Expanding horizons in cancer therapy by immunoconjugates targeting tumor microenvironments.

Immunoconjugates are promising molecules combining antibodies with different agents, such as toxins, drugs, radionuclides, or cytokines that primarily aim to target tumor cells. However, tumor microenvironment (TME), which comprises a complex network of various cells and molecular cues guiding tumor growth and progression, remains a major challenge for effective cancer therapy. Our review underscores the pivotal role of TME in cancer therapy with immunoconjugates, examining the intricate interactions with TME and recent advancements in TME-targeted immunoconjugates. We explore strategies for targeting TME components, utilizing diverse antibodies such as neutralizing, immunomodulatory, immune checkpoint inhibitors, immunostimulatory, and bispecific antibodies. Additionally, we discuss different immunoconjugates, elucidating their mechanisms of action, advantages, limitations, and applications in cancer immunotherapy. Furthermore, we highlight emerging technologies enhancing the safety and efficacy of immunoconjugates, such as antibody engineering, combination therapies, and nanotechnology. Finally, we summarize current advancements, perspectives, and future developments of TME-targeted immunoconjugates.

The effects of simvastatin-loaded nanoliposomes on human multilineage liver fibrosis microtissue.

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 ß, 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.

Erythrocyte membrane-camouflaged mesoporous silica composite nanoparticles for loading and controlled release of the hepatoprotective agent silibinin: A-synthesis and physicochemical characterization.

OBJECTIVES: Milk thistle has long been used in the treatment of liver and biliary disorders. In the present study, to make a long-acting delivery system for silibinin (SBN, a major active constituent of milk thistle seeds with antioxidant and hepatoprotective function), mesoporous silica composite nanoparticles (NC) were synthesized and coated with RBC membrane. METHODS: A modified Stöber method was used for NC synthesis, which was then characterized using FE-SEM, DLS, TEM, FTIR, and EDAX techniques. A suitable lysis buffer was used to prepare RBC-ghost, and sonication was used to coat SBN-loaded NC (SBN-NC). The RBC-ghost coated SBN-NC (SBN-NC-RBCG) was evaluated by SDS-PAGE, Bradford, TEM, EDAX, and DLS methods. SBN release was then compared for the SBN-NC and SBN-NC-RBCG samples. KEY FINDINGS: the RBC membrane proteins were recovered from the coating of SBN-NC-RBCG, and SBN release was sustained over 24 h when compared with the SBN-NC. CONCLUSIONS: Overall, through prolonging circulation in the bloodstream and evading the immune system, the developed system can improve SBN bioavailability in liver inflammation and fibrosis conditions that need further research.

Harnessing the Potential of Self-Assembled Peptide Hydrogels for Neural Regeneration and Tissue Engineering.

Spinal cord injury, traumatic brain injury, and neurosurgery procedures usually lead to neural tissue damage. Self-assembled peptide (SAP) hydrogels, a type of innovative hierarchical nanofiber-forming peptide sequences serving as hydrogelators, have emerged as a promising solution for repairing tissue defects and promoting neural tissue regeneration. SAPs possess numerous features, such as adaptable morphologies, biocompatibility, injectability, tunable mechanical stability, and mimicking of the native extracellular matrix. This review explores the capacity of neural cell regeneration and examines the critical aspects of SAPs in neuroregeneration, including their biochemical composition, topology, mechanical behavior, conductivity, and degradability. Additionally, it delves into the latest strategies involving SAPs for central or peripheral neural tissue engineering. Finally, the prospects of SAP hydrogel design and development in the realm of neuroregeneration are discussed.

Peptide nanovaccine in melanoma immunotherapy.

