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The COVID-19 causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a critical surface protein called spike protein (S protein), which is the target of many vaccines and drugs developments. Among non-structural proteins of SARS-CoV-2, main protease (M pro ) has drawn much attention to itself for designing antiviral drugs since it is very crucial for the virus replication in host cells. In the first part of the present study, the application of metal–organic frameworks (MOFs), one of the developing nanomaterials in the deformation and consequently inhibition of S protein binding to the receptor, angiotensin-converting enzyme 2 (ACE 2), is investigated. In this line, various S protein inhibitors were designed virtually, including ZIF, UIO, and IRMOF that their interactions with S protein and were investigated using molecular dynamics (MD) simulation. The results revealed that ZIF is the best candidate among the investigated MOFs with the least amount of energy interference with S protein. In the second part, the interaction of three-dimensional (3D) MOFs (such as ZIF, IRMOF, and HKUST) with SARS-CoV-2 M pro was investigated. HKUST had the most potent interaction with M pro and showed more promise in deforming this protein's secondary structure among all materials tested. Furthermore, we investigated the interaction of HKUST-OH with M pro to determine the effect of functionalization. The findings of this study could be used in future studies to introduce bioconjugates of MOFs and biological molecules (e.g., antibody or nanobody) or to use MOFs as carriers for antiviral drug delivery.

Organic and inorganic nanoparticles (NPs) have shown promising outcomes in transdermal drug delivery. NPs can not only enhance the skin penetration of small/biomacromolecule therapeutic agents but can also impart control over drug release or target impaired tissue. Thanks to their unique optical, photothermal, and superparamagnetic features, NPs have been also utilized for the treatment of skin disorders, imaging, and biosensing applications. Despite the widespread transdermal applications of NPs, their delivery across the stratum corneum, which is the main skin barrier, has remained challenging. Microneedle array (MN) technology has recently revealed promising outcomes in the delivery of various formulations, especially NPs to deliver both hydrophilic and hydrophobic therapeutic agents. The present work reviews the advancements in the application of MNs and NPs for an effective transdermal delivery of a wide range of therapeutics in cancer chemotherapy and immunotherapy, photothermal and photodynamic therapy, peptide/protein vaccination, and the gene therapy of various diseases. In addition, this paper provides an overall insight on MNs’ challenges and summarizes the recent achievements in clinical trials with future outlooks on the transdermal delivery of a wide range of nanomedicines.

RNA therapeutics, such as mRNA, siRNA, and CRISPR–Cas9, present exciting avenues for treating diverse diseases. However, their potential is commonly hindered by vulnerability to degradation and poor cellular uptake, requiring effective delivery systems. Lipid nanoparticles (LNPs) have emerged as a leading choice for in vivo RNA delivery, offering protection against degradation, enhanced cellular uptake, and facilitation of endosomal escape. However, LNPs encounter numerous challenges for targeted RNA delivery in vivo, demanding advanced particle engineering, surface functionalization with targeting ligands, and a profound comprehension of the biological milieu in which they function. This review explores the structural and physicochemical characteristics of LNPs, in-vivo fate, and customization for RNA therapeutics. We highlight the quality-by-design (QbD) approach for targeted delivery beyond the liver, focusing on biodistribution, immunogenicity, and toxicity. In addition, we explored the current challenges and strategies associated with LNPs for in-vivo RNA delivery, such as ensuring repeated-dose efficacy, safety, and tissue-specific gene delivery. Furthermore, we provide insights into the current clinical applications in various classes of diseases and finally prospects of LNPs in RNA therapeutics. Graphical Abstract

Purpose Methotrexate (MTX) is one of the most widely studied and effective therapeutics agents available to treat many solid tumors, hematologic malignancies, and autoimmune diseases such as rheumatoid arthritis; however, the poor pharmacokinetic and narrow safety margin of the drug limits the therapeutic outcomes of conventional drug delivery systems. For an improved delivery of MTX, several pathophysiological features such as angiogenesis, enhanced permeability and retention effects, acidosis, and expression of specific antigens and receptors can be used either as targets or as tools for drug delivery. Methods There are many novel delivery systems developed to improve the pitfalls of MTX therapy ranged from polymeric conjugates such as human serum albumin, liposomes, microspheres, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, polymeric micelles, in situ forming hydrogels, carrier erythrocyte, and nanotechnology-based vehicles such as carbon nanotubes, magnetic nanoparticles, and gold nanoparticles. Some are further modified with targeting ligands for active targeting purposes. Results Such delivery systems provide prolonged plasma profile, enhanced and specific activity in vitro and in vivo in animal models. Nevertheless, more complementary studies are needed before they can be applied in human. Conclusion This review deals with the challenges of conventional systems and achievements of each pharmaceutical class of novel drug delivery vehicle.

