Recent advances in zwitterionic nanoscale drug delivery systems to overcome biological barriers

Nanoscale drug delivery systems(nDDS)have been employed widely in enhancing the therapeutic efficacy of drugs against diseases with reduced side effects.Although several nDDS have been successfully approved for clinical use up to now,biological barriers between the administration site and the target site hinder the wider clinical adoption of nDDS in disease treatment.Polyethylene glycol(PEG)-modification(or PEGylation)has been regarded as the gold standard for stabilising nDDS in complex biological environment.However,the accelerated blood clearance(ABC)of PEGylated nDDS after repeated injections becomes great challenges for their clinical applications.Zwitterionic polymer,a novel family of antifouling materials,have evolved as an alternative to PEG due to their super-hydrophilicity and biocompatibility.Zwitterionic nDDS could avoid the generation of ABC phenomenon and exhibit longer blood circulation time than the PEGylated analogues.More impressively,zwitterionic nDDS have recently been shown to overcome multiple biological barriers such as nonspecific organ distribution,pressure gradients,impermeable cell membranes and lysosomal degradation without the need of any complex chemical modifications.The realization of overcoming multiple biological barriers by zwitterionic nDDS may simplify the current overly complex design of nDDS,which could facilitate their better clinical translation.Herein,we summarise the recent progress of zwitterionic nDDS at overcoming various biological barriers and analyse their underlyingmechanisms.Finally,prospects and challenges are introduced to guide the rational design of zwitterionic nDDS for disease treatment.

Stem cell technology for antitumor drug loading and delivery in oncology

The main aim of antineoplastic treatment is to maximize patient benefit by augmenting the drug accumulation within affected organs and tissues,thus incrementing drug effects and,at the same time,reducing the damage of non-involved tissues to cytotoxic agents.Mesenchymal stromal cells(MSC)represent a group of undifferentiated multipotent cells presenting wide self-renewal features and the capacity to differentiate into an assortment of mesenchymal family cells.During the last year,they have been proposed as natural carriers for the selective release of antitumor drugs to malignant cll,s thus optimizing cytotoxic action on cancer cll,while significantly reducing adverse side efect on healthy cells.MSC chemotherapeutic drug loading and delivery is an encouraging new area of cell therapy for several tumors,especially for those with unsatisfactory prognosis and limited treatment options available.Although some experim ental models have been sucesfuly developed,phase I dinical studies are needed to confirm this potential application of cell therapy,in particular in the case of primary and secondary lung cancers.

The state-of-the-art of atmospheric pressure plasma for transdermal drug delivery

Plasma-enhanced transdermal drug delivery(TDD) presents advantages over traditional methods,including painless application, minimal skin damage, and rapid recovery of permeability. To harness its clinical potential, factors related to plasma’s unique properties, such as reactive species and electric fields, must be carefully considered.This review provides a concise summary of conventional TDD methods and subsequently offers a comprehensive examination of the current state-of-the-art in plasma-enhanced TDD. This includes an analysis of the impact of plasma on HaCaT human keratinocyte cells, ex vivo/in vivo studies, and clinical research on plasma-assisted TDD. Moreover, the review explores the effects of plasma on skin physical characteristics such as microhole formation, transepidermal water loss(TEWL), molecular structure of the stratum corneum(SC), and skin resistance. Additionally, it discusses the involvement of various reactive agents in plasma-enhanced TDD, encompassing electric fields,charged particles, UV/VUV radiation, heat, and reactive species. Lastly, the review briefly addresses the temporal behavior of the skin after plasma treatment, safety considerations, and potential risks associated with plasma-enhanced TDD.

Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs;as novel solvents for improving the solubility of drugs in carriers;as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs;and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

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.

Insights on drug and gene delivery systems in liver fibrosis

Complications of the liver are amongst the world’s worst diseases.Liver fibrosis is the first stage of liver problems,while cirrhosis is the last stage,which can lead to death.The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver’s metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting.Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis;nevertheless,the working mechanism of anti-fibrotic medications is not fully understood,and there is a need to design delivery systems that are well-understood and can aid in cirrhosis.Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery.As a result,the capability of nanoparticles in hepatic delivery was explored.Another approach is targeted drug delivery,which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells(HSCs).We have addressed numerous delivery strategies that target HSCs,which can eventually aid in fibrosis.Recently genetics have proved to be useful,and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted.To summarize,this review paper sheds light on themost recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.

Milk-derived exosomes as a promising vehicle for oral delivery of hydrophilic biomacromolecule drugs

Exosomes,as promising vehicles,have been widely used in the research of oral drug delivery,but the generally low drug loading efficiency of exosomes seriously limits its application and transformation.In this study,we systematically investigated the effects of drug loading methods and physicochemical properties(lipophilicity and molecular weight)on drug loading efficiency of milk-derived exosomes to explore the most appropriate loading conditions.Our finding revealed that the drug loading efficiency of exosomes was closely related to the drug loading method,drug lipophilicity,drug molecular weight and exosome/drug proportions.Of note,we demonstrated the universality that hydrophilic biomacromolecule drugs were the most appropriate loading drugs for milk-derived exosomes,which was attributed to the efficient loading capacity and sustained release behavior.Furthermore,milk-derived exosomes could significantly improve the transepithelial transport and oral bioavailability of model hydrophilic biomacromolecule drugs(octreotide,exendin-4 and salmon calcitonin).Collectively,our results suggested that the encapsulation of hydrophilic biomacromolecule drugs might be the most promising direction for milk exosomes as oral drug delivery vehicles.

