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 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.

Recent advances in endogenous and exogenous stimuli-responsive nanoplatforms for bacterial infection treatment

As drug-resistant bacterial infections escalate and antimicrobial resources become insufficient,new alternative therapies are critical.The emergence of nano drug delivery system,in addition to giving drugs sustained,targeted or longer half-life characteristics,also plays an important role in improving the therapeutic effect and reducing the toxic side effects of conventional drugs.Despite its potential benefits,the traditional nanomedical drug delivery system has some practical limitations,including incomplete and slow drug release,as well as insufficient accumulation at infection sites.Stimuli responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles,which can provide several advantages like:enhancing the pharmacokinetics and biodistribution of antimicrobial drugs,increasing their effective bioavailability,reducing their dosage frequency,and improving their antimicrobial efficacy against biofilm-related infections,while slowing down the development of antimicrobial resistance,which is expected to trigger a medical revolution in the field of human health,thus bringing huge clinical benefits.In this review,we provide an extensive review of the recent progress of endogenous and exogenous stimuli-responsive nanoplatforms in the antibacterial area.Using specific infectious microenvironments(pH,enzymes,reactive oxygen species and toxins),this review systematically presents the design principles of nano delivery systems and the mechanisms by which endogenous stimuli induce changes in the morphology or properties of delivery systems to achieve programmed drug release.Furthermore,exogenous stimuli such as light,heat,and magnetic fields can also control the release of drugs.Last but not least,we discussed the challenges and opportunities for future clinical translation of stimuli-responsive nanoplatforms in bacterial infections.

Stimuli-responsive emulsions:Recent advances and potential applications

Responsive emulsions are the emulsions that can be reversibly switched on-demand between“stable”and“unstable”by environmental stimulus or trigger,which allows a simple and effective adjustment approach to achieve emulsification and demulsification.In recent years,stimuli-responsive emulsions acting as smart soft material are received considerable attention with the advantages of simple manipulation,good reversibility,low cost,easy treatment,and little effect on the system.In this paper,the recent research progress of emulsions that can respond to external stimuli,including pH,light,magnetic field,CO_(2)/N_(2) and dual responsive are reviewed.Also,the potential applications based on responsive emulsion are discussed,such as catalytic reactions,heavy oil recovery,polymer particles synthesis and optical sensor,aiming to summarize the latest achievements and put forward the possible development trends of responsive emulsions.

Click-Formed Polymer Gels with Aggregation-Induced Emission and Dual Stimuli-Responsive Behaviors

Stimuli-responsive polymer gels have recently attracted great attention due to their heat/solvent resistance,dimensional stability,and unique sensitivity to external stimuli.In this work,we synthesized thiol-functionalized tetraphenylethylene(TPE)and constructed polymer gels through thiol-ene click reaction.The synthetic process of the polymer gels could be monitored by fluorescence emission of TPE moieties based on aggregation-induced emission mechanism.In addition,due to the dual redox-and acid responsiveness of the polymer gels,in the presence of dithiothreitol and trifluoroacetic acid,fluorescence quenching of the polymer gels can be observed.This stimuli-responsive characteristics endows the polymer gels with potential applications in fluorescent sensing and imaging,cancer diagnosis and selfhealing materials.

Recent Advances of D-α-tocopherol Polyethylene Glycol 1000 Succinate Based Stimuli-responsive Nanomedicine for Cancer Treatment

D-a-tocopherol polyethylene glycol 1000 succinate(TPGS)is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA.It's widely applied as a multifunctional drug carrier for nanomedicine.The advantages of TPGS include P-glycoprotein(P-gp)inhibition,penetration promotion,apoptosis induction via mitochondrial-associated apoptotic pathways,multidrug resistant(MDR)reversion,metastasis inhibition and so on.TPGS-based drug delivery systems which are responding to extermal stimulus can combine the inhibitory functions of TPGS towards P-gp with the environmentally responsive controlled release property and thus exerts a synergistic anti-cancer effect,through increased intracellular drug concentration in tumors cells and well-controlled drug release behavior.In this review,TPGS-based nano-sized delivery systems responsive to different stimuli were summarized and discussed,including pH-responsive,redox-responsive and multi-responsive systems in various formulations.The achievements,mechanisms and diffcrent characteristics of TPGS-bascd stimuli-responsive drug-delivery systems in tumor therapy were also outlined.

