Assessing the Effect of Surface Coating on the Stability, Degradation, Toxicity and Cell Endocytosis/Exocytosis of Upconverting Nanoparticles.

Lanthanide-doped up-converting nanoparticles (UCNPs) have emerged as promising biomedical tools in recent years. Most research efforts were devoted to the synthesis of inorganic cores with the optimal physicochemical properties. However, the careful design of UCNPs with the adequate surface coating to optimize their biological performance still remains a significant challenge. Here, we propose the functionalization of UCNPs with four distinct types of surface coatings, which were compared in terms of the provided colloidal stability and resistance to degradation in different biological-relevant media, including commonly avoided analysis in acidic lysosomal-mimicking fluids. Moreover, the influence of the type of particle surface coating on cell cytotoxicity and endocytosis/exocytosis was also evaluated. The obtained results demonstrated that the functionalization of UCNPs with poly(isobutylene-alt-maleic anhydride) grafted with dodecylamine (PMA-g-dodecyl) constitutes an outstanding strategy for their subsequent biomedical application, whereas poly(ethylene glycol) (PEG) coating, although suitable for colloidal stability purposes, hinders extensive cell internalization. Conversely, surface coating with small ligand were found not to be suitable, leading to large degradation degrees of UCNPs. The analysis of particle' behavior in different biological media and in vitro conditions here performed pretends to help researchers to improve the design and implementation of UCNPs as theranostic nanotools.

Chitosan-Coated Silver Nanoparticles Inhibit Adherence and Biofilm Formation of Uropathogenic Escherichia coli.

Urinary tract infections are commonly caused by uropathogenic Escherichia coli (UPEC), which usually presents multiple virulence and resistance mechanisms, making it difficult to treat. It has been demonstrated that silver and polymeric nanoparticles had potential against these pathogens. In this study, we synthesized thiol chitosan-coated silver nanoparticles (SH-Cs-AgNPs) and evaluated their antibacterial, antibiofilm and antiadherence activity against clinical isolates of UPEC. The SH-Cs-AgNPs showed a spherical shape with a size of 17.80 ± 2.67 nm and zeta potential of 18 ± 2 mV. We observed a potent antibacterial and antibiofilm activity as low as 12.5 µg/mL, as well as a reduction in the adherence of UPEC to mammalian cells at concentrations of 1.06 and 0.53 µg/mL. These findings demonstrate that SH-Cs-AgNPs have potential as a new therapeutic compound against infections caused by UPEC.

Novel Gold Nanorods@Thiolated Pectin on the Killing of HeLa Cells by Photothermal Ablation.

Gold nanorods (AuNRs) have attracted attention in the field of biomedicine, particularly for their potential as photothermal agents capable of killing tumor cells by photothermic ablation. In this study, the synthesis of novel AuNRs stabilized with thiolated pectin (AuNR@SH-PEC) is reported. To achieve this, thiolated pectin (SH-PEC) was obtained by chemically binding cysteamine motifs to the pectin backbone. The success of the reaction was ascertained using FTIR-ATR. Subsequently, the SH-PEC was used to coat and stabilize the surface of AuNRs (AuNR@SH-PEC). In this context, different concentrations of SH-PEC (0.25, 0.50, 1.0, 2.0, 4.0, and 8.0 mg/mL) were added to 0.50 mL of AuNRs suspended in CTAB, aiming to determine the experimental conditions under which AuNR@SH-PEC maintains stability. The results show that SH-PEC effectively replaced the CTAB adsorbed on the surface of AuNRs, enhancing the stability of AuNRs without affecting their optical properties. Additionally, scanning electron and atomic force microscopy confirmed that SH-PEC is adsorbed into the surface of the AuNRs. Importantly, the dimension size (60 × 15 nm) and the aspect ratio (4:1) remained consistent with those of AuNRs stabilized with CTAB. Then, the photothermal properties of gold nanorods were evaluated by irradiating the aqueous suspension of AuNR@SH-PEC with a CW laser (808 nm, 1 W). These results showed that photothermal conversion efficiency is similar to the photothermal conversion observed for AuNR-CTAB. Lastly, the cell viability assays confirmed that the SH-PEC coating enhanced the biocompatibility of AuNR@SH-PEC. Most important, the viability cell assays subjected to laser irradiation in the presence of AuNR@SH-PEC showed a decrease in the cell viability relative to the non-irradiated cells. These results suggest that AuNRs stabilized with thiolated pectin can potentially be exploited in the implementation of photothermal therapy.

