Chemo-photothermal therapy of chitosan/gold nanorod clusters for antibacterial treatment against the infection of planktonic and biofilm MRSA.

Bacterial infections trigger inflammation and impede the closure of skin wounds. The misuse of antibiotics exacerbates skin infections by generating multidrug-resistant bacteria. In this study, we developed chemo-photothermal therapy (chemo-PTT) based on near-infrared (NIR)-irradiated chitosan/gold nanorod (GNR) clusters as anti-methicillin-resistant Staphylococcus aureus (MRSA) agents. The nanocomposites exhibited an average size of 223 nm with a surface charge of 36 mV. These plasmonic nanocomposites demonstrated on-demand and rapid hyperthermal action under NIR. The combined effect of positive charge and PTT by NIR-irradiated nanocomposites resulted in a remarkable inhibition rate of 96 % against planktonic MRSA, indicating a synergistic activity compared to chitosan nanoparticles or GNR alone. The nanocomposites easily penetrated the biofilm matrix. The combination of chemical and photothermal treatments by NIR-stimulated clusters significantly damaged the biofilm structure, eradicating MRSA inside the biomass. NIR-irradiated chitosan/GNR clusters increased the skin temperature of mice by 13 °C. The plasmonic nanocomposites induced negligible skin irritation in vivo. In summary, this novel nanosystem demonstrated potent antibacterial effects against planktonic and biofilm MRSA, showcasing the possible efficacy in treating skin infections.

RNA-Based Antipsoriatic Gene Therapy: An Updated Review Focusing on Evidence from Animal Models.

Psoriasis presents as a complex genetic skin disorder, characterized by the interaction between infiltrated immune cells and keratinocytes. Substantial progress has been made in understanding the molecular mechanisms of both coding and non-coding genes, which has positively impacted clinical treatment approaches. Despite extensive research into the genetic aspects of psoriasis pathogenesis, fully grasping its epigenetic component remains a challenging endeavor. In response to the pressing demand for innovative treatments to alleviate inflammatory skin disorders, various novel strategies are under consideration. These include gene therapy employing antisense nucleotides, silencing RNA complexes, stem cell therapy, and antibody-based therapy. There is a pressing requirement for a psoriasis-like animal model that replicates human psoriasis to facilitate early preclinical evaluations of these novel treatments. The authors conduct a comprehensive review of various gene therapy in different psoriasis-like animal models utilized in psoriasis research. The animals included in the list underwent skin treatments such as imiquimod application, as well as genetic and biologic injections, and the results of these interventions are detailed. Animal models play a crucial role in translating drug discoveries from the laboratory to clinical practice, and these models aid in improving the reproducibility and clinical applicability of preclinical data. Numerous animal models with characteristics similar to those of human psoriasis have proven to be useful in understanding the development of psoriasis. In this review, the article focuses on RNA-based gene therapy exploration in different types of psoriasis-like animal models to improve the treatment of psoriasis.

Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. MATERIALS AND METHODS: In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. RESULTS: Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. CONCLUSIONS: We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

Facile adipocyte uptake and liver/adipose tissue delivery of conjugated linoleic acid-loaded tocol nanocarriers for a synergistic anti-adipogenesis effect.

Obesity is a major risk to human health. Adipogenesis is blocked by α-tocopherol and conjugated linoleic acid (CLA). However, their effect at preventing obesity is uncertain. The effectiveness of the bioactive agents is associated with their delivery method. Herein, we designed CLA-loaded tocol nanostructured lipid carriers (NLCs) for enhancing the anti-adipogenic activity of α-tocopherol and CLA. Adipogenesis inhibition by the nanocarriers was examined using an in vitro adipocyte model and an in vivo rat model fed a high fat diet (HFD). The targeting of the tocol NLCs into adipocytes and adipose tissues were also investigated. A synergistic anti-adipogenesis effect was observed for the combination of free α-tocopherol and CLA. Nanoparticles with different amounts of solid lipid were developed with an average size of 121‒151 nm. The NLCs with the smallest size (121 nm) showed greater adipocyte internalization and differentiation prevention than the larger size. The small-sized NLCs promoted CLA delivery into adipocytes by 5.5-fold as compared to free control. The nanocarriers reduced fat accumulation in adipocytes by counteracting the expression of the adipogenic transcription factors peroxisome proliferator activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP)α, and lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Localized administration of CLA-loaded tocol NLCs significantly reduced body weight, total cholesterol, and liver damage indicators in obese rats. The biodistribution study demonstrated that the nanoparticles mainly accumulated in liver and adipose tissues. The NLCs decreased adipocyte hypertrophy and cytokine overexpression in the groin and epididymis to a greater degree than the combination of free α-tocopherol and CLA. In conclusion, the lipid-based nanocarriers were verified to inhibit adipogenesis in an efficient and safe way.