Stimuli-responsive nanocarriers for therapeutic applications in cancer

Cancer has become a very serious challenge with aging of the human population.Advances in nanotechnology have provided new perspectives in the treatment of cancer.Through the combination of nanotechnology and therapeutics,nanomedicine has been successfully used to treat cancer in recent years.In terms of nanomedicine,nanocarriers play a key role in delivering therapeutic agents,reducing severe side effects,simplifying the administration scheme,and improving therapeutic efficacies.Modulations of the structure and function of nanocarriers for improved therapeutic efficacy in cancer have attracted increasing attention in recent years.Stimuli-responsive nanocarriers penetrate deeply into tissues and respond to external or internal stimuli by releasing the therapeutic agent for cancer therapy.Notably,stimuli-responsive nanocarriers reduce the severe side effects of therapeutic agents,when compared with systemic chemotherapy,and achieve controlled drug release at tumor sites.Therefore,the development of stimuli-responsive nanocarriers plays a crucial role in drug delivery for cancer therapy.This article focuses on the development of nanomaterials with stimuli-responsive properties for use as nanocarriers,in the last few decades.These nanocarriers are more effective at delivering the therapeutic agent under the control of external or internal stimuli.Furthermore,nanocarriers with theranostic features have been designed and fabricated to confirm their great potential in achieving effective treatment of cancer,which will provide us with better choices for cancer therapy.

Smart anticorrosion coating based on stimuli-responsive micro/nanocontainer:a review

Smart coating for corrosion protection of metal materials(steel,magnesium,aluminum and their alloys)has drawn great attention because of their capacity to prevent crack propagation in the protective coating by releasing functional molecules(healing agents or corrosion inhibitors)on demand from delivery vehicle,that is,micro/nanocontainer made up of a shell and core material or a coating layer,in a controllable manner.Herein,we summarize the recent achievements during the last 10 years in the field of the micro/nanocontainer with different types of stimuli-responsive properties,i.e.,pH,electrochemical potential,redox,aggressive corrosive ions,heat,light,magnetic field,and mechanical impact,for smart anticorrosion coating.The state-of-the-art design and fabrication of micro/nanocontainer are emphasized with detailed examples.

Stimuli-responsive coordination polymers toward next-generation smart materials and devices

Stimuli-responsive coordination polymers(CPs)are among one of the most prolific research areas in developing the next-generation functional materials.Their capability of being accurately excited by particular external changes with pre-determined and observable/characterizable behaviors correspond,are the so called“stimuli”and“responsive”.Abundant types of CP compounds,especially metal-organic frameworks(MOFs),are of rocketing interest owing to their compositional diversity,structural tunability,and in essence their highly engineerable functionality.This present review is aimed to sketch several common types of stimulation and the corresponding responses for CPs,accompanied with the broad logic and mechanisms underneath.And further from the aspect of material revolution,some representative progresses together with the latest advances of CP-based materials in various fields are covered in attempt to display a broader picture towards the possible prospects of this topic.

Oligopeptide Self-Assembly:Mechanisms,Stimuli-Responsiveness,and Biomedical Applications

Oligopeptide self-assembly materials have emerged as a promising class of biomaterials with diverse applications in biomedicine.This review highlights the recent progress in comprehending the selfassembly mechanisms intrinsic to oligopeptides and their behavior in response to specific stimuli.By methodically structuring the amino acid sequence and managing external stimuli such as pH levels,redox conditions,or enzymatic activity,we can exercise unprecedented control over the self-assembly process.By controlling the self-assembly process of oligopeptides,various structures with extraordinary versatility can be obtained,including micelles,nanofibers,and coacervate droplets,each possessing modifiable mechanical and chemical properties.Furthermore,these self-assembled constructs demonstrate immense potential within varied biomedical applications.The stimuli-sensitive nature of oligopeptide assembly materials facilitates timely encapsulation and release of therapeutic cargos,consequently eliciting desired cellular responses.This approach paves the way for more precise tumor targeting,personalized medicinal treatments,and well-regulated drug dispensation.Their innate biocompatibility and proficiency in replicating the extracellular matrix(ECM)render them ideally suited for applications such as tissue engineering,wound remediation,and regenerative medicine.In summary,oligopeptide self-assembling materials show tremendous potential as adaptable platforms for cutting-edge biomedical applications,thereby bridging the divide between fundamental research and practical clinical application.