Melanoma is an especially fatal neoplasm resistant to traditional treatment. The advancement of novel therapeutical approaches has gained attention in recent years by shedding light on the molecular mechanisms of melanoma tumorigenesis and their powerful interplay with the immune system. The presence of many mutations in melanoma cells results in the production of a varied array of antigens. These antigens can be recognized by the immune system, thereby enabling it to distinguish between tumors and healthy cells. In the context of peptide cancer vaccines, generally, they are designed based on tumor antigens that stimulate immunity through antigen-presenting cells (APCs). As naked peptides often have low potential in eliciting a desirable immune reaction, immunization with such compounds usually necessitates adjuvants and nanocarriers. Actually, nanoparticles (NPs) can provide a robust immune response to peptide-based melanoma vaccines. They improve the directing of peptide vaccines to APCs and induce the secretion of cytokines to get maximum immune response. This review provides an overview of the current knowledge of the utilization of nanotechnology in peptide vaccines emphasizing melanoma, as well as highlights the significance of physicochemical properties in determining the fate of these nanovaccines in vivo, including their drainage to lymph nodes, cellular uptake, and influence on immune responses.

Simvastatin-Releasing Nanofibrous Peptide Hydrogels for Accelerated Healing of Diabetic Wounds.

Wound healing is one of the major global health concerns in diabetic patients. Simvastatin (SMV) is a poorly soluble oral cholesterol-lowering drug that may aid diabetic wound healing. In the current study, a thixotropic peptide hydrogel of Fmoc-diphenylalanine (FmocFF) containing SMV was designed to accelerate skin wound healing effectively and safely in diabetic mice. FmocFF hydrogels were prepared at various concentrations by using the solvent-triggering technique and characterized by spectroscopic methods such as attenuated total reflection Fourier transform infrared (FT-IR) spectroscopy and fluorimetry. Mechanical behaviors were explored by oscillatory rheology. In model mice, the regenerative potential of the FmocFF-SMV hydrogel was evaluated in terms of wound contraction and closure, tissue regeneration, acute and chronic inflammation, granulation, and re-epithelization. The results showed that FmocFF-SMV hydrogels had an entangled nanofibrous microstructure and shear-thinning characteristics. FmocFF-SMV demonstrated a sustained drug release over 7 days. Compared to the unloaded FmocFF hydrogel, treatment with FmocFF-SMV led to superior diabetic wound recovery and reduced inflammation. Therefore, the utilization of the sustained-release FmocFF-SMV hydrogel formulation could become an attractive choice for topical wound therapy in diabetes patients.

Biocompatibility of graphene oxide nanosheets functionalized with various amino acids towards mesenchymal stem cells.

Graphene and its derivatives have gained popularity due to their numerous applications in various fields, such as biomedicine. Recent reports have revealed the severe toxic effects of these nanomaterials on cells and organs. In general, the chemical composition and surface chemistry of nanomaterials affect their biocompatibility. Therefore, the purpose of the present study was to evaluate the cytotoxicity and genotoxicity of graphene oxide (GO) synthesized by Hummer's method and functionalized by different amino acids such as lysine, methionine, aspartate, and tyrosine. The obtained nanosheets were identified by FT-IR, EDX, RAMAN, FE-SEM, and DLS techniques. In addition, trypan blue and Alamar blue methods were used to assess the cytotoxicity of mesenchymal stem cells extracted from human embryonic umbilical cord Wharton jelly (WJ-MSCs). The annexin V staining procedure was used to determine apoptotic and necrotic death. In addition, COMET and karyotyping techniques were used to assess the extent of DNA and chromosome damage. The results of the cytotoxicity assay showed that amino acid modifications significantly reduced the concentration-dependent cytotoxicity of GO to varying degrees. The GO modified with aspartic acid had the lowest cytotoxicity. There was no evidence of chromosomal damage in the karyotyping method, but in the comet assay, the samples modified with tyrosine and lysine showed the greatest DNA damage and rate of apoptosis. Overall, the aspartic acid-modified GO caused the least cellular and genetic damage to WJ-MSCs, implying its superior biomedical applications such as cell therapy and tissue engineering over GO.

