Targeting long non-coding RNAs as new modulators in anti-EGFR resistance mechanisms.

Epidermal growth factor receptor (EGFR) is a cell surface protein that plays a vital role in regulating cell growth and division. However, certain tumors, such as colorectal cancer (CRC), can exhibit an overexpression of EGFR, resulting in uncontrolled cell growth and tumor progression. To address this issue, therapies targeting and inhibiting EGFR activity have been developed to suppress cancer growth. Nevertheless, resistance to these therapies poses a significant obstacle in cancer treatment. Recent research has focused on comprehending the underlying mechanisms contributing to anti-EGFR resistance and identifying new targets to overcome this striking challenge. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. Emerging evidence suggests that lncRNAs may participate in modulating resistance to anti-EGFR therapies in CRC. Consequently, combining lncRNA targeting with the existing treatment modalities could potentially yield improved clinical outcomes. Illuminating the involvement of lncRNAs in anti-EGFR resistance mechanisms of cancer cells can provide valuable insights into the development of novel anti-EGFR therapies in several solid tumors.

Vitamin D Status in Palindromic Rheumatism: A Propensity Score Matching Analysis.

OBJECTIVE: To determine whether there is a correlation between vitamin D levels and palindromic rheumatism (PR) as an at-risk phenotype of rheumatoid arthritis (RA). METHODS: A total of 308 participants were enrolled in this cross-sectional study. We recorded their clinical characteristics and performed propensity-score matching (PSM). Serum 25(OH)D3 levels were determined via enzyme-linked immunosorbent assay. RESULTS: Our PSM resulted in 48 patients with PR and 96 matched control individuals. The multivariate regression analysis we performed after the PSM did not show a significant increase in PR risk in patients with vitamin D deficiency/insufficiency. There was no significant correlation between levels of 25(OH)D3 and frequency/duration of attacks, number of joints affected, and duration of symptoms before diagnosis (P ≥ .05). Mean (SD) serum levels of 25(OH)D3 in patients with and without progression to RA were 28.7 (15.9) ng/mL and 25.1 (11.4) ng/mL, respectively. CONCLUSION: Based on the results, we found no clear association between vitamin D serum levels and the risk, severity, and rate of PR progressing into RA.

The Synthetic Antimicrobial Peptide Derived From Melittin Displays Low Toxicity and Anti-infectious Properties.

The low stability and nonspecific toxicity are the main limiting factors for the clinical applications of melittin (MLT). This study aimed to design and synthesize new analogs of MLT to increase stability, reduce toxicity, and retain their antimicrobial properties against bacterial pathogens. At first, peptide analogs were designed computationally by inducing single mutations in MLT peptides and evaluating their physicochemical properties. The stability of the analogs with the highest scores was determined by Gromacs software. In vitro assays were performed to examine the antimicrobial activity and toxicity of the selected analogs. Two peptide analogs, M1 and M2, were selected based on the SVM score in cell PPD. The M1 analog was created by replacing alanine with leucine on the 15th. The M2 analog was designed by substituting alanine with leucine and isoleucine with arginine at the 15th and 17th positions. According to the Gromacs results, the M2 peptide indicated more stability. RMSD and RMSF results showed no undesirable fluctuations during the 200 ns MD simulation. The MIC and MBC values for the M1 peptide were calculated in a range of 8-128 µg/ml, while the M2 peptide limited the bacterial growth to 32-128 µg/mL. Both peptides indicated less toxicity than natural MLT, based on MTT assay results. The hemolytic activity of the M1 analog was more than M2 at 16 µg/mL concentration. M1 peptide displayed the highest selectivity index against S. aureus and A. baumannii, which were approximately 5.27-fold improvements compared to MLT. In conclusion, we introduced two analogs of MLT with low toxicity, low hemolytic activity, and higher stability, along with retaining antimicrobial properties against gram-negative and positive bacteria.

In situ forming alginate/gelatin hydrogel scaffold through Schiff base reaction embedded with curcumin-loaded chitosan microspheres for bone tissue regeneration.

