Responsive Supramolecular Polymers for Diagnosis and Treatment.

Stimuli-responsive supramolecular polymers are ordered nanosized materials that are held together by non-covalent interactions (hydrogen-bonding, metal-ligand coordination, π-stacking and, host-guest interactions) and can reversibly undergo self-assembly. Their non-covalent nature endows supramolecular polymers with the ability to respond to external stimuli (temperature, light, ultrasound, electric/magnetic field) or environmental changes (temperature, pH, redox potential, enzyme activity), making them attractive candidates for a variety of biomedical applications. To date, supramolecular research has largely evolved in the development of smart water-soluble self-assemblies with the aim of mimicking the biological function of natural supramolecular systems. Indeed, there is a wide variety of synthetic biomaterials formulated with responsiveness to control and trigger, or not to trigger, aqueous self-assembly. The design of responsive supramolecular polymers ranges from the use of hydrophobic cores (i.e., benzene-1,3,5-tricarboxamide) to the introduction of macrocyclic hosts (i.e., cyclodextrins). In this review, we summarize the most relevant advances achieved in the design of stimuli-responsive supramolecular systems used to control transport and release of both diagnosis agents and therapeutic drugs in order to prevent, diagnose, and treat human diseases.

Stimuli responsiveness of recent biomacromolecular systems (concept to market): A review.

Stimuli responsive delivery systems, also known as smart/intelligent drug delivery systems, are specialized delivery vehicles designed to provide spatiotemporal control over drug release at target sites in various diseased conditions, including tumor, inflammation and many others. Recent advances in the design and development of a wide variety of stimuli-responsive (pH, redox, enzyme, temperature) materials have resulted in their widespread use in drug delivery and tissue engineering. The aim of this review is to provide an insight of recent nanoparticulate drug delivery systems including polymeric nanoparticles, dendrimers, lipid-based nanoparticles and the design of new polymer-drug conjugates (PDCs), with a major emphasis on natural along with synthetic commercial polymers used in their construction. Special focus has been placed on stimuli-responsive polymeric materials, their preparation methods, and the design of novel single and multiple stimuli-responsive materials that can provide controlled drug release in response a specific stimulus. These stimuli-sensitive drug nanoparticulate systems have exhibited varying degrees of substitution with enhanced in vitro/in vivo release. However, in an attempt to further increase drug release, new dual and multi-stimuli based natural polymeric nanocarriers have been investigated which respond to a mixture of two or more signals and are awaiting clinical trials. The translation of biopolymeric directed stimuli-sensitive drug delivery systems in clinic demands a thorough knowledge of its mechanism and drug release pattern in order to produce affordable and patient friendly products.

Liquid Metal Nanocores Initiated Construction of Smart DNA-Polymer Microgels with Programmable and Regulable Functions and Near-Infrared Light-Driven Locomotion.

Due to their sequence-directed functions and excellent biocompatibility, smart DNA microgels have attracted considerable research interest, and the combination of DNA microgels with functional nanostructures can further expand their applications in biosensing and biomedicine. Gallium-based liquid metals (LMs) exhibiting both fluidic and metallic properties hold great promise for the development of smart soft materials; in particular, LM particles upon sonication can mediate radical-initiated polymerization reactions, thus allowing the combination of LMs and polymeric matrix to construct "soft-soft" materials. Herein, by forming active surfaces under sonication, LM nanoparticles (LM NPs) initiated localized radical polymerization reactions allow the combination of functional DNA units and different polymeric backbones to yield multifunctional core/shell microgels. The localized polymerization reaction allows fine control of the microgel compositions, and smart DNA microgels with tunable catalytic activities can be constructed. Moreover, due to the excellent photothermal effect of LM NPs, the resulting temperature gradient between microgels and surrounding solution upon NIR light irradiation can drive the oriented locomotion of the microgels, and remote control of the activity of these smart microgels can be achieved. These microgels may hold promise for various applications, such as the development of in vivo and in vitro biosensing and drug delivery systems.

Efficient and Targeted siRNA Delivery to M2 Macrophages by Smart Polymer Blends for M1 Macrophage Repolarization as a Promising Strategy for Future Cancer Treatment.