Acetylshikonin induces necroptosis via the RIPK1/RIPK3-dependent pathway in lung cancer.

Despite advances in therapeutic strategies, lung cancer remains the leading cause of cancer-related death worldwide. Acetylshikonin is a derivative of the traditional Chinese medicine Zicao and presents a variety of anticancer properties. However, the effects of acetylshikonin on lung cancer have not been fully understood yet. This study explored the mechanisms underlying acetylshikonin-induced cell death in non-small cell lung cancer (NSCLC). Treating NSCLC cells with acetylshikonin significantly reduced cell viability, as evidenced by chromatin condensation and the appearance of cell debris. Acetylshikonin has also been shown to increase cell membrane permeability and induce cell swelling, leading to an increase in the population of necrotic cells. When investigating the mechanisms underlying acetylshikonin-induced cell death, we discovered that acetylshikonin promoted oxidative stress, decreased mitochondrial membrane potential, and promoted G2/M phase arrest in lung cancer cells. The damage to NSCLC cells induced by acetylshikonin resembled results involving alterations in the cell membrane and mitochondrial morphology. Our analysis of oxidative stress revealed that acetylshikonin induced lipid oxidation and down-regulated the expression of glutathione peroxidase 4 (GPX4), which has been associated with necroptosis. We also determined that acetylshikonin induces the phosphorylation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1)/RIPK3 and mixed lineage kinase domain-like kinase (MLKL). Treatment with RIPK1 inhibitors (necrostatin-1 or 7-Cl-O-Nec-1) significantly reversed acetylshikonin-induced MLKL phosphorylation and NSCLC cell death. These results indicate that acetylshikonin activated the RIPK1/RIPK3/MLKL cascade, leading to necroptosis in NSCLC cells. Our findings indicate that acetylshikonin reduces lung cancer cells by promoting G2/M phase arrest and necroptosis.

Topically applied pH-responsive nanogels for alkyl radical-based therapy against psoriasiform hyperplasia.

Phototherapy is a conventional antipsoriatic approach based on oxygen-relevant generation of oxidative stress to inhibit keratinocyte hyperproliferation. However, this therapy can be restricted due to local hypoxia in psoriatic lesions. The generation of alkyl radicals is oxygen-independent and suppresses hyperproliferation. Herein, we established alkyl radical-based therapy to treat psoriatic hyperplasia. Because alkyl radicals are short-lived compounds, we loaded 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) as a precursor of alkyl radicals into the chitosan nanogels to improve stability. The present study presented a topically applied nanogel that led to a pH-responsive network sensitive to skin pH. This pH responsiveness of the nanogels allowed fast alkyl radical release in the target site. The physicochemical properties of the prepared nanogels were determined through size, zeta potential, scanning electron microscopy, and absorption spectroscopy. The antipsoriatic activity was examined with keratinocyte- and animal-based studies. The nanogels displayed a smooth and spherical morphology with a hydrodynamic diameter of 215 nm. This size was largely increased as the environmental pH increased to 6. The nanogels heated at 44 °C produced alkyl radicals to induce keratinocyte death through the necrosis pathway. Bioimaging demonstrated that topically applied nanogels could deliver alkyl radicals into the epidermis. This targeting was accompanied by the accumulation of free radicals in the epidermis according to the 2',7'-dichlorodihydrofluorescein diacetate assay. The imiquimod-stimulated psoriasiform animal model indicated a remarkable reduction in erythema, scaling, and overexpressed cytokines upon topical treatment of the nanogels. The transepidermal water loss of the psoriasiform skin was inhibited from 51.7 to 27.0 g/m2/h, suggesting barrier function recovery by the nanocarriers. The nanogels lowered hyperplasia by decreasing the epidermal thickness from 212 to 89 µm. The incorporation of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) as a pH-sensitive fluorescence dye in the nanogels could be used to diagnose the severity of the psoriasiform plaque due to the stronger fluorescence of HPTS in skin with lower pH (psoriasiform skin pH = 4.4) than in healthy skin (pH = 4.9). It was possible to deliver the prepared nanogels into the epidermis to restrain hyperplasia without causing cutaneous irritation.