In this study, we developed a biocompatible composite hydrogel that incorporates microspheres. This was achieved using a Schiff base reaction, which combines the amino and aldehyde groups present in gelatin (Gel) and oxidized alginate (OAlg). We suggest this hydrogel as a promising scaffold for bone tissue regeneration. To further boost its osteogenic capabilities and mechanical resilience, we synthesized curcumin (Cur)-loaded chitosan microspheres (CMs) and integrated them into the Gel-OAlg matrix. This formed a robust composite gel framework. We conducted comprehensive evaluations of various properties, including gelation time, morphology, compressive strength, rheological behavior, texture, swelling rate, in vitro degradation, and release patterns. A remarkable observation was that the inclusion of 30 mg/mL Cur-CMs significantly enhanced the hydrogel's mechanical and bioactive features. Over three weeks, the Gel-OAlg/Cur-CMs (30) composite showed a cumulative curcumin release of 35.57%. This was notably lower than that observed in standalone CMs and Gel-OAlg hydrogels. Additionally, the Gel-OAlg/Cur-CMs (30) hydrogel presented a reduced swelling rate and weight loss relative to hydrogels devoid of Cur-CMs. On the cellular front, the Gel-OAlg/Cur-CMs (30) hydrogel showcased superior biocompatibility. It also displayed increased calcium deposition, alkaline phosphatase (ALP) activity, and elevated osteogenic gene expression in human bone marrow mesenchymal stem cells (hBMSCs). These results solidify its potential as a scaffold for bone tissue regeneration.

SARS-CoV-2 vaccine-triggered autoimmunity: Molecular mimicry and/or bystander activation of the immune system.

Induced autoimmunity or autoinflammatory-like conditions as a rare vaccine-related adverse event have been reported following COVID-19 vaccination. Such inadvertent adverse reactions have raised somewhat concerns about the long-term safety of the developed vaccines. Such multifactorial phenomena may be related to the cross-reactivity between the viral-specific antigens with the host self-proteins through molecular mimicry mechanism and/or nonspecific bystander activation of the non-target antigen-independent immunity by the entities of the vaccine products. However, due to the low incidence of the reported/identified individuals and insufficient evidence, autoimmunity following the COVID-19 vaccination has not been approved. Thereby, it seems that further designated studies might warrant post-monitoring of the inevitable adverse immunologic reactions in the vaccinated individuals, especially among hypersensitive cases, to address possible immunological mechanisms induced by the viral vaccines, incorporated adjuvants, and even vaccine delivery systems.

Development of biomimetic triazine-based affinity ligands for efficient immunoglobulin G purification from human and rabbit plasma.

Immunoglobulin purification from different biological fluids is considered one of the most critical steps in antibody production for diagnostic, therapeutic, and research purposes. The current study aimed to elucidate the role of the different aryl substituents in triazine-based affinity ligands on the performance of an affinity chromatography purification media to separate immunoglobulin G (IgG). The biomimetic triazine-based affinity ligand was chosen as a varied containing fix spacer and support. The sepharose beads were activated by epichlorohydrin, and five types of aryl substituents were replaced in the triazine ring and covalently immobilized to the resin surface by 1, 4-diaminobutane spacer. All affinity resins with various ligands were characterized and validated using FTIR, SEM, EDX, and microscopic images. The findings revealed that using R1=3-aminophenol and R2=3-aminophenol substituents in the triazine ring, as affinity ligands attached to the sepharose surface with a 10-atom linker CAES-6B-Cl@R1= MAF, R2= MAF (No. 4), leads to better purification of IgG from human and rabbit plasma with 22.8 mg/mL resin binding capacity in 73±5% yield and 95% of purity. All results confirmed that the designed triazine-based affinity ligands could effectively purify IgG compatible with a fast and low-cost approach.

Autoimmune inflammatory rheumatic diseases post-COVID-19 vaccination.

