M2 Macrophage Membrane-Mediated Biomimetic-Nanoparticle Carrying COX-siRNA Targeted Delivery for Prevention of Tendon Adhesions by Inhibiting Inflammation.

Tendon adhesion is the most common outcome of tendon or tendon-to-bone healing after injury. Our group developed a hydrogel-nanoparticle sustained-release system previously to inhibit cyclooxygenases (COXs) expression and consequently prevent tendon adhesion and achieved satisfactory results. However, effective treatment of multiple tendon adhesions is always a challenge in research on the prevention of tendon adhesion. In the present study, an M2M@PLGA/COX-siRNA delivery system is successfully constructed using the cell membranes of M2 macrophages and poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Targeting properties and therapeutic effects are observed in mice or rat models of flexor digitorum longus (FDL) tendon injury combined with rotator cuff injury. The results showed that the M2M@PLGA/COX-siRNA delivery system has low toxicity and remarkable targeting properties to the injured areas. Treatment with the M2M@PLGA/COX-siRNA delivery system reduced the inflammatory reaction and significantly improved tendon adhesion in both the FDL tendon and rotator cuff tissues. These findings indicate that the M2M@PLGA delivery system can provide an effective biological strategy for preventing multiple tendon adhesions.

Improving the biological activities of astaxanthin using targeted delivery systems.

The antioxidant and anti-inflammatory properties of astaxanthin (AST) enable it to protect against oxidative stress-related and inflammatory diseases with a range of biological effects. These activities provide the potential to develop healthier food products. Therefore, it would be beneficial to design delivery systems for AST to overcome its low stability, control its release, and/or improve its bioavailability. This review discusses the basis for AST's various biological activities and the factors limiting these activities, including stability, solubility, and bioavailability. It also discusses the different systems available for the targeted delivery of AST and their applications in enhancing the biological activity of AST. These include systems that are candidates for preventive and therapeutic effects, which include nerves, liver, and skin, particularly for possible cancer reduction. Targeted delivery of AST to specific regions of the gastrointestinal tract, or more selectively to target tissues and cells, can be achieved using targeted delivery systems to increase the biological activities of AST.

First application of CE-ICP-MS for monitoring the formation of cisplatin targeting delivery systems with gold nanocarriers.

Cisplatin is a drug frequently used in chemotherapy of various types of tumors due to its strong cytostatic activity against cancer cells. However, this therapy is not free from severe side effects related to the nonselective action of the drug. The solution to this problem could be the application of drug-targeted delivery systems (DTDSs). Gold nanoparticles can be used in such systems as selective drug carriers, ensuring its transportation through the bloodstream to destination tissue. The method of DTDSs analysis providing qualitative and quantitative information about the formation of this conjugation is crucial to establish the kinetics of reaction and stoichiometry of reagents, which ensures the best drug binding rate. Moreover, the status of so far proposed techniques/methods dedicated to elaborating the course of DTDSs formation is preliminary and in majority guarantee only the confirmation of drug-carrier conjugate formation. In this paper, we demonstrate the procedures of reagents' preparation and cisplatin-gold nanoparticles DTDS formation, which have a significant influence on the rate and stoichiometry of the reaction. We also present the novel application of CE-ICP-MS hyphenation for effective separation and online monitoring of all components of the reaction mixture.

Selective targeting of cancer signaling pathways with nanomedicines: challenges and progress.

Cancer is one of the leading causes of death worldwide. Regardless of advances in understanding the molecular mechanics of cancer, its treatment is still lacking and the death rates for many forms of the disease remain the same as six decades ago. Although a variety of therapeutic agents and strategies have been reported, these therapies often failed to provide efficient therapy to patients as a consequence of the inability to deliver right and adequate chemotherapeutic agents to the right place. However, the situation has started to revolutionize substantially with the advent of novel 'targeted' nanocarrier-based cancer therapies. Such therapies hold great potential in cancer management as they are biocompatible, tailored to specific needs, tolerated and deliver enough drugs at the targeted site. Their use also enhances the delivery of chemotherapeutics by improving biodistribution, lowering toxicity, inhibiting degradation and increasing cellular uptake. However, in some instances, nonselective targeting is not enough and the inclusion of a ligand moiety is required to achieve tumor targeting and enhanced drug accumulation at the tumor site. This contemporary review outlines the targeting potential of nanocarriers, highlighting the essentiality of nanoparticles, tumor-associated molecular signaling pathways, and various biological and pathophysiological barriers.

Antibody Conjugation of Nanoparticles as Therapeutics for Breast Cancer Treatment.

