Ionizable drug delivery systems for efficient and selective gene therapy

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.

Mesenchymal stem cells-based drug delivery systems for diabetic foot ulcer:A review

The complication of diabetes,which is known as diabetic foot ulcer(DFU),is a significant concern due to its association with high rates of disability and mortality.It not only severely affects patients’quality of life,but also imposes a substantial burden on the healthcare system.In spite of efforts made in clinical practice,treating DFU remains a challenging task.While mesenchymal stem cell(MSC)therapy has been extensively studied in treating DFU,the current efficacy of DFU healing using this method is still inadequate.However,in recent years,several MSCs-based drug delivery systems have emerged,which have shown to increase the efficacy of MSC therapy,especially in treating DFU.This review summarized the application of diverse MSCs-based drug delivery systems in treating DFU and suggested potential prospects for the future research.

Recent progress of respiratory inhalation drug delivery systems

With the influence of many factors such as the aging of the population,the younger smokers,and the serious air pollution,the incidence of chronic respiratory diseases is increasing year by year.In the treatment of respiratory diseases,clinical intervention is still mainly based on drug control of pulmonary symptoms.However,systemic drugs have disadvantages such as many adverse reactions and severe systemic side effects.In recent years,the research and development of local drug delivery systems for the respiratory tract has brought new changes to the treatment of respiratory diseases.Locally delivered drugs can directly act on the airways and have the characteristics of fast onset,good curative effect and small side effects.It is a simple,efficient and safe treatment method,which has a very significant effect,and has become a hot topic of current research and promotion.This paper briefly reviews the development track and latest research progress of respiratory local drug delivery systems at home and abroad,in order to provide reference for clinical workers in drug selection and application.

Targeted drug delivery systems for pancreatic ductal adenocarcinoma:overcoming tumor microenvironment challenges with CAF-specific nanoparticles

Pancreatic ductal adenocarcinoma(PDAC)stands as a profoundly heterogeneous and aggressive malignancy,manifesting a discouragingly limited response to conventional therapeutic interventions.Within the intricate tapestry of the tumor microenvironment(TME),cancer-associated fibroblasts(CAFs)emerge as pivotal constituents,wielding the capacity to propel the malignant attributes of neoplastic cells while bolstering their deftness in thwarting treatments.The rapid evolution of nanomedicinal technologies ushers in fresh avenues for thera-peutic paradigms meticulously honed to target CAFs.Notably,a recent proposition by Yuan et al.introduces a PDAC treatment strategy metaphorically akin to“shooting fish in a barrel.”By adeptly capitalizing on the spatial distribution of the CAF barricade encircling the tumor,this innovative approach orchestrates a metamorphosis of CAFs,transitioning them from impediments to drug delivery into reservoirs of therapeutic agents.The resultant outcome,an augmentation of chemotherapy and immunotherapy efficacy,attests to the transformative potential of this concept.The study not only bequeaths novel insights and methodologies to surmount barriers in drug delivery for tumor treatment but also holds promise in elevating the precision,efficacy,and safety of tailored therapeutic regimens.Within this discourse,we meticulously evaluate Yuan et al.’s research,scrutinizing its merits and limitations,and cast a forward-looking gaze upon the formulation,validation of efficacy,and clinical translation of nanomedicines targeting CAFs.

A review on phospholipids and their main applications in drug delivery systems

Phospholipids have the characteristics of excellent biocompatibility and a especial amphiphilicity.These unique properties make phospholipids most appropriate to be employed as important pharmaceutical excipients and they have a very wide range of applications in drug delivery systems.The aim of this review is to summarize phospholipids and some of their related applications in drug delivery systems,and highlight the relationship between the properties and applications,and the effect of the species of phospholipids on the efficiency of drug delivery.We refer to some relevant literatures,starting from the structures,main sources and properties of phospholipids to introduce their applications in drug delivery systems.The present article focuses on introducing five types of carriers based on phospholipids,including liposomes,intravenous lipid emulsions,micelles,drug-phospholipids complexes and cochleates.

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.

From oral formulations to drug-eluting implants:using 3D and 4D printing to develop drug delivery systems and personalized medicine

Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.