Vaccination against COVID-19 is one of the critical tools to provide herd immunity, reduce mortality, and control the pandemic worldwide. Despite the safety of vaccination against SARS-CoV-2 in the healthy population, a minority of people may develop rare post-vaccine adverse reactions such as autoimmune syndromes. The current study aimed to identify and present a series of patients with de-novo autoimmune rheumatic diseases (ARDs) associated with COVID-19 vaccines. Inclusion criteria were the onset of ARDs symptoms at ∼3-4 weeks post-vaccination, age ≥ 16, no previous history of ARDs, meeting the classification criteria for one of the ARDs, and staying in the follow-up. The most commonly used vaccines in patients were Sinopharm [7 cases (50%)] and AstraZeneca [6 cases (42.9%)]. ARDs were significantly more common in subjects who received the AstraZeneca vaccine than in those who received other vaccines. Based on the results, patients were diagnosed with rheumatoid arthritis or one of its subtypes (5 cases), vasculitis (4 cases), systemic lupus erythematosus (3 cases), and peripheral seronegative spondyloarthritis (2 cases). Except for one patient with self-limitation of ARD, others were treated with disease-modifying antirheumatic drugs, and one case developed irreversible neurological complications. Indeed, our data can warn physicians about the possibility of ARDs post-vaccination, lead to faster diagnosis, prevent loss of window of opportunity for treatment, and prevent irreversible organ damage. Based on the published literature, autoimmune phenomena post-COVID-19 vaccination may be related to the overstimulation of mediators and cytokines due to complicated antigen-specific/non-specific immunological responses and mechanisms.

Recombinant production and characterization of L-glutaminase (glsA) as a promiscuity therapeutic enzyme.

Because of the therapeutical impacts of hydrolytic enzymes in different diseases, in particular malignancies, we aimed to produce a recombinant putative L-glutaminase (GLS ASL-1) from a recently characterized halo-thermotolerant Bacillus sp. SL-1. For this purpose, the glsA gene was identified and efficiently overexpressed in the Origami™ B (DE3) strain. The yield of the purified GLS ASL-1 was ~ 20 mg/L, indicating a significant expression of recombinant enzyme in the Origami. The enzyme activity assay revealed a significant hydrolytic effect of the recombinant GLS ASL-1 on L-asparagine (Asn) (i.e., Km 39.8 µM, kcat 19.9 S-1) with a minimal affinity for L-glutamine (Gln). The GLS ASL-1 significantly suppressed the growth of leukemic Jurkat cells through apoptosis induction (47.5%) in the IC50 dosage of the enzyme. The GLS ASL-1 could also change the Bax/Bcl2 expression ratio, indicating its apoptotic effect on cancer cells. The in silico analysis was conducted to predict structural features related to the histidine-tag exposure in the N- or C-terminal of the recombinant GLS ASL-1. In addition, molecular docking simulation for substrate specificity revealed a greater binding affinity of Asn to the enzyme binding-site residues than Gln, which was confirmed in experimental procedures as well. In conclusion, the current study introduced a recombinant GLS ASL-1 with unique functional and structural features, highlighting its potential pharmaceutical and medical importance. GLS ASL-1 represents the first annotated enzyme from Bacillus with prominent asparaginase activity, which can be considered for developing alternative enzymes in therapeutic applications. KEY POINTS: • Hydrolytic enzymes have critical applications in different types of human malignancies. • A recombinant L-glutaminase (GLS ASL-1) was produced from halo-thermotolerant Bacillus sp. SL-1. • GLS ASL-1 displayed a marked hydrolytic activity on L-asparagine compared to the L-glutamine. • GLS ASL-1 with significant substrate promiscuity may be an alternative for developing novel pharmaceuticals.

Bio-nano scale modifications of melittin for improving therapeutic efficacy.

INTRODUCTION: Melittin (MLT), a natural membrane-active component, is the most prominent cytolytic peptide from bee venom. Remarkable biological properties of MLT, including anti-inflammatory, antimicrobial, anticancer, anti-protozoan, and antiarthritic activities, make it an up-and-coming therapeutic candidate for a wide variety of human diseases. Therapeutic applications of MLT may be hindered due to low stability, high toxicity, and weak tissue penetration. Different bio-nano scale modifications hold promise for improving its functionality and therapeutic efficacy. AREAS COVERED: In the current review, we aimed to provide a comprehensive insight into strategies used for MLT conjugations and modifications, cellular delivery of modified forms, and their clinical perspectives by reviewing the published literature on PubMed, Scopus, and Google Scholar databases. We also emphasized the MLT structure modifications, mechanism of action, and cellular toxicity. EXPERT OPINION: Developing new analogs and conjugates of MLT as a natural drug with improved functions and fewer side effects is crucial for the clinical translation of this approach worldwide, especially where the chemicals and synthetic drugs are more expensive or unavailable in the healthcare system. MLT-nanoconjugation may be one of the best-optimized strategies for improving peptide delivery, increasing its therapeutic efficacy, and providing minimal nonspecific cellular lytic activity. [Figure: see text].