The Southern European Atlantic Diet and Its Supplements: The Chemical Bases of Its Anticancer Properties.

Scientific evidence increasingly supports the strong link between diet and health, acknowledging that a well-balanced diet plays a crucial role in preventing chronic diseases such as obesity, diabetes, cardiovascular issues, and certain types of cancer. This perspective opens the door to developing precision diets, particularly tailored for individuals at risk of developing cancer. It encompasses a vast research area and involves the study of an expanding array of compounds with multilevel "omics" compositions, including genomics, transcriptomics, proteomics, epigenomics, miRNomics, and metabolomics. We review here the components of the Southern European Atlantic Diet (SEAD) from both a chemical and pharmacological standpoint. The information sources consulted, complemented by crystallographic data from the Protein Data Bank, establish a direct link between the SEAD and its anticancer properties. The data collected strongly suggest that SEAD offers an exceptionally healthy profile, particularly due to the presence of beneficial biomolecules in its foods. The inclusion of olive oil and paprika in this diet provides numerous health benefits, and scientific evidence supports the anticancer properties of dietary supplements with biomolecules sourced from vegetables of the brassica genus. Nonetheless, further research is warranted in this field to gain deeper insights into the potential benefits of the SEAD's bioactive compounds against cancer.

Inhibiting HER3 Hyperphosphorylation in HER2-Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells.

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+ /HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

Gold Half-Shell-Coated Paclitaxel-Loaded PLGA Nanoparticles for the Targeted Chemo-Photothermal Treatment of Cancer.

Conventional cancer therapies suffer from nonspecificity, drug resistance, and a poor bioavailability, which trigger severe side effects. To overcome these disadvantages, in this study, we designed and evaluated the in vitro potential of paclitaxel-loaded, PLGA-gold, half-shell nanoparticles (PTX-PLGA/Au-HS NPs) conjugated with cyclo(Arg-Gly-Asp-Phe-Lys) (cyRGDfk) as a targeted chemo-photothermal therapy system in HeLa and MDA-MB-231 cancer cells. A TEM analysis confirmed the successful gold half-shell structure formation. High-performance liquid chromatography showed an encapsulation efficiency of the paclitaxel inside nanoparticles of more than 90%. In the release study, an initial burst release of about 20% in the first 24 h was observed, followed by a sustained drug release for a period as long as 10 days, reaching values of about 92% and 49% for NPs with and without near infrared laser irradiation. In in vitro cell internalization studies, targeted nanoparticles showed a higher accumulation than nontargeted nanoparticles, possibly through a specific interaction of the cyRGDfk with their homologous receptors, the ανß3 y ανß5 integrins on the cell surface. Compared with chemotherapy or photothermal treatment alone, the combined treatment demonstrated a synergistic effect, reducing the cell viability to 23% for the HeLa cells and 31% for the MDA-MB-231 cells. Thus, our results indicate that these multifuncional nanoparticles can be considered to be a promising targeted chemo-photothermal therapy system against cancer.

3D-Printing of Capsule Devices as Compartmentalization Tools for Supported Reagents in the Search of Antiproliferative Isatins.

The application of high throughput synthesis methodologies in the generation of active pharmaceutical ingredients (APIs) currently requires the use of automated and easily scalable systems, easy dispensing of supported reagents in solution phase organic synthesis (SPOS), and elimination of purification and extraction steps. The recyclability and recoverability of supported reagents and/or catalysts in a rapid and individualized manner is a challenge in the pharmaceutical industry. This objective can be achieved through a suitable compartmentalization of these pulverulent reagents in suitable devices for it. This work deals with the use of customized polypropylene permeable-capsule devices manufactured by 3D printing, using the fused deposition modeling (FDM) technique, adaptable to any type of flask or reactor. The capsules fabricated in this work were easily loaded "in one step" with polymeric reagents for use as scavengers of isocyanides in the work-up process of Ugi multicomponent reactions or as compartmentalized and reusable catalysts in copper-catalyzed cycloadditions (CuAAC) or Heck palladium catalyzed cross-coupling reactions (PCCCRs). The reaction products are different series of diversely substituted isatins, which were tested in cancerous cervical HeLa and murine 3T3 Balb fibroblast cells, obtaining potent antiproliferative activity. This work demonstrates the applicability of 3D printing in chemical processes to obtain anticancer APIs.