Dendritic hybrid materials comprising polyhedral oligomeric silsesquioxane (POSS) and hyperbranched polyglycerol for effective antifungal drug delivery and therapy in systemic candidiasis.

Systemic Candida infections are routinely treated with amphotericin B (AMB), a highly effective antimycotic drug. However, due to severe toxicities linked to the parenteral administration of conventional micellar formulations (Fungizone®), its clinical utility is limited. Hyperbranched polyglycerols (HPGs) are multi-branched three-dimensional hydrophilic macromolecules that can be used to lessen the toxicity of AMB while also increasing its aqueous solubility. In the current research, to improve the safety and therapeutic efficacy of AMB, we developed new polyhedral oligomeric silsesquioxane - hyperbranched polyglycerol dendrimers with cholesterol termini (POSS-HPG@Chol) using azide-alkyne click reaction. Compared with Fungizone®, the as-synthesized POSS-HPG@Chol/AMB had lower minimum inhibitory and fungicidal concentrations against almost all studied Candida spp., as well as much less hemolysis and cytotoxicity. POSS-HPG@Chol/AMB revealed total protection of Balb/C mice from severe Candida infections in an experimental model of systemic candidiasis and can effectively reduce or eliminate AMB liver and kidney tissue injuries. Thanks to their safety, biocompatibility, and unique therapeutic properties, the developed POSS-polyglycerol dendrimers could be viable nanostructures for the delivery of poorly soluble drugs like AMB.

L-asparaginase immobilization in supramolecular nanogels of PEG-grafted poly HPMA and bis(α-cyclodextrin) to enhance pharmacokinetics and lower enzyme antigenicity.

L-asparaginase (ASNase) enzyme has limited therapeutic use due to its poor pharmacokinetics and immunogenicity. To overcome these obstacles, we immobilized ASNase in biocompatible poly hydroxypropyl methacrylamide (P(HPMA))-based nanogels simply formed through the host-guest inclusion complex of ASNase-conjugated random copolymer of HPMA and polyethylene glycol (PEG) acrylate (P(HPMA-MPEGA)) and α-cyclodextrin dimer (bisCD) using cystamine as a linker. The effects of bisCD and polymer concentrations on particle size, gelation time, and recovery of enzyme activity were investigated. The ASNase-conjugated bisCD nanogels were discrete, homogeneous, and spherical with a mean projected diameter of 148 ± 41 nm. ASNase immobilized in the bisCD nanogels caused cytotoxicity on HL-60 cell line with IC50 of 3 IU/ml. In-vivo rat study revealed that the immobilized ASNase reduced the enzyme antigenicity and resulted in 8.1 folds longer circulation half-life than the native enzyme. Conclusively, immobilization of ASNase in P(HPMA-MPEGA) and bisCD supramolecular nanogels could enhance the therapeutic value of ASNase in cancer chemotherapy.

Indirect co-culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells.

Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM-MSCS with angiomiR-126 and -210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow-mesenchymal stem cells (BM-MSCs), followed by 3-day indirect co-culturing with islets laden in collagen (Col)-based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN-containing scaffolds, particularly in the miRNA-126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM-MSCs/miRNA-126 treated group. VEGF was upregulated in the LMN-containing scaffolds in both miRNA-treated groups, specifically in the miRNA-210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN-free scaffolds; while a drastic downregulation was seen in the LMN-containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA-126. LMN-containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.

Nanotechnology-based cell-mediated delivery systems for cancer therapy and diagnosis.

The global prevalence of cancer is increasing, necessitating new additions to traditional treatments and diagnoses to address shortcomings such as ineffectiveness, complications, and high cost. In this context, nano and microparticulate carriers stand out due to their unique properties such as controlled release, higher bioavailability, and lower toxicity. Despite their popularity, they face several challenges including rapid liver uptake, low chemical stability in blood circulation, immunogenicity concerns, and acute adverse effects. Cell-mediated delivery systems are important topics to research because of their biocompatibility, biodegradability, prolonged delivery, high loading capacity, and targeted drug delivery capabilities. To date, a variety of cells including blood, immune, cancer, and stem cells, sperm, and bacteria have been combined with nanoparticles to develop efficient targeted cancer delivery or diagnosis systems. The review paper aimed to provide an overview of the potential applications of cell-based delivery systems in cancer therapy and diagnosis.