Breast cancer is the most common invasive tumor in women and the second leading cause of cancer-related death. Nanomedicine raises high expectations for millions of patients as it can provide better, more efficient, and affordable healthcare, and it has the potential to develop novel therapeutics for the treatment of solid tumors. In this regard, targeted therapies can be encapsulated into nanocarriers, and these nanovehicles are guided to the tumors through conjugation with antibodies-the so-called antibody-conjugated nanoparticles (ACNPs). ACNPs can preserve the chemical structure of drugs, deliver them in a controlled manner, and reduce toxicity. As certain breast cancer subtypes and indications have limited therapeutic options, this field provides hope for the future treatment of patients with difficult to treat breast cancers. In this review, we discuss the application of ACNPs for the treatment of this disease. Given the fact that ACNPs have shown clinical activity in this clinical setting, special emphasis on the role of the nanovehicles and their translation to the clinic is placed on the revision.

Targeted Delivery Systems for Molecular Therapy in Skeletal Disorders.

Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation.

Delivery Systems for Mitochondrial Gene Therapy: A Review.

Mitochondria are membrane-bound cellular organelles of high relevance responsible for the chemical energy production used in most of the biochemical reactions of cells. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). Inherited solely from the mother, this genome is quite susceptible to mutations, mainly due to the absence of an effective repair system. Mutations in mtDNA are associated with endocrine, metabolic, neurodegenerative diseases, and even cancer. Currently, therapeutic approaches are based on the administration of a set of drugs to alleviate the symptoms of patients suffering from mitochondrial pathologies. Mitochondrial gene therapy emerges as a promising strategy as it deeply focuses on the cause of mitochondrial disorder. The development of suitable mtDNA-based delivery systems to target and transfect mammalian mitochondria represents an exciting field of research, leading to progress in the challenging task of restoring mitochondria's normal function. This review gathers relevant knowledge on the composition, targeting performance, or release profile of such nanosystems, offering researchers valuable conceptual approaches to follow in their quest for the most suitable vectors to turn mitochondrial gene therapy clinically feasible. Future studies should consider the optimization of mitochondrial genes' encapsulation, targeting ability, and transfection to mitochondria. Expectedly, this effort will bring bright results, contributing to important hallmarks in mitochondrial gene therapy.

Harnessing sortase A transpeptidation for advanced targeted therapeutics and vaccine engineering.

The engineering of potent prophylactic and therapeutic complexes has always required careful protein modification techniques with seamless capabilities. In this light, methods that favor unobstructed multivalent targeting and correct antigen presentations remain essential and very demanding. Sortase A (SrtA) transpeptidation has exhibited these attributes in various settings over the years. However, its applications for engineering avidity-inspired therapeutics and potent vaccines have yet to be significantly noticed, especially in this era where active targeting and multivalent nanomedications are in great demand. This review briefly presents the SrtA enzyme and its associated transpeptidation activity and describes interesting sortase-mediated protein engineering and chemistry approaches for achieving multivalent therapeutic and antigenic responses. The review further highlights advanced applications in targeted delivery systems, multivalent therapeutics, adoptive cellular therapy, and vaccine engineering. These innovations show the potential of sortase-mediated techniques in facilitating the development of simple plug-and-play nanomedicine technologies against recalcitrant diseases and pandemics such as cancer and viral infections.

Tumor-Associated Macrophage Targeting of Nanomedicines in Cancer Therapy.

The tumor microenvironment (TME) is pivotal in tumor growth and metastasis, aligning with the "Seed and Soil" theory. Within the TME, tumor-associated macrophages (TAMs) play a central role, profoundly influencing tumor progression. Strategies targeting TAMs have surfaced as potential therapeutic avenues, encompassing interventions to block TAM recruitment, eliminate TAMs, reprogram M2 TAMs, or bolster their phagocytic capabilities via specific pathways. Nanomaterials including inorganic materials, organic materials for small molecules and large molecules stand at the forefront, presenting significant opportunities for precise targeting and modulation of TAMs to enhance therapeutic efficacy in cancer treatment. This review provides an overview of the progress in designing nanoparticles for interacting with and influencing the TAMs as a significant strategy in cancer therapy. This comprehensive review presents the role of TAMs in the TME and various targeting strategies as a promising frontier in the ever-evolving field of cancer therapy. The current trends and challenges associated with TAM-based therapy in cancer are presented.

Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.

Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.

Methodology for characterization of platinum-based drug's targeted delivery nanosystems.

Conventional anticancer therapies exploiting platinum-based drugs rely principally on the intravascular injection of the therapeutic agent. The anticancer drug is distributed throughout the body by the systemic blood circulation undergoing cellular uptake, rapid clearance and excretion. Consequently, only a small portion of the platinum-based drug reaches the tumor site, which is associated with severe side effects. For this reason, targeted delivery systems are of great need since they offer enhanced and selective delivery of a drug to cancerous cells making the therapy safe and more effective. Up to date, a variety of the Pt-based drug targeted delivery systems (Pt-based DTDSs) utilizing nanomaterials have been developed and tested using a range of analytical techniques that provided essential information on their synthesis, stability, biodistribution and cytotoxicity. Here we summarize those experimental techniques indicating their applicability at different stages of the research, as well as pointing out their strengths, advantages, drawbacks and limitations. Also, the existing strategies and approaches are critically reviewed with the objective to reveal and give rise to the development of the analytical methodology suitable for reliable Pt-based DTDSs characterization which would eventually result in novel therapies and better patients' outcomes.