Recent advances on thermosensitive hydrogels-mediated precision therapy

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites,increased therapeutic efficacy,and reduced adverse effects.Over the past few years,sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential.These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature.Inspired by their unique properties,thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine.In this review,the state-of-theart developments in thermosensitive hydrogels for precision therapy are investigated,which covers from the thermo-gelling mechanisms and main components to biomedical applications,including wound healing,anti-tumor activity,osteogenesis,and periodontal,sinonasal and ophthalmic diseases.The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.

Multistimuli-Responsive Luminescent Porous Organic Polymers with Chiroptical Properties and Acid-Induced Degradation

Porous organic polymers(POPs)have attracted great attention in past decades.Although diverse functional POPs have been developed,multistimuli-responsive POPs with excellent aggregate-state luminescence together with good chiroptical properties have rarely been reported.Herein,two pairs of Salen-type enantiomeric PoPs with multistimuli-responsive luminescence and chiral features were designed and synthesized by facile polycondensation reactions between polyfunctional aggregation-induced emission luminogen(AlEgen)-containing salicylaldehyde derivatives and chiral diamines.With Salen units in polymer backbones as tetradentate ligands,a series of POP-metal complexes were further prepared.The obtained POPs and metal complexes show good porosity,high thermal stability,and obvious circular dichroism signals.Moreover,benefiting from the coexistence of AlEgen and Salen units in polymer structures,these POPs exhibit excellent luminescence performance in aggregate states and tunable fluorescence behaviors in response to external stimuli of Zn^(2+)ion,mechanical forces,organic solvent,and acids.Due to the dynamic feature of Schiff base C=N bonds,the present POPs can efficiently undergo hydrolysis reactions under strong acidic conditions to reproduce the AlEgencontaining monomers,and such an acid-induced degradation process can be directly visualized and dynamically monitored via fluorescence variation.These properties collectively make the POPs candidate materials for applications in heterogeneous asymmetric catalysis,fluorescence sensing,biomedicine,etc.

Stimuli-responsive hydrogels for bone tissue engineering

The treatment of bone defects remains a great clinical challenge.With the development of science and technology,bone tissue engineering technology has emerged,which can mimic the structure and function of natural bone tissues and create solutions for repairing or replacing human bone tissues based on biocompatible materials,cells and bioactive factors.Hydrogels are favoured by researchers due to their high water content,degradability and good biocompatibility.This paper describes the hydrogel sources,roles and applications.According to the different types of stimuli,hydrogels are classified into three categories:physical,chemical and biochemical responses,and the applications of different stimuli-responsive hydrogels in bone tissue engineering are summarised.Stimuli-responsive hydrogels can form a semi-solid with good adhesion based on different physiological environments,which can carry a variety of bone-enhancing bioactive factors,drugs and cells,and have a long retention time in the local area,which is conducive to a long period of controlled release;they can also form a scaffold for constructing tissue repair,which can jointly promote the repair of bone injury sites.However,it also has many defects,such as poor biocompatibility,immunogenicity and mechanical stability.Further studies are still needed in the future to facilitate its clinical translation.

Synthesis of stimuli-responsive pillararene-based supramolecular polymer materials for the detection and separation of metal ions

A stimuli-responsive supramolecular polymer network(G-(CN)_(2)⊂BXDSP5)with aggregation-induced emission(AIE)properties has been efficiently constructed by host-guest interactions between pillar[5]arene derivative BXDSP5 and a homoditopic guest G-(CN)_(2),which shows not only excellent fluorescence properties due to the AIE effect but also desirable ion-sensing abilities in both solution and solid states,holding great potential in the applicable fluorescence detection for Fe^(3+).The resultant G-(CN)_(2)⊂BXDSP5 can be transformed into supramolecular polymer gel at high concentration via multiple noncovalent interactions,showing multi-stimuli-responsiveness in response to temperature change,mechanical force,and competitive agent.Meanwhile,the xerogel of supramolecular polymer material has been successfully used to remove Fe^(3+)from water with high adsorption efficiency.In addition,an ionresponsive film based on supramolecular polymer has also been developed,which can serve as a practical and convenient fluorescence test kit for detecting Fe^(3+).

ROS-responsive drug delivery systems for biomedical applications

In the field of biomedicine, stimuli-responsive drug delivery systems(DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species(ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes,whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore,ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.

Engineering cancer vaccines using stimuli-responsive biomaterials

Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.