Baricitinib combination therapy: a narrative review of repurposed Janus kinase inhibitor against severe SARS-CoV-2 infection.

PURPOSE: The Coronavirus disease 2019 (COVID-19) pandemic is one of the most devastating global problems. Regarding the lack of disease-specific treatments, repurposing drug therapy is currently considered a promising therapeutic approach in pandemic situations. Recently, the combination therapy of Janus kinase (JAK) inhibitor baricitinib has been authorized for emergency COVID-19 hospitalized patients; however, this strategy's safety, drug-drug interactions, and cellular signaling pathways remain a tremendous challenge. METHODS: In this study, we aimed to provide a deep insight into the baricitinib combination therapies in severe COVID-19 patients through reviewing the published literature on PubMed, Scopus, and Google scholar databases. We also focused on cellular and subcellular pathways related to the synergistic effects of baricitinib plus antiviral agents, virus entry, and cytokine storm (CS) induction. The safety and effectiveness of this strategy have also been discussed in moderate to severe forms of COVID-19 infection. RESULTS: The severity of COVID-19 is commonly associated with a dysregulated immune response and excessive release of pro-inflammatory agents, resulting in CS. It has been shown that baricitinib combined with antiviral agents could modulate the inflammatory response and provide a series of positive therapeutic outcomes in hospitalized adults and pediatric patients (age ≥ two years old). CONCLUSION: Baricitinib plus the standard of care treatment might be a potential strategy in hospitalized patients with severe COVID-19.

Micronutrient therapy and effective immune response: a promising approach for management of COVID-19.

The escalating prevalence of coronavirus disease 2019 (COVID-19) worldwide, with an increased rate of morbidity and mortality, highlights an urgent need to develop more effective therapeutic interventions. Despite the authorized treatment against COVID-19 by the European Union (EU), the safety and effectiveness of this therapeutic strategy for a wide variety of patients have remained a significant challenge. In this respect, micronutrients such as vitamins and minerals, as essential factors, can be considered for improving the function of the immune system and accelerating the treatment procedure. Dietary supplements can attenuate vascular and inflammatory manifestations related to infectious diseases in large part due to their anti-inflammatory and antioxidant properties. Recently, it has been revealed that poor nutritional status may be one of the notable risk factors in severe COVID-19 infections. In the current review, we focus on the micronutrient therapy of COVID-19 patients and provide a comprehensive insight into the essential vitamins/minerals and their role in controlling the severity of the COVID-19 infection. We also discuss the recent advancements, challenges, negative and positive outcomes in relevance to this approach.

Enzyme replacement combinational therapy: effective treatments for mucopolysaccharidoses.

INTRODUCTION: Mucopolysaccharidoses (MPS), as a group of inherited lysosomal storage disorders (LSDs), are clinically heterogeneous and characterized by multi-systemic manifestations, such as skeletal abnormalities and neurological dysfunctions. The currently used enzyme replacement therapy (ERT) might be associated with several limitations including the low biodistribution of the enzymes into the main targets, immunological responses against foreign enzymes, and the high cost of the treatment procedure. Therefore, a suitable combination approach can be considered for the successful treatment of each type of MPS. AREAS COVERED: In this review, we provide comprehensive insights into the ERT-based combination therapies of MPS by reviewing the published literature on PubMed and Scopus. We also discuss the recent advancements in the treatment of MPS and bring up the hopes and hurdles in the futuristic treatment strategies. EXPERT OPINION: Given the complex pathophysiology of MPS and its involvement in different tissues, the ERT of MPS in combination with stem cell therapy or gene therapy is deemed to provide a personalized precision treatment modality with the highest therapeutic responses and minimal side effects. By the same token, new combinational approaches need to be evaluated by using drugs that target alternative and secondary pathological pathways.

Mutational Analysis of Ocriplasmin to Reduce Proteolytic and Autolytic Activity in Pichia pastoris.