Novel drug delivery systems for inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic illness characterized by relapsing inflammation of the intestines.The disorder is stratified according to the severity and is marked by its two main phenotypical representations:Ulcerative colitis and Crohn’s disease.Pathogenesis of the disease is ambiguous and is expected to have interactivity between genetic disposition,environmental factors such as bacterial agents,and dysregulated immune response.Treatment for IBD aims to reduce symptom extent and severity and halt disease progression.The mainstay drugs have been 5-aminosalicylates(5-ASAs),corticosteroids,and immunosuppressive agents.Parenteral,oral and rectal routes are the conventional methods of drug delivery,and among all,oral administration is most widely adopted.However,problems of systematic drug reactions and low specificity in delivering drugs to the inflamed sites have emerged with these regular routes of delivery.Novel drug delivery systems have been introduced to overcome several therapeutic obstacles and for localized drug delivery to target tissues.Enteric-coated microneedle pills,various nano-drug delivery techniques,prodrug systems,lipid-based vesicular systems,hybrid drug delivery systems,and biologic drug delivery systems constitute some of these novel methods.Microneedles are painless,they dislodge their content at the affected site,and their release can be prolonged.Recombinant bacteria such as genetically engineered Lactococcus Lactis and eukaryotic cells,including GM immune cells and red blood cells as nanoparticle carriers,can be plausible delivery methods when evaluating biologic systems.Nano-particle drug delivery systems consisting of various techniques are also employed as nanoparticles can penetrate through inflamed regions and adhere to the thick mucus of the diseased site.Prodrug systems such as 5-ASAs formulations or their derivatives are effective in reducing colonic damage.Liposomes can be modified with both hydrophilic and lipophilic particles and act as lipid-based vesicular systems,while hybrid drug delivery systems containing an internal nanoparticle section for loading drugs are potential routes too.Leukosomes are also considered as possible carrier systems,and results from mouse models have revealed that they control anti-and pro-inflammatory molecules.

Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor^(■) RH40 using experimental design

The development of self-nanoemulsifying drug delivery systems(SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil(Kolliphor ~? RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80(LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides(40% to 75%), Kolliphor ~? RH40(5% to 55%), LPC(0 to 40%) and ethanol(0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of mediumchain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor~? RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor~? RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor ~? RH40 as a reference for formulation developers.

Drug delivery systems for colorectal cancer chemotherapy

Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.

Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy:A review of recent advances

Radiotherapy(RT)is a crucial treatment for cancer;however,its effectiveness is limited by adverse effects on normal tissues,radioresistance,and tumor recurrence.To overcome these challenges,hydrogels have been employed for delivery of radiosensitizers and other therapeutic agents.This review summarizes recent advancements in the application of hydrogel-based local drug delivery systems for improving the therapeutic efficacy of RT in cancer treatment.Firstly,we introduce the classification and properties of hydrogels.Next,we detail hydrogel-based platforms designed to enhance both external beam radiation therapy and brachytherapy.We also discuss hydrogels used in combination therapy involving RT and immunotherapy.Lastly,we highlight the challenges that hydrogels face in RT.By surveying the latest developments in hydrogel applications for RT,this review aims to provide insights into the development of more effective and targeted cancer therapies.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic,systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate.Several drugs have been used for the treatment of rheumatoid arthritis,but their use is limited by suboptimal bioavailability,serious adverse effects,and nonnegligible first-pass effects.In contrast,transdermal drug delivery systems(TDDSs)can avoid these drawbacks and improve patient compliance,making them a promising option for the treatment of rheumatoid arthritis(RA).Of course,TDDSs also face unique challenges,as the physiological barrier of the skin makes drug delivery somewhat limited.To overcome this barrier and maximize drug delivery efficiency,TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology,and different generations of TDDSs have been derived,which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery.In this review,we summarize the different generations of transdermal drug delivery systems,the corresponding transdermal strategies,and their applications in the treatment of RA.

Inhalable microparticles as drug delivery systems to the lungs in a dry powder formulations

Inhalation-administrated drugs remain an interesting possibility of addressing pulmonary diseases.Direct drug delivery to the lungs allows one to obtain high concentration in the site of action with limited systemic distribution,leading to a more effective therapy with reduced required doses and side effects.On the other hand,there are several difficulties in obtaining a formulation that would meet all the criteria related to physicochemical,aerodynamic and biological properties,which is the reason why only very few of the investigated systems can reach the clinical trial phase and proceed to everyday use as a result.Therefore,we focused on powders consisting of polysaccharides,lipids,proteins or natural and synthetic polymers in the form of microparticles that are delivered by inhalation to the lungs as drug carriers.We summarized the most common trends in research today to provide the best dry powders in the right fraction for inhalation that would be able to release the drug before being removed by natural mechanisms.This review article addresses the most common manufacturing methods with novel modifications,pros and cons of different materials,drug loading capacities with release profiles,and biological properties such as cytocompatibility,bactericidal or anticancer properties.

Recent advances in drug delivery systems for targeting cancer stem cells

Cancer stem cells(CSCs)are a subpopulation of cancer cells with functions similar to those of normal stem cells.Although few in number,they are capable of self-renewal,unlimited proliferation,and multi-directional differentiation potential.In addition,CSCs have the ability to escape immune surveillance.Thus,they play an important role in the occurrence and development of tumors,and they are closely related to tumor invasion,metastasis,drug resistance,and recurrence after treatment.Therefore,specific targeting of CSCs may improve the efficiency of cancer therapy.A series of corresponding promising therapeutic strategies based on CSC targeting,such as the targeting of CSC niche,CSC signaling pathways,and CSC mitochondria,are currently under development.Given the rapid progression in this field and nanotechnology,drug delivery systems(DDSs)for CSC targeting are increasingly being developed.In this review,we summarize the advances in CSC-targeted DDSs.Furthermore,we highlight the latest developmental trends through the main line of CSC occurrence and development process;some considerations about the rationale,advantages,and limitations of different DDSs for CSCtargeted therapies were discussed.