Secreted Expression of mRNA-Encoded Truncated ACE2 Variants for SARS-CoV-2 via Lipid-Like Nanoassemblies.

The transfer of foreign synthetic messenger RNA (mRNA) into cells is essential for mRNA-based protein-replacement therapies. Prophylactic mRNA COVID-19 vaccines commonly utilize nanotechnology to deliver mRNA encoding SARS-CoV-2 vaccine antigens, thereby triggering the body's immune response and preventing infections. In this study, a new combinatorial library of symmetric lipid-like compounds is constructed, and among which a lead compound is selected to prepare lipid-like nanoassemblies (LLNs) for intracellular delivery of mRNA. After multiround optimization, the mRNA formulated into core-shell-structured LLNs exhibits more than three orders of magnitude higher resistance to serum than the unprotected mRNA, and leads to sustained and high-level protein expression in mammalian cells. A single intravenous injection of LLNs into mice achieves over 95% mRNA translation in the spleen, without causing significant hematological and histological changes. Delivery of in-vitro-transcribed mRNA that encodes high-affinity truncated ACE2 variants (tACE2v mRNA) through LLNs induces elevated expression and secretion of tACE2v decoys, which is able to effectively block the binding of the receptor-binding domain of the SARS-CoV-2 to the human ACE2 receptor. The robust neutralization activity in vitro suggests that intracellular delivery of mRNA encoding ACE2 receptor mimics via LLNs may represent a potential intervention strategy for COVID-19.

Vitamins for the Gut Microbiome.

A main target in microbiome research is the understanding and ability to safely and effectively modulate the microbiome to improve health. Hereto, we discuss the role of vitamins in relation to the gut microbiome and present a rationale for the modulation of gut microbial communities via selected systemic and colon-targeted vitamin administration.

Bone Diseases: Current Approach and Future Perspectives in Drug Delivery Systems for Bone Targeted Therapeutics.

Bone diseases include a wide group of skeletal-related disorders that cause mobility limitations and mortality. In some cases, e.g., in osteosarcoma (OS) and metastatic bone cancer, current treatments are not fully effective, mainly due to low patient compliance and to adverse side effects. To overcome these drawbacks, nanotechnology is currently under study as a potential strategy allowing specific drug release kinetics and enhancing bone regeneration. Polymers, ceramics, semiconductors, metals, and self-assembled molecular complexes are some of the most used nanoscale materials, although in most cases their surface properties need to be tuned by chemical or physical reactions. Among all, scaffolds, nanoparticles (NPs), cements, and hydrogels exhibit more advantages than drawbacks when compared to other nanosystems and are therefore the object of several studies. The aim of this review is to provide information about the current therapies of different bone diseases focusing the attention on new discoveries in the field of targeted delivery systems. The authors hope that this paper could help to pursue further directions about bone targeted nanosystems and their application for bone diseases and bone regeneration.

A Novel Strategy for Treating Inflammatory Bowel Disease by Targeting Delivery of Methotrexate through Glucan Particles.

Therapy of inflammatory bowel disease (IBD) has been a difficult task in the medical field. There is a great clinical need for more effective treatments for IBD. Herein, a targeted oral delivery system of yeast glucan particles (YGPs) carrying a clinically used anti-inflammatory drug methotrexate (MTX) to the inflamed sites in IBD mice for therapy is reported. In the findings, MTX is effectively loaded into YGPs through re-precipitation followed by gelation reaction of alginate to obtain the composite YGPs/MTX, which are internalized into RAW264.7 macrophage cells through dectin-1 and CR3 receptors. Furthermore, YGPs/MTX can suppress the proliferation of macrophage cells efficiently, leading to down-regulation of pro-inflammatory cytokines induced by lipopolysaccharides. Additionally, YGPs accumulate in the inflammation site of colitis mice, enabling YGPs/MTX to target the inflammatory site, significantly improve the efficacy of MTX, and reduce the cytotoxicity of MTX. Therefore, the YGPs-based drug delivery system provides a new strategy for MTX application in the clinical treatment of IBD.

Strategies of Drug Delivery for Deep Fungal Infection: A Review.