BACKGROUND: Ocriplasmin (Jetrea) is using for the treatment of symptomatic vitreomacular adhesion. This enzyme undergoes rapid inactivation and limited activity duration as a result of its autolytic nature after injection within the eye. Moreover, the proteolytic activity can cause photoreceptor damage, which may result in visual impairment in more serious cases. RESULTS: The present research aimed to reduce the disadvantages of ocriplasmin using site-directed mutagenesis. To reduce the autolytic activity of ocriplasmin in the first variant, lysine 156 changed to glutamic acid and, in the second variant for the proteolytic activity reduction, alanine 59 mutated to threonine. The third variant contained both mutations. Expression of wild type and three mutant variants of ocriplasmin constructs were done in the Pichia pastoris expression system. The mutant variants were analyzed in silico and in vitro and compared to the wild type. The kinetic parameters of ocriplasmin variants showed both variants with K156E substitution were more resistant to autolytic degradation than wild-type. These variants also exhibited reduced Kcat and Vmax values. An increase in their Km values, leading to a decreased catalytic efficiency (the Kcat/Km ratio) of autolytic and mixed variants. Moreover, in the variant with A59T mutation, Kcat and Vmax values have reduced compared to wild type. The mix variants showed the most increase in Km value (almost 2-fold) as well as reduced enzymatic affinity to the substrate. Thus, the results indicated that combined mutations at the ocriplasmin sequence were more effective compared with single mutations. CONCLUSIONS: The results indicated such variants represent valuable tools for the investigation of therapeutic strategies aiming at the non-surgical resolution of vitreomacular adhesion.

Therapeutic impacts of enzyme-responsive smart nanobiosystems.

An important arena of the sophisticated nanosystems (NSs) is the combination of the responsive features of NSs with the biocatalytic properties of enzymes. The development of such smart drug delivery systems (DDSs) has seminal effectiveness in targeting, imaging, and monitoring of cancer. These NSs can exhibit site-specific delivery of the toxic cargo in response to the endogenous/exogenous stimuli. Enzyme responsive/targeted DDSs display enhanced accumulation of cargo molecules in the tumor microenvironment (TME) with a spatiotemporal controlled-release behavior. Based on the unique features of enzyme responsive/targeted DDSs, they offer incredible promise in overcoming some limitations of the currently used conventional DDSs. Taken all, targeting TME with the enzyme-responsive targeted DDSs may lead to versatile clinical outcomes in various malignancies.

PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells.

Introduction: Currently, drug-induced reactive oxygen species (ROS) mediating apoptosis pathway have extensively been investigated in designing effective strategies for colorectal cancer (CRC) chemotherapy. Bovine pancreatic ribonuclease A (RNase A) represents a new class of cytotoxic and non-mutagenic enzymes, and has gained more attention as a potential anticancer modality; however, the cytosolic ribonuclease inhibitors (RIs) restrict the clinical application of this enzyme. Nowadays, nanotechnology-based diagnostic and therapeutic systems have provided potential solutions for cancer treatments. Methods: In this study, the gold nanoparticles (AuNPs) were synthesized, stabilized by polyethylene glycol (PEG), functionalized, and covalently conjugated with RNase A. The physicochemical properties of engineered nanobiomedicine (AuNPs-PEG-RNase A) were characterized by scanning electron microscope (SEM), dynamic light scattering (DLS), and UV-vis spectrum. Then, its biological impacts including cell viability, apoptosis, and ROS production were evaluated in the SW-480 cells. Results: The engineered nanobiomedicine, AuNPs-PEG-RNase A, was found to effectively induce apoptosis in SW-480 cells and result in a significant reduction in cancer cell viability. Besides, the maximum production of ROS was obtained after the treatment of cells with an IC50 dose of AuNPs-PEG-RNase A. Conclusion: Based on the efficient ROS-responsiveness and the anticancer activity of RNase A of the engineered nanomedicine, this nanoscaled biologics may be considered as a potential candidate for the treatment of CRC.

Multifunctional nanomedicines for targeting epidermal growth factor receptor in colorectal cancer.