Tanshinone IIA suppresses burning incense-induced oxidative stress and inflammatory pathways in astrocytes.

The burning incense (BI) behavior could be widely observed in Asia families. Incense sticks are often believed to be made from natural herbs and powders, and to have minimal impact on human health; however, there is limited research to support this claim. The current study aimed to identify the components of BI within the particulate matter 2.5 µm (PM2.5) range and explore if BI has bio-toxicity effects on rat astrocytes (CTX-TNA2). The study also examined the protective effects and underlying molecular mechanisms of tanshinone IIA, a primary lipid-soluble compound found in the herb danshen (Salvia miltiorrhiza Bunge), which has been shown to benefit the central nervous system. Results showed that despite the differences in BI components compared to the atmospheric particulate matter (PM) standards, BI still had a bio-toxicity on astrocytes. BI exposure caused early and late apoptosis, reactive oxygen species (ROS) production, MAPKs (JNK, p38, and ERK), and Akt signaling activation, and inflammation-related proteins (cPLA2, COX-2, HO-1, and MMP-9) increases. Our results further exhibit that the tanshinone IIA pre-treatment could significantly avoid the BI-induced apoptosis and inflammatory signals on rat astrocytes. These findings suggest that BI exposure may cause oxidative stress in rat astrocytes and increase inflammation-related proteins and support the potential of tanshinone IIA as a candidate for preventing BI-related adverse health effects.

IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation.

New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression.

AuAg nanocomposites suppress biofilm-induced inflammation in human osteoblasts.

Staphylococcus aureus (S. aureus)forms biofilm that causes periprosthetic joint infections and osteomyelitis (OM) which are the intractable health problems in clinics. The silver-containing nanoparticles (AgNPs) are antibacterial nanomaterials with less cytotoxicity than the classic Ag compounds. Likewise, gold nanoparticles (AuNPs) have also been demonstrated as excellent nanomaterials for medical applications. Previous studies have showed that both AgNPs and AuNPs have anti-microbial or anti-inflammatory properties. We have developed a novel green chemistry that could generate the AuAg nanocomposites, through the reduction of tannic acid (TNA). The bioactivity of the nanocomposites was investigated inS. aureusbiofilm-exposed human osteoblast cells (hFOB1.19). The current synthesis method is a simple, low-cost, eco-friendly, and green chemistry approach. Our results showed that the AuAg nanocomposites were biocompatible with low cell toxicity, and did not induce cell apoptosis nor necrosis in hFOB1.19 cells. Moreover, AuAg nanocomposites could effectively inhibited the accumulation of reactive oxygen species (ROS) in mitochondria and in rest of cellular compartments after exposing to bacterial biofilm (by reducing 0.78, 0.77-fold in the cell and mitochondria, respectively). AuAg nanocomposites also suppressed ROS-triggered inflammatory protein expression via MAPKs and Akt pathways. The current data suggest that AuAg nanocomposites have the potential to be a good therapeutic agent in treating inflammation in bacteria-infected bone diseases.

Targeting anti-inflammatory immunonanocarriers to human and murine neutrophils via the Ly6 antigen for psoriasiform dermatitis alleviation.