Evaluation of a polymeric topical formulation of Endoxifen in an estrogen receptor positive breast cancer murine model.

Breast cancer (BC) has surpassed lung cancer as the most diagnosed cancer and, in terms of mortality, is the fifth leading cause with 684,996 new deaths (6.7% of all cancer-related deaths) and the highest mortality amongst all cancers (15.5%) in women. Selective estrogen-receptor modulators (SERMs) have been used for the last thirty years for estrogen receptor-positive (ER+) BC prevention and treatment. Tamoxifen (TAM), the most widely used SERM, is orally administered and its long-term oral administration has been associated to toxicity and adverse side effects. Endoxifen (EDX) is one of the known active metabolites of TAM, with an affinity to ERα 100 times higher than TAM. Furthermore, EDX has shown antiproliferative activity against the ER+ BC cell line MCF-7. Alternative administration routes that avoid the metabolic processing of TAM seem an appealing alternative to its oral administration. With this aim, we have prepared a polymeric gel-like solution of Pluronic® F127 as vehicle for topical administration of EDX. In order to shed light on the potential clinical use of this formulation, we have compared it with the standard pharmaceutical form, i.e. orally administered TAM. The biodistribution, antitumor efficacy and toxic effects of topical EDX and oral TAM were evaluated in ER+ tumor xenograft athymic nu/nu mouse models. The results showed a statistically significant antitumor effect and reduced toxicity of topical EDX as compared to oral TAM or empty F127 gel. This novel administration route of SERMs could also have a strong impact in the prevention of BC at early development stages and could help to ameliorate the mortality and morbidity related to this disease.

Pluronic F127 and P104 Polymeric Micelles as Efficient Nanocarriers for Loading and Release of Single and Dual Antineoplastic Drugs.

The potential application of biodegradable and biocompatible polymeric micelles formed by Pluronic F127 and P104 as nanocarriers of the antineoplastic drugs docetaxel (DOCE) and doxorubicin (DOXO) is presented in this work. The release profile was carried out under sink conditions at 37 °C and analyzed using the Higuchi, Korsmeyer-Peppas, and Peppas-Sahlin diffusion models. The cell viability of HeLa cells was evaluated using the proliferation cell counting kit CCK-8 assay. The formed polymeric micelles solubilized significant amounts of DOCE and DOXO, and released them in a sustained manner for 48 h, with a release profile composed of an initial rapid release within the first 12 h followed by a much slower phase the end of the experiments. In addition, the release was faster under acidic conditions. The model that best fit the experimental data was the Korsmeyer-Peppas one and denoted a drug release dominated by Fickian diffusion. When HeLa cells were exposed for 48 h to DOXO and DOCE drugs loaded inside P104 and F127 micelles, they showed lower IC50 values than those reported by other researchers using polymeric nanoparticles, dendrimers or liposomes as alternative carriers, indicating that a lower drug concentration is needed to decrease cell viability by 50%.

Hybrid Gold Nanorod-Based Nanoplatform with Chemo and Photothermal Activities for Bimodal Cancer Therapy.

Metal nanoparticles (NPs), particularly gold nanorods (AuNRs), appear as excellent platforms not only to transport and deliver bioactive cargoes but also to provide additional therapeutic responses for diseased cells and tissues and/or to complement the action of the carried molecules. In this manner, here, we optimized a previous developed metal-based nanoplatform composed of an AuNR core surrounded by a polymeric shell constructed by means of the layer-by-layer approach, and in which very large amounts of the antineoplasic drug doxorubicin (DOXO) in a single loading step and targeting capability thanks to an outer hyaluronic acid layer were incorporated by means of an optimized fabrication process (PSS/DOXO/PLL/HA-coated AuNRs). The platform retained its nanometer size with a negative surface charge and was colloidally stable in a range of physiological conditions, in which only in some of them some particle clustering was noted with no precipitation. In addition, the dual stimuli-responsiveness of the designed nanoplatform to both endogenous proteases and external applied light stimuli allows to perfectly manipulate the chemodrug release rates and profiles to achieve suitable pharmacodynamics. It was observed that the inherent active targeting abilities of the nanoplatfom allow the achievement of specific cell toxicity in tumoral cervical HeLa cells, whilst healthy ones such as 3T3-Balb fibroblast remain safe and alive in agreement with the detected levels of internalization in each cell line. In addition, the bimodal action of simultaneous chemo- and photothermal bioactivity provided by the platform largely enhances the therapeutic outcomes. Finally, it was observed that our PSS/DOXO/PLL/HA-coated AuNRs induced cell mortality mainly through apoptosis in HeLa cells even in the presence of NIR light irradiation, which agrees with the idea of the chemo-activity of DOXO predominating over the photothermal effect to induce cell death, favoring an apoptotic pathway over necrosis for cell death.