Systemic administration of chemotherapeutics by nanocarriers (NCs) functionalized with targeting agents provides a localized accumulation of drugs in the target tissues and cells. Advanced nanoscaled medicaments can enter into the tumor microenvironment (TME) and overcome the uniquely dysregulated biological settings of TME, including highly pressurized tumor interstitial fluid in an acidic milieu. Such multimodal nanomedicines seem to be one of the most effective treatment modalities against solid tumors such as colorectal cancer (CRC). To progress and invade, cancer cells overexpress various oncogenes and molecular markers such as epidermal growth factor receptors (EGFRs), which can be exploited for targeted delivery of nanoscaled drug delivery systems (DDSs). In fact, to develop effective personalized multimodal nanomedicines, the type of solid tumor and status of the disease in each patient should be taken into consideration. While the development of such multimodal-targeted nanomedicines is largely dependent on the expression level of oncomarkers, the type of NCs and homing/imaging agents play key roles in terms of their efficient applications. In this review, we provide deep insights into the development of EGFR-targeting nanomedicines and discuss various types of nanoscale DDSs (e.g., organic and inorganic nanoparticles) for targeting of the EGFR-positive solid tumors such as CRC.

Karyotypic abnormalities and molecular analysis of Y chromosome microdeletion in Iranian Azeri Turkish population infertile men.

Infertility is one of the major health-threatening problems in communities which may lead to psychological problems among couples. Y chromosome abnormalities and microdeletions have recently been considered as one of the male infertility factors. The aim of this study was to evaluate different chromosomal disorders and azoospermia factor b (AZFb), AZFc and AZFd microdeletions in idiopathic non-obstructive oligo or azoospermia infertile men. One hundred infertile (78 azoospermia and 22 oligospermia) and 100 fertile men were included in this study. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were evaluated by electrochemiluminescence. Karyotyping was performed according to standard methods and interpreted using the International System for Human Cytogenetic Nomenclature (ISHCN) recommendation. For Y chromosome microdeletion analysis, a multiplex polymerase chain reaction (PCR) was performed using STS primers. Higher FSH (24.32 ± 15.32 versus 8.02 ± 3.37, p < 0.0001) and LH (14.97 ± 8.26 versus 5.42 ± 2.73, p < 0.0001) were observed in infertile patients compared to their fertile counterpart. Additionally, 14% of infertile patients exhibited abnormal karyotype. The  frequency of Y chromosome microdeletions in azoospermic and oligospermic patients was 32.05% (25/78) and 0% (0/22), respectively. Additionally, in azoospermic patients, the highest microdeletion frequency was related to the AZFc region (80%). Our data indicate the presence of chromosomal changes in the most infertile men, suggesting karyotype and molecular analysis of Y chromosome microdeletions for genetic counseling before assisted reproduction.Abbreviations: ART: assisted reproductive technology; AZF: azoospermia factor; DAZ: deleted in azoospermia; FCS: fetal calf serum; FSH: follicle stimulating hormone; LH: luteinizing hormone; PCR: polymerase chain reaction; SRY: sex-determining region Y; STS: sequence-tagged sites.

Recent advances in targeted therapy of colorectal cancer: impacts of monoclonal antibodies nanoconjugates.

Despite rapid advances in diagnostic and treatment approaches, the overall survival rate of cancer has not been improved. Colorectal cancer (CRC) is recognized as the third leading cause of neoplasm-related deaths worldwide, in large part due to its considerable metastasis and drug resistance. For developing new anticancer strategies, rapid progression of multimodal nanomedicines and nanoconjugates has provided promising treatment modalities for effective therapy of cancer. The limitations of cancer chemotherapy might be overcome through the use of such nanosized therapeutics, including nanoconjugates of monoclonal antibodies (mAbs) along with drugs and organic/inorganic nanoparticles. CRC cells express various molecular markers against which mAbs can be designed and used as targeting/therapeutic agents. This editorial highlights the importance of such targeted nanosystems against CRC.

Targeted enzyme delivery systems in lysosomal disorders: an innovative form of therapy for mucopolysaccharidosis.

Mucopolysaccharidoses (MPSs), which are inherited lysosomal storage disorders caused by the accumulation of undegraded glycosaminoglycans, can affect the central nervous system (CNS) and elicit cognitive and behavioral issues. Currently used enzyme replacement therapy methodologies often fail to adequately treat the manifestations of the disease in the CNS and other organs such as bone, cartilage, cornea, and heart. Targeted enzyme delivery systems (EDSs) can efficiently cross biological barriers such as blood-brain barrier and provide maximal therapeutic effects with minimal side effects, and hence, offer great clinical benefits over the currently used conventional enzyme replacement therapies. In this review, we provide comprehensive insights into MPSs and explore the clinical impacts of multimodal targeted EDSs.