Leukocyte-derived biomimetic nanoparticulate drug delivery systems for cancer therapy

Precise drug delivery to tumors with low system toxicity is one of the most important and challenging tasks for pharmaceutical researchers. Despite progress in the field of nanotherapeutics, the use of artificially synthesized nanocarriers still faces several challenges, including rapid clearance from blood circulation and limited capability of overcoming multiple physiological barriers, which hamper the clinical application of nanoparticle-based therapies. Since leukocytes(including monocytes/macrophages,neutrophils, dendritic cells and lymphocytes) target tumors and can migrate across physiological barriers,leukocytes are increasing utilized as carriers to transfer nanoparticles to tumors. In this review we specifically focus on the molecular and cellular mechanisms of leukocytes that can be exploited as a vehicle to deliver nanoparticles to tumors and summarize the latest research on how leukocytes can be harnessed to improve therapeutic end-points. We also discuss the challenges and opportunities of this leukocyte-derived nanoparticle drug delivery system.

pH-Sensitive nanoscale materials as robust drug delivery systems for cancer therapy

Cancer is one of the diseases that have the highest mortality,which threatens the human health.Chemotherapy functions as the most widely used strategy in clinic to treat cancer,still exists urgent problems,like lacking selectivity and causing severe side effects.According to detailed researches on the metabolism,functions and histology of cancer tissues,many different features of cancer are uncovered,like lower pH in microenvironment,abnormal redox level in intracellular compartments and elevated expression level of several enzymes and receptors.Recently,the development of smart nanoparticles that response to tumor specific microenvironment has lighted up hope for selective cancer therapy.Herein,this review mainly focuses on pH-sensitive nano scale materials for anti-cancer drug delivery.We summarized the formation progress of acidic tumor microenvironment,the mechanism of pHresponsive drug delivery system and nanomaterials that responsive to acidic pH in tumor microenvironment.

Environment-responsive drug delivery systems for targeted cancer therapy

In order to deliver and/or release anti-cancer therapeutics at the tumor sites, novel environment-responsive drug delivery systems are designed to specifically respond to tumor microenvironment （such as low pH and hypoxia）. Due to their extraordinary advantages, these environment-responsive drug delivery systems can improve antitumor efficacy, and most importantly, they can decrease toxicity associated with the anti-cancer therapeutics. This review highlights different mechanisms of environmentresponsive drug delivery systems and their applications for targeted cancer therapy.

Challenges in cell membrane-camouflaged drug delivery systems:Development strategies and future prospects

Extensive research has been performed on cell membrane camouflaged-based drug delivery systems in recent years.Herein,we provide an overview of the challenges in system preparation,functional design,continuous industrial production of these systems,and solution strategies for these challenges.Further,we analyze and discuss the frontier medical applications of cell membrane-camouflaged drug delivery systems in anti-inflammatory,anti-pathogenic microorganisms,and biological detoxification.This review takes a challenge-oriented perspective and seeks innovative strategies,provides a literature review of research into cell membrane-camouflaged drug delivery systems,and promotes the development of personalized clinical treatments.

Dynamic covalent chemistry-regulated stimuli-activatable drug delivery systems for improved cancer therapy

Drug delivery systems(DDSs)are of paramount importance to deliver drugs at the intended targets,e.g.,tumor cells or tissue by prolonging blood circulation and optimizing the pharmaceutical profiles.However,the therapeutic efficacy of DDSs is severely impaired by insufficient or non-specific drug release.Dynamic chemical bonds having stimuli-liable prope rties are the refore introduced into DDSs for regulating the drug release kinetics.This review summarizes the recent advances of dynamic covalent chemistry in the DDSs for improving cancer therapy.The review discusses the constitutions of the major classes of dynamic covalent bonds,and the respective applications in the tumor-targe ted DDSs which are based on the different responsive mechanisms,including acid-activatable and reduction-activatable.Furthermore,the review also discusses combination strategies of dual dynamic covale nt bonds which can response to the complex tumor microenvironment much more accurately,and then summarizes and analyzes the prospects for the application of dynamic covalent chemistry in DDSs.

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment response, and low toxicity, stimuli-responsive nano-based drug delivery systems(NDDSs) have been a promising approach in AS treatments. Herein, we will systematically summarize the recent advances in stimuli-responsive NDDSs for AS treatment, including internal stimuli(reactive oxygen species, enzyme, shear stress, and pH) and external stimuli(light, ultrasound, and magnetism) responsive NDDSs. Besides, we will also summarize in detail the classification of stimuli-responsive NDDSs for AS, such as organic NDDSs(e.g., lipid-based and polymer-based nanomaterials), inorganic NDDSs(e.g., metal-based nanoparticles and nonmetallic nanomaterials), and composite multifunctional NDDSs. Finally, the critical challenges and prospects of this field will also be proposed and discussed.