The deep fungal infection poses serious threats to human health, mainly due to the increase in the number of immunocompromised individuals. Current first-line antifungal agents such as Amphotericin B, Fluconazole and Itraconazole, may decrease the severity of fungal infection to some extent, but the poor drug bioavailability, drug toxicity and poor water solubility seriously restrict their clinical utility. This review focuses on the study of drug delivery strategies for the treatment of deep fungal infections. We summarize the drug delivery strategies recently reported for the treatment of deep fungal infection, and explain each part with research examples. We discuss the use of pharmaceutical approaches to improve the physicochemical properties of the antifungal drugs to provide a basis for the clinical application of antifungal drugs. We then highlight the strategies for targeting drug delivery to the infection sites of fungi and fungal surface moieties, which have the potential to get developed as clinically relevant targeted therapies against deep fungal infections. It is worth noting that the current research on fungal infections still lags behind the research on other pathogens, and the drug delivery strategy for the treatment of deep fungal infections is far from meeting the treatment needs. Therefore, we envision the potential strategies inspired by the treatment of diseases with referential pathology or pathophysiology, further enriching the delivery of antifungal agents, providing references for basic research of fungal infections. Lay Summary: The deep fungal infections pose serious threats to the health of immunodeficiency patients. It is worth noting that the current research on fungi is still lagging behind that on other pathogens. The drug delivery strategies for the treatment of deep fungal infections are far from meeting the treatment needs. We summarize the recently reported drug delivery strategies for treating deep fungal infection, and envision the potential strategies to further enrich the delivery of antifungal agents.

M cell targeting engineered biomaterials for effective vaccination.

Vaccines are one of the greatest medical interventions of all time and have been successful in controlling and eliminating a myriad of diseases over the past two centuries. Among several vaccination strategies, mucosal vaccines have wide clinical applications and attract considerable interest in research, showing potential as innovative and novel therapeutics. In mucosal vaccination, targeting (microfold) M cells is a frontline prerequisite for inducing effective antigen-specific immunostimulatory effects. In this review, we primarily focus on materials engineered for use as vaccine delivery platforms to target M cells. We also describe potential M cell targeting areas, methods to overcome current challenges and limitations of the field. Furthermore, we present the potential of biomaterials engineering as well as various natural and synthetic delivery technologies to overcome the challenges of M cell targeting, all of which are absent in current literature. Finally, we briefly discuss manufacturing and regulatory processes to bring a robust perspective on the feasibility and potential of this next-generation vaccine technology.

Cancer-targeted delivery systems based on peptides.

There is a growing interest for the discovery of new cancer-targeted delivery systems for drug delivery and diagnosis. A synopsis of the bibliographic data will be presented on bombesin, neurotensin, octreotide, Arg-Gly-Asp, luteinizing hormone-releasing hormone and other peptides. Many of them have reached the clinics for therapeutic or diagnostic purposes, and have been utilized as carriers of known cytotoxic agents such as doxorubicin, paclitaxel, cisplatin, methotrexate or dyes and radioisotopes. In our article, recent advances in the development of peptides as carriers of cytotoxic drugs or radiometals will be analyzed.

Enzyme replacement therapies: what is the best option?

Despite many beneficial outcomes of the conventional enzyme replacement therapy (ERT), several limitations such as the high-cost of the treatment and various inadvertent side effects including the occurrence of an immunological response against the infused enzyme and development of resistance to enzymes persist. These issues may limit the desired therapeutic outcomes of a majority of the lysosomal storage diseases (LSDs). Furthermore, the biodistribution of the recombinant enzymes into the target cells within the central nervous system (CNS), bone, cartilage, cornea, and heart still remain unresolved. All these shortcomings necessitate the development of more effective diagnosis and treatment modalities against LSDs. Taken all, maximizing the therapeutic response with minimal undesired side effects might be attainable by the development of targeted enzyme delivery systems (EDSs) as a promising alternative to the LSDs treatments, including different types of mucopolysaccharidoses ( MPSs ) as well as Fabry, Krabbe, Gaucher and Pompe diseases.

A novel dissolution method for evaluation of polysaccharide based colon specific delivery systems: A suitable alternative to animal sacrifice.

The most extensively used test for predicting in-vivo release kinetics of a drug from its orally administered dosage forms is dissolution testing. For polysaccharide based, colon targeted oral delivery systems, the entire path of the gut traversed by the dosage form needs to be simulated for assessing its in-vivo dissolution pattern. This includes the dissolution testing sequentially in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). For SGF and SIF, simple and standardized composition is well-known. However, preparation of SCF requires addition of either the colonic contents of rodents or human faecal slurry. A method is proposed, wherein a mixture of five probiotics cultured in the presence of a prebiotic under anaerobic conditions is able to surrogate the colonic fluid. Release profiles of drug from colon targeted delivery systems in this medium were studied and compared to those generated in the conventionally used media containing rodent caecal contents and human faecal slurry. The results from the three studies were found to be quite similar. These findings suggest that the proposed medium may prove to be useful not only as a biorelevant and discriminatory method but may also help in achieving the 3Rs objective regarding the ethical use of animals.