PEGylated nanohydrogels delivering anti-MicroRNA-21 suppress ovarian tumor-associated angiogenesis in matrigel and chicken chorioallantoic membrane models.

Introduction: Recently, MicroRNAs have gained increasing popularity as a novel nucleic acid-mediated medicine to regulate cancer-related protein expression. MicroRNA-21 (miR-21) is known as an oncogenic microRNA which is overexpressed in almost all cancers, including ovarian carcinoma that causes cisplatin (cis-Pt) resistance and vascular endothelial growth factor (VEGF) upregulation. So, miRNA-based therapy can be regarded as knocking down miR-21 expression, inducing tumor cell apoptosis, and suppressing tumor-associated angiogenesis. Methods: PEG5k-carboxymethylated polyethyleneimine nanohydrogels (PEG5k-CMPEI) were loaded with AntagomiR-21 (As-21) at different ratios of nitrogen to phosphorus (N/P). Particle size and ζ potential were determined for the As-21 loaded nanohydrogels. In the cellular experiments, miR-21 expression, cytotoxicity, and cis-Pt sensitivity were studied on A2780 ovarian cancer cell lines. Finally, tumor cell apoptosis and tumor cell-associated angiogenesis were explored in vitro and in vivo. Results: The nanohydrogels, featuring homogeneous size distribution and redox-responsiveness, were steadily loaded by As-21 at the optimum N/P ratio of 5 without any aggregation as determined by transmission electron microscopy (TEM). As-21-loaded nanohydrogels caused sequence-specific suppression of miR-21 expression and provoked apoptosis through ROS generation and caspase 3 activation. Cisplatin cytotoxicity was remarkably enhanced in A2780R as compared to A2780S following co-incubation with As-21-loaded nanohydrogels. Interestingly, the condition of the medium derived from As-21 nanohydrogel-treated A2780R cells inhibited VEGF suppression in human umbilical vein endothelial cells (HUVECs) and the formation of tubes in Matrigel. Moreover, the condition medium caused angiogenesis inhibition in the chicken chorioallantoic membrane (CAM) model. Conclusion: These results suggest that nanohydrogel-based delivery of As-21 can be a promising neoadjuvant therapy for treating resistant tumors via apoptosis induction and angiogenesis suppression.

A computational study of metal-organic frameworks (MOFs) as potential nanostructures to combat SARS-CoV-2.

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 (Mpro) 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 Mpro was investigated. HKUST had the most potent interaction with Mpro and showed more promise in deforming this protein's secondary structure among all materials tested. Furthermore, we investigated the interaction of HKUST-OH with Mpro 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.

PLGA-graphene quantum dot nanocomposites targeted against αvß3 integrin receptor for sorafenib delivery in angiogenesis.