Psoriasis is a refractory and difficult-to-treat skin disorder. The neutrophil-targeting approach represents a promising option for psoriasis therapy. This study developed and examined NIMP-R14-conjugated immunonanoparticles for specific targeting to neutrophils associated with psoriasiform dermatitis. In the process, roflumilast (RFL), as a phosphodiesterase (PDE) 4 inhibitor, was encapsulated in the nanocarriers to assess the anti-inflammatory capability against primary neutrophil activation and murine psoriasiform lesion. The average size and surface charge of the immunonanocarriers were 305 ± 36 nm and -18 ± 6 mV, respectively. The monovalent antibody-conjugated nanoparticles offered precise uptake by both human and mouse neutrophils but failed to exhibit this effect in monocytes and lymphocytes. The intracellular RFL concentration of the immunonanocarriers was five-fold superior to that of the passive counterparts. The immunonanocarriers specifically recognized the neutrophils through the Ly6 antigen with no apparent cytotoxicity. The antibody-conjugated nanoparticles mitigated superoxide anion production and migration of the activated human neutrophils. The in vivo biodistribution in the psoriasiform mice, found using an in vivo imaging system (IVIS) and liquid chromatography (LC)-mass-mass analysis, showed that the antibody conjugation increased the nanoparticle residence in systemic circulation after intravenous administration. On the other hand, most of the nanoparticles were accumulated in the lesional skin after subcutaneous injection. The actively-targeted nanocarriers were better than the free RFL and unfunctionalized nanoparticles in suppressing psoriasiform inflammation. The immunonanocarriers reduced neutrophil recruitment and epidermal hyperplasia in the plaque. Intravenous and subcutaneous treatments with the immunonanocarriers significantly reduced the overexpressed cytokines and chemokines in the inflamed skin, demonstrating that the nanosystems could both systematically and locally alleviate inflammation. The results indicated that the NIMP-R14-conjugated RFL-loaded nanoparticles have potential as an anti-autoimmune disease delivery system for neutrophil targeting.

The role of cytokines/chemokines in an aging skin immune microenvironment.

Reversing or slowing down the skin aging process is one of the most intriguing areas of focus across the social and scientific communities around the world. While aging is considered a universal and inevitable natural process of physiological decline, the aging of the skin is the most apparent visual representation of an individual's health. Aging skin may be objectively defined by epidermal thinning; increased transepidermal water loss; decreased cutaneous barrier function; loss of elasticity, laxity, and textured appearance; and gradual deterioration of the epidermal immune environment. As the largest structure of the immune system and of the body as a whole, the skin is the most vulnerable barrier of defense against the environment. The skin reflects an individual's exposures, lifestyle habits, and overall health. From an immunological perspective, cytokines and chemokines act as a central character in the communicating of the immunity in skin aging. These cell signaling proteins serve as the intercellular communication link. This review aims to elucidate how cell-cell crosstalk through cytokines and chemokines, and the interplay between host cells, infiltrating immune cells, and exogenous factors contribute to the overall aging skin.

Polydopamine/IR820 nanoparticles as topical phototheranostics for inhibiting psoriasiform lesions through dual photothermal and photodynamic treatments.

Dual photothermal and photodynamic therapy (PTT and PDT) is an attractive approach that generates a synergistic effect for inhibiting keratinocyte hyperproliferation in the treatment of psoriasis. Here, we developed phototheranostic nanocarriers capable of producing hyperthermia and reactive oxygen species (ROS) in response to near-infrared (NIR) illumination. To this end, IR820 with photothermal and photodynamic features was embedded in nano-sized polydopamine (PDA) acting as a PTT agent. A comprehensive characterization of the PDA/IR820 nanosystem was performed according to its morphology, size, zeta potential, UV absorbance, and heat generation. Its therapeutic efficacy was assessed by a keratinocyte-based study and using an imiquimod (IMQ)-stimulated psoriasiform murine model. PDA/IR820 nanoparticles were facilely internalized into keratinocytes and mainly resided in lysosomes. Upon irradiation with NIR light, ROS were generated inside the keratinocytes to cause a photodynamic effect. The live/dead cell assay and cytotoxicity assay demonstrated that PDA and IR820 acted as effective photoabsorbers to induce keratinocyte death. The highest cytotoxic effect was detected in the group of NIR-irradiated PDA/IR820 nanoparticles, which killed 52% of keratinocytes. The nanosystem acted through the caspase and poly ADP-ribose polymerase (PARP) pathways to induce keratinocyte apoptosis. In vitro and in vivo skin permeation indicated the selective accumulation of the topically applied PDA/IR820 nanoparticles within psoriasiform skin, suggesting their skin-targeting capability. The combination of PDA/IR820 nanoparticles and NIR irradiation increased the skin temperature by 11.7 °C. PTT/PDT eliminated psoriasiform plaques in mice by decreasing hyperplasia, inhibiting cytokine overexpression, and recovering the barrier function. The epidermal thickness of the IMQ-treated skin was reduced from 134 to 34 µm by the nanocarriers plus NIR. The IR820 nanoparticles were largely deposited on the inflamed areas of psoriasiform lesions for monitoring the severity of inflammation. The image-guided phototheranostic nanoparticles showed their potential for applications in psoriasis management via noninvasive topical administration.