Stimuli-Responsive Gene Delivery Nanocarriers for Cancer Therapy

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Interpeduncular cistern intrathecal targeted drug delivery for intractable postherpetic neuralgia: A case report

BACKGROUND Intractable postherpetic neuralgia(PHN)can be difficult to manage even with aggressive multimodal therapies.Patients who experience uncontrolled refractory cranial PHN despite conservative treatment may benefit from an intrathecal drug delivery system(IDDS).For craniofacial neuropathic pain,the traditional approach has been to place the intrathecal catheter tip below the level of the cranial nerve root entry zones,which may lead to insufficient analgesia.CASE SUMMARY We describe a 69-year-old man with a 1-year history of PHN after developing a vesicular rash in the ophthalmic division of cranial nerve V(trigeminal nerve)distribution.The pain was rated 7-8 at rest and 9-10 at breakthrough pain(BTP)on a numeric rating scale.Despite receiving aggressive multimodal therapies including large doses of oral analgesics(gabapentin 150 mg q12 h,oxycodone 5 mg/acetaminophen 325 mg q6 h,and lidocaine 5%patch 700 mg q12 h)and sphenopalatine ganglion block,there was no relief of pain.Subsequently,the patient elected to have an implantable IDDS with the catheter tip placed at the interpeduncular cistern.The frequency of BTP episodes decreased.The patient’s continuous daily dose was adjusted to 0.032 mg/d after 3 mo of follow-up and stopped 5 mo later.He did not report pain or other discomfort at outpatient follow-up 6 mo and 1 year after stopping intracisternal hydromorphone.CONCLUSION The use of interpeduncular cistern intrathecal infusion with low-dose hydromorphone by IDDS may be effective for severe craniofacial PHN.

In situ forming hydrogels based on chitosan for drug delivery and tissue regeneration

In situ forming hydrogels with simple sol–gel transition are more practicable as injectable hydrogels for drug delivery and tissue regeneration. State-of-the-art in situ gelling systems can easily and efficiently be formed by different mechanisms in situ. Chitosan is a kind of natural polysaccharide that is widely exploited for biomedical applications due to its good biocompatibility, low immunogenicity and specific biological activities. Chitosan-based in situ gelling systems have already gained much attention as smart biomaterials in the development of several biomedical applications, such as for drug delivery systems and regeneration medicine. Herein, we review the typical in situ gelling systems based on chitosan and mechanisms involved in hydrogel forming, and report advances of chitosan-based in situ gels for the applications in drug delivery and tissue regeneration. Finally, development prospects of in situ forming hydrogels based on chitosan are also discussed in brief.

Preparation and evaluation of controllable drug delivery system:A light responsive nanosphere based on β-cyclodextrin/mesoporous silica

A novel light responsive nanosphere was constructed,and it was used as a drug carrier to investigate the loading and release properties of the Quercetin(QU).In this paper,mesoporous silica nanoparticles(MSN)were used as a substrate,and 3-aminopropyl triethyoxysilane was used as a surface modification agent to introduce—NH_(2),and the azobenzene-4,4’-dicarboxylic acid(AZO)was used as light responsive agent to introduce the group of—N=N—,and thenβ-cyclodextrin(β-CD)was combined with AZO through host-guest interaction to construct light responsive nanoparticles(MSN@β-CD).The structure and properties of the carrier were analyzed by FTIR,BET,XPS,TGA,XRD,SEM and TEM.In vitro drug release studies showed the release rate of QU@MSN@β-CD(dark)was 12.19%within 72 h,but the release rate of QU@MSN@β-CD(light 10 min)was 26.09%,exhibiting a light-responsive property.The CCK8 tests demonstrated that MSN@β-CD could significantly decrease the toxicity of QU.Therefore,the controllable light-responsive drug delivery system has great application prospects.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular(IA)injection has proved to be effective in osteoarthritis(OA)therapy,limited by the drug efficiency and short retention time of the drug delivery systems(DDSs).Herein,a series of modified cross-linked dextran(Sephadex,S0)was fabricated by respectively grafting with linear alkyl chains,branched alkyl chains or aromatic chain,and acted as DDSs after ibuprofen(Ibu)loading for OA therapy.This DDSs expressed sustained drug release,excellent anti-inflammatory and chondroprotective effects both in IL-1βinduced chondrocytes and OA joints.Specifically,the introduction of a longer hydrophobic chain,particularly an aromatic chain,distinctly improved the hydrophobicity of S0,increased Ibu loading efficiency,and further led to significantly improving OA therapeutic effects.Therefore,hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