A functional polycation nanonetwork was developed for delivery of water soluble chemotherapeutic agents. The complexes of polyethyleneimine grafted methoxy polyethylene glycol (PEI-g-mPEG) and Zn(2+) were utilized as the micellar template for cross-linking with dithiodipropionic acid, followed by an acidic pH dialysis to remove the metal ion from the micellar template. The synthesis method was optimized according to pH, the molar ratio of Zn(2+), and the cross-link ratio. The atomic force microscopy showed soft, discrete, and uniform nano-networks. They were sensitive to the simulated reductive environment as determined by Ellman's assay. They showed few positive ζ potential and an average hydrodynamic diameter of 162±10 nm, which decreased to 49±11 nm upon dehydration. The ionic character of the nano-networks allowed the achievement of a higher-loading capacity of methotrexate (MTX), approximately 57% weight per weight, depending on the cross-link and the drug feed ratios. The nano-networks actively loaded with MTX presented some suitable properties, such as the hydrodynamic size of 117±16 nm, polydispersity index of 0.22, and a prolonged swelling-controlled release profile over 24 hours that boosted following reductive activation of the nanonetwork biodegradation. Unlike the PEI ionomer, the nano-networks provided an acceptable cytotoxicity profile. The drug-loaded nano-networks exhibited more specific cytotoxicity against human hepatocellular carcinoma cells if compared to free MTX at concentrations above 1 μM. The enhanced antitumor activity in vitro might be attributed to endocytic entry of MTX-loaded nano-networks that was found in the epifluorescence microscopy experiment for the fluorophore-labeled nano-networks.

In this in vitro study, for the first time, we evaluate the effects of simvastatin‐loaded liposome nanoparticles (SIM‐LipoNPs) treatment on fibrosis‐induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non‐alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM‐LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel‐like factor (KLF) 2, and pro‐inflammatory cytokines (interleukin(IL)‐1 α, IL‐1 β, IL‐6 and tumour necrosis factor‐α), and the expression of collagen I. Our results indicated that SIM‐LipoNPs application showed promising results. SIM‐LipoNPs effectively amplified the SIM‐klf2‐NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM‐LipoNPs administration also resulted in a significant reduction in pro‐inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM‐LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM‐LipoNPs in activating the KLF2‐NO pathway and anti‐oxidative and anti‐inflammatory response.

Background Vitiligo is an autoimmune disorder primarily categorized into non-segmental (NSV) and segmental (SV) subtypes. Interleukin-21 (IL-21) is a pleiotropic cytokine implicated in immune dysregulation. Objective To investigate the association of serum IL-21 levels and two genetic variants (rs2055979 and rs4833837) with susceptibility to NSV and SV in an Iranian cohort. Methods The study included 264 vitiligo patients (225 NSV, 39 SV) and up to 390 healthy controls. Serum IL-21 was measured by ELISA. Genotyping for rs2055979 was performed by RFLP-PCR, and for rs4833837 by ASO-PCR. Results Serum IL-21 levels were significantly elevated in both NSV (median 71.50 pg/mL) and SV (median 65.35 pg/mL) patients compared to controls (median 18.70 pg/mL; p  < 0.0001). For rs2055979, the GT genotype was associated with increased risk of NSV (unadjusted OR = 2.99, 95% CI = 1.86–4.80, p  < 0.0001; age- and sex-adjusted OR = 1.809, 95% CI = 1.061–3.085, p  = 0.029) and SV (unadjusted OR = 4.29, 95% CI = 1.45–12.7, p  = 0.005; adjusted OR = 3.486, 95% CI = 1.006–12.077, p  = 0.049). The unadjusted G allele was a risk factor for NSV (OR = 1.52, 95% CI = 1.19–1.94, p  = 0.0009) but not for SV ( p  = 0.09). The GG genotype also conferred elevated unadjusted risk for NSV (OR = 2.51, 95% CI = 1.44–4.37, p  = 0.0009). In contrast, rs4833837 showed no significant association with either vitiligo subtype. Conclusion The IL-21 rs2055979 polymorphism is associated with vitiligo susceptibility, with the GT genotype representing a risk factor for both NSV and SV after adjustment for age and sex. The marked elevation of serum IL-21 in both NSV and SV further supports a pathogenic role for IL-21, suggesting the IL-21/IL-21R axis as a potential therapeutic target.