Anti-Inflammatory microRNAs for Treating Inflammatory Skin Diseases.

Skin inflammation occurs due to immune dysregulation because of internal disorders, infections, and allergic reactions. The inflammation of the skin is a major sign of chronic autoimmune inflammatory diseases, such as psoriasis, atopic dermatitis (AD), and lupus erythematosus. Although there are many therapies for treating these cutaneous inflammation diseases, their recurrence rates are high due to incomplete resolution. MicroRNA (miRNA) plays a critical role in skin inflammation by regulating the expression of protein-coding genes at the posttranscriptional level during pathogenesis and homeostasis maintenance. Some miRNAs possess anti-inflammatory features, which are beneficial for mitigating the inflammatory response. miRNAs that are reduced in inflammatory skin diseases can be supplied transiently using miRNA mimics and agomir. miRNA-based therapies that can target multiple genes in a given pathway are potential candidates for the treatment of skin inflammation. This review article offers an overview of the function of miRNA in skin inflammation regulation, with a focus on psoriasis, AD, and cutaneous wounds. Some bioactive molecules can target and modulate miRNAs to achieve the objective of inflammation suppression. This review also reports the anti-inflammatory efficacy of these molecules through modulating miRNA expression. The main limitations of miRNA-based therapies are rapid biodegradation and poor skin and cell penetration. Consideration was given to improving these drawbacks using the approaches of cell-penetrating peptides (CPPs), nanocarriers, exosomes, and low-frequency ultrasound. A formulation design for successful miRNA delivery into skin and target cells is also described in this review. The possible use of miRNAs as biomarkers and therapeutic modalities could open a novel opportunity for the diagnosis and treatment of inflammation-associated skin diseases.

The Potential Implications of Hydrogen Sulfide in Aging and Age-Related Diseases through the Lens of Mitohormesis.

The growing increases in the global life expectancy and the incidence of chronic diseases as a direct consequence have highlighted a demand to develop effective strategies for promoting the health of the aging population. Understanding conserved mechanisms of aging across species is believed helpful for the development of approaches to delay the progression of aging and the onset of age-related diseases. Mitochondrial hormesis (or mitohormesis), which can be defined as an evolutionary-based adaptive response to low-level stress, is emerging as a promising paradigm in the field of anti-aging. Depending on the severity of the perceived stress, there are varying levels of hormetic response existing in the mitochondria called mitochondrial stress response. Hydrogen sulfide (H2S) is a volatile, flammable, and toxic gas, with a characteristic odor of rotten eggs. However, H2S is now recognized an important gaseous signaling molecule to both physiology and pathophysiology in biological systems. Recent studies that elucidate the importance of H2S as a therapeutic molecule has suggested its protective effects beyond the traditional understanding of its antioxidant properties. H2S can also be crucial for the activation of mitochondrial stress response, postulating a potential mechanism for combating aging and age-related diseases. Therefore, this review focuses on highlighting the involvement of H2S and its sulfur-containing derivatives in the induction of mitochondrial stress response, suggesting a novel possibility of mitohormesis through which this gaseous signaling molecule may promote the healthspan and lifespan of an organism.

Laser-assisted nanocarrier delivery to achieve cutaneous siRNA targeting for attenuating psoriasiform dermatitis.