Silk fibroin/cholinium gallate-based architectures as therapeutic tools.

The combination of natural resources with biologically active biocompatible ionic liquids (Bio-IL) is presented as a combinatorial approach for developing tools to manage inflammatory diseases. Innovative biomedical solutions were constructed combining silk fibroin (SF) and Ch[Gallate], a Bio-IL with antioxidant and anti-inflammatory features, as freeze-dried 3D-based sponges. An evaluation of the effect of the Ch[Gallate] concentration (≤3% w/v) on the SF/Ch[Gallate] sponges was studied. Structural changes observed on the sponges revealed that the Ch[Gallate] presence positively affected the ß-sheet formation while not influencing the silk native structure, which was suggested by the FTIR and solid-state NMR results, respectively. Also, it was possible to modulate their mechanical properties, antioxidant activity and stability/degradation in an aqueous environment, by changing the Ch[Gallate] concentration. The architectures showed high water uptake ability and a weight loss that follows the controlled Ch[Gallate] release rate studied for 7 days. Furthermore, the sponges supported human adipose stem cells growth and proliferation, up to 7 days. TNF-α, IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory) release quantification from a human monocyte cell line revealed a decrease in the pro-inflammatory cytokines concentrations in samples containing Ch[Gallate]. These outcomes encourage the use of the developed architectures as tissue engineering solutions, potentially targeting inflammation processes. STATEMENT OF SIGNIFICANCE: Combining natural resources with active biocompatible ionic liquids (Bio-IL) is herein presented as a combinatorial approach for the development of tools to manage inflammatory diseases. We propose using silk fibroin (SF), a natural protein, with cholinium gallate, a Bio-IL, with antioxidant and anti-inflammatory properties, to construct 3D-porous sponges through a sustainable methodology. The morphological features, swelling, and stability of the architectures were controlled by Bio-IL content in the matrices. The sponges were able to support human adipose stem cells growth and proliferation, and their therapeutic effect was proved by the blockage of TNF-α from activated and differentiated THP-1 monocytes. We believe that these bio-friendly and bioactive SF/Bio-IL-based sponges are effective for targeting pathologies with associated inflammatory processes.

Polymeric nanoparticles for the delivery of Sonoran desert propolis: Synthesis, characterization and antiproliferative activity on cancer cells.

Sonoran propolis (SP) exerts remarkable biological activities attributed to its polyphenolic composition, mostly described as poplar-type flavonoids. It is known that polyphenols present low bioavailability derived of their molecular weight, glycosylation level, metabolic conversion, as well as interaction with the intestinal microbiota, affording limitations for possible in vivo applications. The aim of this work was to synthesize Poly-(lactide-co-glycolide) acid (PLGA) nanoparticles for encapsulation of SP, as a matrix to increase solubility of their polyphenolic compounds and improve delivery, for the evaluation of its antiproliferative activity on cancer cells. The Sonoran propolis-loaded PLGA nanoparticles (SP-PLGA NPs) were synthesized (by nanoprecipitation), and their physicochemical parameters were determined (size, morphology, zeta potential, stability, and drug release). Additionally, the antiproliferative activity of SP-PLGA nanoparticles was evaluated in vitro against murine (M12.C3.F6) and human (HeLa) cancer cell lines, including a non-cancer human cell line (ARPE-19) as control. SP-PLGA NPs presented a mean size of 152.6 ± 7.1 nm with an average negative charge of - 21.2 ± 0.7 mV. The encapsulation yield of SP into PLGA system was approximately 68.2 ± 6.0% with an in vitro release of 45% of propolis content at 48 h. SP-PLGA NPs presented antiproliferative activity against both cancer cell lines tested, with lower IC50 values in M12.C3.F6 and HeLa cell lines (7.8 ± 0.4 and 3.8 ± 0.4 µg/mL, respectively) compared to SP (24.0 ± 4.3 and 7.4 ± 0.4 µg/mL, respectively). In contrast, the IC50 of SP-PLGA NPs and SP against ARPE-19 was higher than 50 µg/mL. Cancer cells treated with SP and SP-PLGA NPs presented morphological features characteristic of apoptosis (cellular shrinkage and membrane blebs), as well as elongated cells, effect previously reported for SP, meanwhile, no morphological changes were observed with ARPE-19 cells. The obtained delivery system demonstrates appropriate encapsulation characteristics and antiproliferative activity to be used in the field of nanomedicine, therefore SP could be potentially used in antitumoral in vivo assays upon its encapsulation into PLGA nanoparticles.