Background Mesenchymal-based therapy has been utilized as a practical approach in the treatment of renal ischemia/reperfusion (I/R) injury. However, low cell retention and survival in the ischemic site have remained challenging issues. To bridge this gap, the integrin receptor-binding RGD peptide-functionalized, s-nitroso-n-acetyl penicillamine (SNAP)-loaded hydrogel was used to transplant Wharton's jelly-mesenchymal stem cells (WJ-MSCs). Methods Apart from physicochemical and rheological characterizations that confirmed entangled interlocking β-sheets with nanofibrous morphology, real-time RT-PCR, ROS production, serum biomarker concentrations, and histopathological alterations were explored in a mouse model to assess the therapeutic efficacy of formulations in the treatment of renal I/R injury. Results The RGD-functionalized Fmoc-diphenylalanine (Fmoc-FF + Fmoc-RGD) hydrogel supported the spread and proliferation of WJ-MSCs in vivo . Notably, intralesional injection of nitric oxide donor combined with the embedded WJ-MSCs caused superior recovery of renal I/R injury compared to free WJ-MSCs alone in terms of histopathological scores and renal function indices. Compared to the I/R control group, oxidative stress and inducible nitric oxide synthase (iNOS) expression biomarkers showed a significant decline, whereas endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) expression exhibited a significant increment, indicating regeneration of the injured endothelial tissue. Conclusion The findings confirmed that the hydrogels containing WJ-MSCs and nitric oxide donors can promote the regeneration of renal I/R injuries by increasing angiogenic factors and cell engraftment.

Objective Activated macrophages play important roles during immune responses by polarizing into M1 and M2 subsets and overproducing several mediators such as nitric oxide (NO), pro- and anti-inflammatory cytokines, and indoleamine 2,3-dioxygenase (IDO). This study aims to investigate the possible effects of piperine, a major component of the pepper plant, on the expression of M1 and M2 macrophage markers. Results Piperine dose-dependently decreased iNOS gene expression and NO level in LPS-stimulated macrophages. Additionally, at concentrations of 1–20 µg/ml, it significantly suppressed the production and/or gene expression levels of proinflammatory M1-related cytokines. Its effects on cytokine genes were dose-dependent, and reduced IL-1β , TNF-α , and IFN-γ expression (17 ± 11.8, 1.33 ± 0.76, and 25.4 ± 5.2 fold, respectively, compared with LPS-stimulated cells). Piperine at 1 µg/ml didn’t affect the IL-10 gene but significantly increased IDO1 (from 8.4 ± 0.24-fold in LPS-treated cells to 28.3 ± 5.3-fold in piperine-treated cells), and decreased IL-4 gene expressions at the higher concentrations. Dexamethasone (a glucocorticoid anti-inflammatory drug) reduced most mediators but did not affect the IDO gene. Our data demonstrate that piperine dose-dependently inhibits M1-macrophages and upregulates IDO1 at low concentration, a unique mechanism of action, positioning it as a multifaceted therapeutic candidate for inflammatory conditions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is exponentially spreading across the world, leading to an outbreak of serious viral pneumonia. Antiviral therapies using chloroquine, hydroxychloroquine, and favipiravir have been approved by several countries to increase the quality of life of SARS-CoV-2-infected patients. Currently, several companies are intensively working on the production of coronavirus (CoV) vaccines, resulting in some specific vaccines that have been approved for CoV infections in humans. Nevertheless, efficient and specific prevention, treatment, and diagnosis are urgently required to combat the biological diversity and rapid mutation in CoV infections. Recently, significant attention has devoted to nanoformulation or nanoparticles (NPs) due to their specific features like high surface-to-volume ratio, drug encapsulation abilities, and specific optical properties to remove the complications of applied conventional therapeutic and diagnosis options. In this regard, NPs are increasingly used as new anti-CoV agents, vaccine carriers or adjuvants, and nanoscale biorecognition elements. The present review article provides a comprehensive discussion on the recent updates regarding the prevention, diagnosis, and treatment of different CoV infections with an emphasis on the application of NPs in vaccination, treatment, and diagnosis of CoV infections.