Psoriasis is an autoimmune skin disorder presenting the excessive expression of interleukin (IL)-6. The topical use of small interfering RNA (siRNA) has been increasingly discovered for treating skin diseases. A delivery system capable of protecting siRNA while facilitating both skin targeting and cellular entrance is critical for the successful medication of topically-applied siRNA. Herein, we developed a delivery system for siRNA based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles and combined this system with an ablative laser to promote skin absorption for topical psoriasis therapy. The siRNA absorption enhancement was compared by two laser modalities: a fractional CO2 laser and a fully-ablative Er:YAG laser. We characterized the effect of the delivery system by the cellular uptake, IL-6 silencing, in vitro skin absorption, cutaneous biodistribution, and in vivo psoriasiform dermatitis in mice. The nanocarriers showed minimal cytotoxicity and facile cellular uptake to knock down the IL-6 expression. The nanoformulation containing a cationic surfactant (Forestall) for ion pairing with siRNA achieved a 66% and 77% IL-6 knockdown efficiency toward keratinocytes and macrophages, respectively. In the Franz cell absorption, the lasers increased the naked siRNA penetration to the receptor compartment by 3.7-5.0-fold but remarkably reduced skin deposition using imiquimod (IMQ)-treated psoriasiform skin as the barrier. The fractional laser facilitated nanoparticle-associated siRNA skin deposition up to 3.3-fold, whereas the transport of the nanocarriers to the receptor was negligible. Qualitatively, the lasers increased nanoparticle delivery in the epidermis with limited effect to elevate the penetration depth. The fractional-mediated nanocarrier delivery dramatically attenuated the erythema and scaly lesions of psoriasiform dermatitis. The histological examination displayed a reduction of epidermal hyperplasia and macrophage infiltration by the combination of laser and nanosystem. The passive and laser-assisted naked siRNA delivery was less effective in mitigating dermatitis. The topical delivery of fractional laser-assisted nanoparticles on mice resulted in a 56% IL-6 knockdown. Our results manifested the benefit of cutaneous siRNA targeting using ablative lasers to deliver nanocarriers for treating psoriatic inflammation.

Photothermal treatment by PLGA-gold nanorod-isatin nanocomplexes under near-infrared irradiation for alleviating psoriasiform hyperproliferation.

Psoriasis is a chronic autoimmune skin disorder that involves keratinocyte hyperproliferation and inflammatory cell recruitment. A strategy to mitigate psoriatic lesions is to induce keratinocyte apoptosis for proliferation suppression. Herein we designed a nanoformulation capable of treating psoriasis via hyperthermia-induced apoptosis in response to near-infrared (NIR) irradiation. To this end, gold nanorods (GNRs) and isatin, which is an anti-inflammatory agent for synergizing antipsoriatic activity, were loaded into a poly (lactic-co-glycolic acid) (PLGA) matrix to form the nanocomplexes. The physicochemical and photothermal properties of the nanocomplexes were determined in terms of size, surface charge, NIR-absorbing feature, isatin release, keratinocyte uptake, and cytotoxicity. The nanocomplexes showed a spherical shape with an average size of about 180 nm. The GNR-loaded nanoparticles can efficiently convert NIR light at 0.42 W/cm2 into heat with an increased temperature of 10 °C. When combined with NIR exposure, the nanocomplexes were internalized into keratinocyte cytoplasm with an inhibition of keratinocyte viability to about 60%. Live/dead cell assay and flow cytometry confirmed that the nanocomplexes could serve as NIR-absorbers to specifically elicit keratinocyte apoptosis through caspase and poly ADP-ribose polymerase (PARP) pathways. The in vivo psoriasiform murine model indicated that the combined nanocomplexes and NIR inhibited epidermal hyperplasia and neutrophil infiltration. The overexpressed cytokines in the lesion could be recovered to normal baseline level after the photothermal management. The subcutaneous nanocomplexes remained in the skin for at least 5 days. The nanocomposites produced a negligible toxicity in the skin or liver of healthy mice. The photothermal nanosystems, as designed in this study, shed new light on the therapeutic approach against psoriasis.

Monovalent antibody-conjugated lipid-polymer nanohybrids for active targeting to desmoglein 3 of keratinocytes to attenuate psoriasiform inflammation.