Applications and developments of gene therapy drug delivery systems for genetic diseases

Genetic diseases seriously threaten human health and have always been one of the refractory conditions facing humanity.Currently,gene therapy drugs such as siRNA,shRNA,antisense oligonucleotide,CRISPR/Cas9 system,plasmid DNA and miRNA have shown great potential in biomedical applications.To avoid the degradation of gene therapy drugs in the body and effectively deliver them to target tissues,cells and organelles,the development of excellent drug delivery vehicles is of utmost importance.Viral vectors are the most widely used delivery vehicles for gene therapy in vivo and in vitro due to their high transfection efficiency and stable transgene expression.With the development of nanotechnology,novel nanocarriers are gradually replacing viral vectors,emerging superior performance.This review mainly illuminates the current widely used gene therapy drugs,summarizes the viral vectors and non-viral vectors that deliver gene therapy drugs,and sums up the application of gene therapy to treat genetic diseases.Additionally,the challenges and opportunities of the field are discussed from the perspective of developing an effective nano-delivery system.

Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by erythema,scaling,and skin thickening.Topical drug application is recommended as the first-line treatment.Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment.However,these preparations usually have low viscosity and limited retention on the skin surface,resulting in low drug delivery efficiency and poor patient satisfaction.In this study,we developed the first water-responsive gel(WRG),which has a distinct water-triggered liquid-to-gel phase transition property.Specifically,WRG was kept in a solution state in the absence of water,and the addition of water induced an immediate phase transition and resulted in a high viscosity gel.Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis.In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin.In a mouse model of psoriasis,curcumin loaded WRG(CUR-WRG)effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration.Further mechanism study demonstrated that the anti-hyperplasia,anti-inflammation,anti-angiogenesis,anti-oxidation,and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency.Notably,neglectable local or systemic toxicity was observed for CUR-WRG application.This study suggests that WRG is a promising formulation for topically psoriasis treatment.

Smart stimuli-responsive drug delivery systems in spotlight of COVID-19

The world has been dealing with a novel severe acute respiratory syndrome(SARS-CoV-2)since the end of 2019,which threatens the lives of many peopleworldwide.COVID-19 causes respiratory infection with different symptoms,from sneezing and coughing to pneumonia and sometimes gastric symptoms.Researchers worldwide are actively developing novel drug delivery systems(DDSs),such as stimuli-responsive DDSs.The ability of these carriers to respond to external/internal and even multiple stimuli is essential in creating“smart”DDS that can effectively control dosage,sustained release,individual variations,and targeted delivery.To conduct a comprehensive literature survey for this article,the terms“Stimuli-responsive”,“COVID-19”and“Drug delivery”were searched on databases/search engines like“Google Scholar”,“NCBI”,“PubMed”,and“Science Direct”.Many different types of DDSs have been proposed,including those responsive to various exogenous(light,heat,ultrasound andmagnetic field)or endogenous(microenvironmental changes in pH,ROS and enzymes)stimuli.Despite significant progress in DDS research,several challenging issues must be addressed to fill the gaps in the literature.Therefore,this study reviews the drug release mechanisms and applications of endogenous/exogenous stimuli-responsive DDSs while also exploring their potential with respect to COVID-19.

Can the venerated silk be the next generation nanobiomaterialfor biomedical device designing, regenerative medicine and drugdelivery? Prospects and hitches

Of late, the relevance of silk in a myriad of material science and biotechnological realms has been realized, as attested by the incessantly clambering number of reports and patents in the scienti fic repositories. The write-up is geared off with a scrutiny into the pertinence of the basic nano-structural features of silk, christened as the ‘queen of textile’ for exemplary bioengi- neering applications including designing and fabrication of devices for micro fluidics, opto fluidics, chemo/bio sensing, etc. Then, the major thrust of this short review is directed towards comprehending the prospects of using silk-based biomaterials (e.g. sca ffolds, electrospun membranes, films, hydrogels, bioinks) for tissue engineering and regenerative medicine as well as targeted delivery of various biomolecular cargoes/therapeutic agents, etc., as vouched by few avant-garde endeavours of the recent years. The write-up is entwined with a discussion on the various factors that could plausibly hinder the realization of silk as the next-generation nanobiomaterial, suggestions for some approaches to dodge and deal with the practical snags and what lies ahead!

Nasal implants for drug delivery:Advancements and applications

Nasal implants have emerged as a pioneering technology for nasal drug delivery systems.These are breakthrough options made of biocompatible materials that are temporarily inserted into the nasal passages for both functional and cosmetic purposes.Drug-eluting nasal implants are beneficial for improving patient compliance,reducing the need for repeated drug administration,and achieving controlled release of therapeutic agents.This article offers a comprehensive insight into nasal implants and their applications,and addresses a patent perspective in the same context.Important considerations for clinically approved implants,such as Propel,Sinuva,Sinu-Foam,and Relieva Stratus,have also been discussed.

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.

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.