Development of functional hybrid scaffolds for wound healing applications.

Hybrid hydrogels composed of chitosan (CS) and hyaluronic acid (HA) and collagen (Coll) were prepared by polyelectrolyte complex self-assembly. These scaffolds displayed a good intermingling of the polymeric chains, with porosities above 80% and good interconnected structures with pore sizes lying between 30-115 µm. The ionic interactions between CS and HA make the scaffolds have larger storage modulus and longer LVR regions than their pure counterparts. Both quantities progressively decrease as the HA and Coll concentrations in the formulation rise. These hybrid hydrogels showed good swelling extents from ca. 420 to ca. 690% and suitable resistance to enzymatic degradation, which was slightly lower for scaffolds containing CS to larger extents or Coll in the formulation. All scaffolds were largely cytocompatible and allowed the proliferation of both mouse fibroblast and human keratinocytes with their infiltration inside, thus becoming optimal matrices for intended tissue engineering applications as well as transdermal drug delivery depots.

Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors.

Atherosclerosis is an underlying risk factor in cardiovascular diseases (CVDs). The combination of drugs with microRNAs (miRNA) inside a single nanocarrier has emerged as a promising anti-atherosclerosis strategy to achieve the exploitation of their complementary mechanisms of action to achieve synergistic therapeutic effects while avoiding some of the drawbacks associated with current systemic statin therapies. We report the development of nanometer-sized polymeric PLGA nanoparticles (NPs) capable of simultaneously encapsulating and delivering miRNA-124a and the statin atorvastatin (ATOR). The polymeric NPs were functionalized with an antibody able to bind to the vascular adhesion molecule-1 (VCAM1) overexpressed in the inflamed arterial endothelium. The dual-loaded NPs were non-toxic to cells in a large range of concentrations, successfully attached overexpressed VCAM receptors and released the cargoes in a sustainable manner inside cells. The combination of both ATOR and miRNA drastically reduced the levels of proinflammatory cytokines such as IL-6 and TNF-α and of reactive oxygen species (ROS) in LPS-activated macrophages and vessel endothelial cells. In addition, dual-loaded NPs precluded the accumulation of low-density lipoproteins (LdL) inside macrophages as well as morphology changes to a greater extent than in single-loaded NPs. The reported findings validate the present NPs as suitable delivery vectors capable of simultaneously targeting inflamed cells in atherosclerosis and providing an efficient approach to combination nanomedicines.

Bacterial Morphotypes as Important Trait for Uropathogenic E. coli Diagnostic; a Virulence-Phenotype-Phylogeny Study.

Urinary tract infections (UTIs) belong to the most common pathologies in Mexico and are mainly caused by Uropathogenic Escherichia coli (UPEC). UPEC possesses a wide diversity of virulence factors that allow it to carry out its pathogenesis mechanism in the urinary tract (UT). The development of morphotypes in UT represents an important feature of UPEC because it is associated with complications in diagnosis of UTI. The aim of this study was to determine the presence of bacterial morphotypes, virulence genes, virulence phenotypes, antibiotic resistant, and phylogenetic groups in clinical isolates of UPEC obtained from women in Sonora, Mexico. Forty UPEC isolates were obtained, and urine morphotypes were observed in 65% of the urine samples from where E. coli was isolated. Phylogenetic group B2 was the most prevalent. The most frequent virulence genes were fimH (100%), fliCD (90%), and sfaD/focC (72%). Biofilm formation (100%) and motility (98%) were the most prevalent phenotypes. Clinical isolates showed high resistance to aminoglycosides and ß-lactams antibiotics. These data suggest that the search for morphotypes in urine sediment must be incorporated in the urinalysis procedure and also that clinical isolates of UPEC in this study can cause upper, lower, and recurrent UTI.

Spontaneously Self-Assembled Microgel Film as Co-Delivery System for Skincare Applications.

