% and 20%, respectively. The developed CT delivery systems were characterized by modified release (45% and 85% of CT released in 15 and 60 min, respectively) compared to pure CT (100% CT released in 15 min). In vitro tests showed that the encapsulation of CT in polymer particles did not reduce its pharmacological activity; the minimum inhibitory concentrations of both encapsulated CT and pure CT were 1 µg/mL (against Pseudomonas aeruginosa).

Mucoadhesive and mucus-penetrating interpolyelectrolyte complexes for nose-to-brain drug delivery.

Nasal administration offers a possibility of delivering drugs to the brain. In the present work, nasal drug delivery systems were designed based on cationic Eudragit® EPO (EPO) and anionic Eudragit® L100-55 (L100-55) methacrylate copolymers. Two types of nanocarriers were prepared using interpolyelectrolyte complexation between these polymers. The first type of nanoparticles was prepared by forming interpolyelectrolyte complexes between unmodified EPO and L100-55. The second type of nanoparticles was formed through the complexation between PEGylated L100-55 and EPO. For this purpose, PEGylated L100-55 was synthesized by chemical conjugation of L100-55 with O-(2-aminoethyl)polyethylene glycol. The mucoadhesive properties of these nanoparticles were evaluated ex vivo using sheep nasal mucosa. Nanoparticles based on EPO and L100-55 exhibited mucoadhesive properties towards nasal mucosa, whereas PEGylated nanoparticles were non-mucoadhesive hence displayed mucus-penetrating properties. Both types of nanoparticles were used to formulate haloperidol and their ability to deliver the drug to the brain was evaluated in rats in vivo.