Angiogenesis is a vital step in many severe diseases such as cancer, diabetic retinopathy, and rheumatoid arthritis. Sorafenib (SFB), a multi-tyrosine kinase inhibitor, has recently been shown to inhibit tumor progression and suppress angiogenesis. Its narrow therapeutic window, however, has limited its clinical application and therapeutic efficacy. Accordingly, in this study, a nanocomposite formulation comprising of graphene quantum dots (GQDs) and poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles was functionalized with an integrin-targeting ligand (RGD peptide) to improve SFB delivery for the treatment of angiogenesis. Physicochemical and biological properties of the targeted nanocomposite were evaluated in terms of chemical structure, morphology, particle size, zeta potential, photoluminescence, and cell toxicity. The loading capacity of the nanocomposite was optimized at different drug-to-PLGA ratios. Drug release behavior was also investigated at 37 °C in pH = 7.4. The SFB-to-PLGA ratio of 1:3 was selected as the optimum condition which resulted in the encapsulation efficiency and encapsulation capacity of 68.93 ± 1.39 and 18.77 ± 0.46, respectively. Photoluminescence properties of GQD in nanocomposite were used to track the delivery system. The results indicated that conjugating targeting ligand could enhance cellular uptake of nanocomposite in cells overexpressing integrin receptors. In vivo anti-angiogenesis activity of targeted nanocomposite was investigated in chick chorioallantoic membrane (CAM). The findings showed that SFB loaded in the targeted nanocomposite reduced VEGF secretion in vitro and its anti-angiogenic effect surpass free SFB. Thanks to its unique therapeutic and bioimaging properties, the developed nanocomposite could be an effective drug delivery system for poorly water-soluble therapeutic agents.

Amphiphilic hyperbranched polyglycerol nanoarchitectures for Amphotericin B delivery in Candida infections.

Although Amphotericin B (AMB) is considered the most effective anti-mycotic agent for treating Candida infections, its clinical use is limited due to its high toxicity. To address this issue, we developed cholesterol-based dendritic micelles of hyperbranched polyglycerol (HPG), including cholesterol-cored HPG (Chol-HPG) and cholesterol end-capped HPG (HPG@Chol), for AMB delivery. The findings suggested that the presence of cholesterol moieties could control AMB loading and release properties. Dendritic micelles inhibited AMB hemolysis and cytotoxicity in HEK 293 and RAW 264.7 cell lines while increasing antifungal activity against C. albicans biofilm formation. Furthermore, significantly lower levels of renal and liver toxicity biomarkers compared to Fungizone® ensured AMB-incorporated dendritic micelle biosafety, which was confirmed by histopathological evaluations. Overall, the Chol-HPG and HPG@Chol dendritic micelles may be a viable alternative to commercially available AMB formulations as well as an effective delivery system for other poorly soluble antifungal agents.

Integrin receptor-binding nanofibrous peptide hydrogel for combined mesenchymal stem cell therapy and nitric oxide delivery in renal ischemia/reperfusion injury.

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 ß-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.

Biotin receptor-targeting nanogels loaded with methotrexate for enhanced antitumor efficacy in triple-negative breast cancer in vitro and in vivo models.

High-dose methotrexate (MTX) chemotherapeutic applications confront drug specificity and pharmacokinetic challenges, which can be overcome by utilizing targeted drug delivery systems. In the present study, biotin-PEG conjugated nanogels of carboxymethyl polyethyleneimine (Biotin-PEG-CMPEI) were developed for active targeted delivery of MTX in triple negative breast cancer (TNBC). TEM and DLS analyses revealed uniform, discrete, and spherical particles with a mean hydrodynamic diameter of about 100 nm and ζ-potential of + 15 mV (pH = 7.4). Biotin-PEG-CMPEI nanogels exhibited a zero-order MTX release kinetics at pH = 7.5 and a swelling-controlled release at pH = 5.5. In 4 T1 cells treated with the MTX-loaded Biotin-PEG-CMPEI, the IC50 was reduced by about 10 folds compared to the free drug, while the unloaded nanogels showed no significant toxicity. In the model mice, the group treated with the MTX-loaded Biotin-PEG-CMPEI had a lower tumor volume and mortality rate animal model when compared to free drug. Additionally, histopathological analyses showed that the group treated with the MTX-loaded nanogels had less lung metastasis and glomerular damage caused by MTX. Overall, the MTX-loaded Biotin-PEG-CMPEI targeted directly against overexpressed biotin receptors in TNBC have been shown to improve the MTX safety and therapeutic efficacy.