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

Facile skin targeting of a thalidomide analog containing benzyl chloride moiety alleviates experimental psoriasis via the suppression of MAPK/NF-κB/AP-1 phosphorylation in keratinocytes.

BACKGROUND: Thalidomide can be a TNF-α inhibitor for treating skin inflammation. This drug exhibits a strong toxicity that limits its application. OBJECTIVE: We synthesized a thalidomide analog containing the benzyl chloride group (2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione, CDI) to examine anti-inflammatory activity against psoriasis. METHODS: The evaluation was conducted by the experimental platforms of in vitro TNF-α- or imiquimod (IMQ)-stimulated HaCaT cells and in vivo IMQ-induced psoriasiform plaque. RESULTS: Using the in vitro keratinocyte model, we demonstrated a greater inhibition of IL-1ß, IL-6, and IL-24 by CDI than by thalidomide. No significant cytotoxicity was observed at 100 µM. CDI delivered facilely into the skin with a cutaneous targeting ability 228-fold greater than thalidomide. CDI caused a negligible irritation on healthy mouse skin. We showed that topically applied CDI reduced IMQ-induced red scaly lesions, hyperplasia, microabscesses, and cytokine expression in the mouse model. The skin-barrier function measured by transepidermal water loss (TEWL) could be partially recovered from 50.6-36.3 g/m2/h by CDI. The mechanistic study showed that CDI suppressed cytokine production by inhibiting the phosphorylation of NF-κB and AP-1 via MAPK pathways. CONCLUSION: CDI would be beneficial for the development of a therapeutic agent against psoriasis.

Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency.

BACKGROUND: Oleic acid (OA) is reported to show anti-inflammatory activity toward activated neutrophils. It is also an important material in nanoparticles for increased stability and cellular internalization. We aimed to evaluate the anti-inflammatory activity of injectable OA-based nanoparticles for treating lung injury. Different sizes of nanocarriers were prepared to explore the effect of nanoparticulate size on inflammation inhibition. RESULTS: The nanoparticles were fabricated with the mean diameters of 105, 153, and 225 nm. The nanocarriers were ingested by isolated human neutrophils during a 5-min period, with the smaller sizes exhibiting greater uptake. The size reduction led to the decrease of cell viability and the intracellular calcium level. The OA-loaded nanosystems dose-dependently suppressed the superoxide anion and elastase produced by the stimulated neutrophils. The inhibition level was comparable for the nanoparticles of different sizes. In the ex vivo biodistribution study, the pulmonary accumulation of nanoparticles increased following the increase of particle size. The nanocarriers were mainly excreted by the liver and bile clearance. Mice were exposed to intratracheal lipopolysaccharide (LPS) to induce acute respiratory distress syndrome (ARDS), like lung damage. The lipid-based nanocarriers mitigated myeloperoxidase (MPO) and cytokines more effectively as compared to OA solution. The larger nanoparticles displayed greater reduction on MPO, TNF-α, and IL-6 than the smaller ones. The histology confirmed the decreased pulmonary neutrophil recruitment and lung-architecture damage after intravenous administration of larger nanoparticles. CONCLUSIONS: Nanoparticulate size, an essential property governing the anti-inflammatory effect and lung-injury therapy, had different effects on activated neutrophil inhibition and in vivo therapeutic efficacy.

Prodrugs in combination with nanocarriers as a strategy for promoting antitumoral efficiency.

Prodrug entrapment into nanocarriers for tumor delivery is a strategy to achieve a valid therapy with high efficiency. The prodrug contains anticancer agents conjugating with functional moieties or ligands so that the active component is released after metabolism in the body or tumor. The advantages of nanosystems for loading prodrugs include high loading, increased prodrug stability, improved bioavailability and enhanced targeting to tumor cells. In the present article, we introduce the prodrug delivery approaches according to nanomedicine and the recent advances in prodrug-loaded nanocarriers. First, we discuss the conceptional design of combined prodrugs and nanocarriers in response to the obstruction in anticancer therapy. Then we describe the cases of prodrug-loaded nanoparticles for cancer treatment during the past 5 years.