Facile Synthesis of Cellulose Acetate Ultrafiltration Membrane with Stimuli-Responsiveness to pH and Temperature Using the Additive of F127-b-PDMAEMA

We fabricate a novel cellulose acetate （CA） ultrafiltration membrane modified by block copolymer F127-b- PDMAEMA, which is synthesized using F127 and DMAEMA via the ARGET ATRP method. Compared to conven- tional ultrafiltration membranes, the incorporation of both F 127 and PDMAEMA can not only readily increase the hydrophilicity of the membrane, but also exhibit stimuli-responsiveness to temperature and pH. Fourier transform infrared spectroscopy （FT-IR）, nuclear magnetic resonance spectroscopy （NMR）, and gel permeation chromatog- raphy （GPC） are employed to analyze the structure of the F 127-b-PDMAEMA. The membrane properties are eval- uated via scanning electron microscope （SEM） imaging, porosity test, automatic target recognition Fourier trans- form infrared spectroscopy （ATR-FTIR）, water contact angle test and permeation test. The results indicate that the F 127-b-PDMAEMA is an excellent pore agent, which contributes to an enhancement of the membrane in sensitivity to temperature and pH. The modified membrane also exhibits lower water contact angle （64.5~）, which is attributed to the good anti-fouling performance and high water permeation.

Design, preparation and pharmacodynamics of ICG-Fe(Ⅲ) based HCPT nanocrystals against cancer

The use of nanocrystal technology to manufacture drug delivery systems intended to enhance therapeutic efficacy has attracted the attention of the pharmaceutical industry.However,the clinical application of nanocrystal drugs for injection is restricted by Ostwald ripening and the large-scale use of stabilizers such as polysorbate and lecithin,which have potential toxicity risks including hemolysis and allergies.Here,we designed an amorphous nanocrystal drug complex(IHNC),which is stabilizer-free and composed of indocyanine green(ICG)framework loading with a chemotherapeutic agent of 10-hydroxycamptothecin(HCPT).Considering the possibility of industrial manufacturing,IHNC was simply prepared with the assistance of ferric ion(III)via supramolecular assembly strategy.The theoretical result of Materials Studio simulation indicated that the prepared ICG-Fe(III)framework showed a stable spherical structure with the appropriate cavity for encapsulating the two drugs of HCPT and ICG with equal mass ratio.The IHNC was stable at physiological pH,with excellent PTT/PDT efficacy,and in vivo probing characteristics.The nanoscale size and reductive stimuli-responsiveness can be conducive to drug accumulation into the tumor site and rapid unloading of cargo.Moreover,such combination therapy showed synergistic photo/chemotherapy effect against 4T1 breast cancer and its tumor inhibition rate even up to 79.4%.These findings demonstrated that the nanocrystal drug delivery strategy could avoid the use of stabilizers and provide a new strategy for drug delivery for combination therapy.

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.

Dual stimuli-responsive polyurethane-based hydrogels as smart drug delivery carriers for the advanced treatment of chronic skin wounds

The design of multi-stimuli-responsive vehicles for the controlled and localized release of drugs is a challenging issue increasingly catching the attention of many research groups working on the advanced treatment of hard-to-close wounds.In this work,a thermo-and pH-responsive hydrogel(P-CHP407)was prepared from an ad hoc synthesized amphiphilic poly(ether urethane)(CHP407)exposing a significant amount of-COOH groups(8.8±0.9 nmol/g_(polymer)).The exposure of acid moieties in P-CHP407 hydrogel led to slightly lower initial gelation temperature(12.1◦C vs.14.6◦C,respectively)and gelation rate than CHP407 hydrogel,as rheologically assessed.Nanoscale hydrogel characterization by Low Field NMR(LF-NMR)spectroscopy suggested that the presence of carboxylic groups in P-CHP407 caused the formation of bigger micelles with a thicker hydrated shell than CHP407 hydrogels,as further proved by Dynamic Light Scattering analyses.In addition,P-CHP407 hydrogel showed improved capability to change its internal pH compared to CHP407 one when incubated with an alkaline buffer(pH 8)(e.g.,pH_(change_5min)=3.76 and 1.32,respectively).Moreover,LF-NMR characterization suggested a stronger alkaline-pH-induced interaction of water molecules with micelles exposing-COOH groups.Lastly,the hydrogels were found biocompatible according to ISO 10993 and able to load and release Ibuprofen:delivery kinetics of Ibuprofen was enhanced by P-CHP407 hydrogels at alkaline pH,suggesting their potential use as smart delivery systems in the treatment of chronic infected wounds.