Bioengineering exosomes for treatment of organ ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a leading cause of death worldwide. It arises from blood reflowing after tissue hypoxia induced by ischemia that causes severe damages due to the accumulation of reactive oxygen species and the activation of inflammatory responses. Exosomes are the smallest members of the extracellular vesicles' family, which originate from nearly all eukaryotic cells. Exosomes have a great potential in the treatment of I/R injury either in native or modified forms. Native exosomes are secreted by different cell types, such as stem cells, and contain components such as specific miRNA molecules with tissue protective properties. On the other hand, exosome bioengineering has recently received increased attention in context of current advances in the purification, manipulation, biological characterization, and pharmacological applications. There are various pre-isolation and post-isolation manipulation approaches that can be utilized to increase the circulation half-life of exosomes or the availability of their bioactive cargos in the target site. In this review, the various therapeutic actions of native exosomes in different I/R injury will be discussed first. Exosome bioengineering approaches will then be explained, including pre- and post-isolation manipulation methods, applicability for delivery of bioactive agents to injured tissue, clinical translation issues, and future perspectives.

Nanoscale aggregation of doxorubicin-short peptide conjugates for enzyme-responsive delivery with various MOF carriers: In-silico steps towards smart cancer chemotherapy.

Drug conjugation with enzyme-sensitive peptides is one of the innovative smart delivery systems for cancer therapy. This delivery method has some advantages, such as lowering side effects and increasing treatment selectivity. Herein, two conjugates of doxorubicin and small peptide are designed that are sensitive to Cathepsin B, a tumor homing enzyme. The formation of nanoparticles at three different numbers of drug peptide prodrugs (including 30, 50, and 70 prodrugs) was studied. In addition, three metal-organic frameworks (MOF) nanocarriers, including Zeolitic Imidazolate Frameworks (ZIF), Universitetet I Oslo MOF (UIO-66), and MOF of Hong Kong University of Science and Technology (HKUST-1), were used to increase the resistance of the prodrugs to decomposition during blood flow circulation. Then, the interactions between doxorubicin's prodrug and different MOFs were investigated. Furthermore, the impact of microfluidics on nanoparticle interactions was studied. Molecular dynamic simulation was used to investigate thermodynamic and conformational parameters. The results showed that the concentration of doxorubicin prodrugs affected cluster formation. Moreover, based on Gibb's free energy analysis, the interaction of these prodrugs with various types of MOFs revealed more spontaneous interactions in microfluidic modeling conditions. ZIF had the best and most stable interactions with the prodrugs in bulk and microfluidic modeling. As a result, the best and most stable state was associated with a lower concentration of these prodrugs with ZIF in the microfluidic condition.

Novel bioengineered MBenes for the treatment of Alzheimer's disease: An in-Sillico study.

Alzheimer's disease is a neurodegenerative disease caused by the deposition and accumulation of amyloid-ß (Aß) peptides in the brain neurons. Current medications are not a definitive cure for this disease, but they can hamper the signs and symptoms of Alzheimer's disease. Therefore, prevention is the best way to deal with this disease. In this study, the novel structures based on MBenes (such as Cd2B, Mo2B, Cu2B, and Ta2B) are proposed to prevent amyloid-ß accumulation in Alzheimer's disease. Regarding the remarkable MBene properties such as tunability, biocompatibility, and low manufacturing cost, the effect of these structures on amyloid-ß deformation was explored using molecular dynamics simulation. To provide an atomic analysis of Beta-amyloid behavior in the presence of these structures, the compaction, contact area, and stability of Beta-amyloid were investigated. The results indicated the satisfactory performance of MBenes on the destabilization of amyloid-ß structures. Moreover, given the higher interactions between Cd2B and amyloid-ß, the instability, compaction, and the contact area of amyloid-ß particles were investigated in this complex. The findings confirmed Cd2B as the best structure to prevent amyloid-ß accumulation. The results of this investigation paved the way for the development of these structures as a medicinal agent to prevent Alzheimer's disease.