Nowadays, the design of innovative delivery systems is driving new product developments in the field of skincare. In this regard, serving as potential candidates for on-demand drug delivery and fulfilling advanced mechanical and optical properties together with surface protection, spontaneously self-assembled microgel films can be proposed as ideal smart skincare systems. Currently, the high encapsulation of more than one drug simultaneously in a film is a very challenging task. Herein, different ratios (1:1, 3:1, 9:1) of different mixtures of hydrophilic/hydrophobic UVA/UVB-absorbers working together in synergy and used for skin protection were encapsulated efficiently into spontaneously self-assembled microgel films. In addition, in vitro release profiles show a controlled release of the different active molecules regulated by the pH and temperature of the medium. The analysis of the release mechanisms by the Peppas-Sahlin model indicated a superposition of diffusion-controlled and swelling-controlled releases. Finally, the distribution of active molecule mixtures into the film was studied by confocal Raman microscopy imaging corroborating the release profiles obtained.

Restoring Endogenous Repair Mechanisms to Heal Chronic Wounds with a Multifunctional Wound Dressing.

Current treatment of chronic wounds has been critically limited by various factors, including bacterial infection, biofilm formation, impaired angiogenesis, and prolonged inflammation. Addressing these challenges, we developed a multifunctional wound dressing-based three-pronged approach for accelerating wound healing. The multifunctional wound dressing, composed of nanofibers, functional nanoparticles, natural biopolymers, and selected protein and peptide, can target multiple endogenous repair mechanisms and represents a promising alternative to current wound healing products.

Correction: Vescalagin and castalagin reduce the toxicity of amyloid-beta42 oligomers through the remodelling of its secondary structure.

Correction for 'Vescalagin and castalagin reduce the toxicity of amyloid-beta42 oligomers through the remodelling of its secondary structure' by Ana R. Araújo et al., Chem. Commun., 2020, 56, 3187-3190, DOI: .

Liposomes embedded in layer by layer constructs as simplistic extracellular vesicles transfer model.

Extracellular vesicles (EVs) are particles originating from the exfoliation of the cellular membrane. They are involved in cell-to-cell and cell-to-matrix signaling, exchange of bioactive molecules, tumorigenesis and metastasis, among others. To mitigate the limited understanding of EVs transfer phenomena, we developed a simplistic model that mimics EVs and their interactions with cells and the extracellular matrix. The proposed model is a layer by layer (LbL) film built from the polycationic poly-l-lysine (PLL) and the glycosaminoglycan hyaluronic acid (HA) to provide ECM mimicry. Positively charged 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and N1,N1,N14,N14-tetramethyl-N1,N14-ditetradecyltetradecane-1,14-diaminium dibromide (GS14) liposomes were embedded in this construct to act as EVs analogs. To simulate EVs carrying substances, Nile Red was loaded as a model of lipophilic cargo molecules. The integration of each component was followed by quartz crystal microbalance measurements, which confirmed the immobilization of intact liposomes on the underlying (PLL/HA)3 soft film. The release of Nile Red from liposomes either embedded in the LbL construct or exposed at its surface revealed a fast first order release. This system was validated as a model for EV/cell interactions by incubation with breast cancer cells MDA-MB-231. We observed higher internalization for embedded liposomes when compared with surface-exposed ones, showcasing that the ECM mimic layers do not constitute a barrier to liposome/cell interactions but favor them.

Magnetic Nanocomposite Hydrogels for Tissue Engineering: Design Concepts and Remote Actuation Strategies to Control Cell Fate.

Most tissues of the human body are characterized by highly anisotropic physical properties and biological organization. Hydrogels have been proposed as scaffolding materials to construct artificial tissues due to their water-rich composition, biocompatibility, and tunable properties. However, unmodified hydrogels are typically composed of randomly oriented polymer networks, resulting in homogeneous structures with isotropic properties different from those observed in biological systems. Magnetic materials have been proposed as potential agents to provide hydrogels with the anisotropy required for their use on tissue engineering. Moreover, the intrinsic properties of magnetic nanoparticles enable their use as magnetomechanic remote actuators to control the behavior of the cells encapsulated within the hydrogels under the application of external magnetic fields. In this review, we combine a detailed summary of the main strategies to prepare magnetic nanoparticles showing controlled properties with an analysis of the different approaches available to their incorporation into hydrogels. The application of magnetically responsive nanocomposite hydrogels in the engineering of different tissues is also reviewed.