Cancer remains an issue on a global scale. It is estimated that nearly 10 million people succumbed to cancer worldwide in 2020. New treatment options are urgently needed. A promising approach is a conversion of tumor-promoting M2 tumor-associated macrophages (TAMs) as part of the tumor microenvironment to tumor-suppressive M1 TAMs by small interfering RNA (siRNA). In this work, we present a well-characterized polymeric nanocarrier system capable of targeting M2 TAMs by a ligand-receptor interaction. Therefore, we developed a blended PEI-based polymeric nanoparticle system conjugated with mannose, which is internalized after interaction with macrophage mannose receptors (MMRs), showing low cytotoxicity and negligible IL-6 activation. The PEI-PCL-PEI (5 kDa-5 kDa-5 kDa) and Man-PEG-PCL (2 kDa-2 kDa) blended siRNA delivery system was optimized for maximum targeting capability and efficient endosomal escape by evaluation of different polymer and N/P ratios. The nanoparticles were formulated by surface acoustic wave-assisted microfluidics, achieving a size of ∼80 nm and a zeta potential of approximately +10 mV. Special attention was given to the endosomal escape as the so-called bottleneck of RNA drug delivery. To estimate the endosomal escape capability of the nanocarrier system, we developed a prediction method by evaluating the particle stability via the inflection temperature. Our predictions were then verified in an in vitro setting by applying confocal microscopy. For cellular experiments, however, human THP-1 cells were polarized to M2 macrophages by cytokine treatment and validated through MMR expression. To show the efficiency of the nanoparticle system, GAPDH and IκBα knockdown was performed in the presence or absence of an MMR blocking excess of mannan. Cellular uptake, GAPDH knockdown, and NF-κB western blot confirmed efficient mannose targeting. Herein, we presented a well-characterized nanoparticle delivery system and a promising approach for targeting M2 macrophages by a mannose-MMR interaction.

Switching it Up: The Promise of Stimuli-Responsive Polymer Systems in Biomedical Science.

Responsive polymer systems have the ability to change properties or behavior in response to external stimuli. The properties of responsive polymer systems can be fine-tuned by adjusting the stimuli, enabling tailored responses for specific applications. These systems have applications in drug delivery, biosensors, tissue engineering, and more, as their ability to adapt and respond to dynamic environments leads to improved performance. However, challenges such as synthesis complexity, sensitivity limitations, and manufacturing issues need to be addressed for successful implementation. In our review, we provide a comprehensive summary on stimuli-responsive polymer systems, delving into the intricacies of their mechanisms and actions. Future developments should focus on precision medicine, multifunctionality, reversibility, bioinspired designs, and integration with advanced technologies, driving the dynamic growth of sensitive polymer systems in biomedical applications.

Dual Stimulus-Responsive Enzyme@Metal-Organic Framework-Polymer Composites toward Enhanced Catalytic Performance for Visual Detection of Glucose.

Enzyme immobilization on a metal-organic framework (enzyme@MOF) has been proven to be a promising strategy for boosting catalysis and biosensing applications. However, promoting the catalytic performance of polymer-modified enzyme@MOF composites remains an ongoing challenge. Herein, a protocol for enzyme immobilization was designed by using a smart polymer-modified MOF (UiO-66-NH2, UN) as the support. Through in situ polymerization, the dual stimulus-responsive poly(N-2-dimethylamino ethyl methacrylate) (PDM) was prepared. The PDM as a "soft cage" protected the immobilized glucose oxidase (GOx)-horseradish peroxidase (HRP) on the surface of the rigid UN. The confinement effect was generated by varying the temperature and pH, thereby improving the catalytic activity of the GOx-HRP@UN-PDM composites. In comparison with free enzymes, the fabricated composites exhibited an 8.9-fold enhancement in catalytic performance (Vmax) at pH 5.0 and 49 °C. Furthermore, relying on a cascade reaction generated in the composites, an assay was developed for the visual detection of glucose in rat serum. This study introduces a groundbreaking approach for the construction of smart enzyme@MOF-polymer composites with high catalytic activity for sensitive monitoring of biomolecules.

Stimuli-Responsive Polymer-Based Nanosystems for Cancer Theranostics.

Stimuli-responsive polymers can respond to internal stimuli, such as reactive oxygen species (ROS), glutathione (GSH), and pH, biological stimuli, such as enzymes, and external stimuli, such as lasers and ultrasound, etc., by changing their hydrophobicity/hydrophilicity, degradability, ionizability, etc., and thus have been widely used in biomedical applications. Due to the characteristics of the tumor microenvironment (TME), stimuli-responsive polymers that cater specifically to the TME have been extensively used to prepare smart nanovehicles for the targeted delivery of therapeutic and diagnostic agents to tumor tissues. Compared to conventional drug delivery nanosystems, TME-responsive nanosystems have many advantages, such as high sensitivity, broad applicability among different tumors, functional versatility, and improved biosafety. In recent years, a great deal of research has been devoted to engineering efficient stimuli-responsive polymeric nanosystems, and significant improvement has been made to both cancer diagnosis and therapy. In this review, we summarize some recent research advances involving the use of stimuli-responsive polymer nanocarriers in drug delivery, tumor imaging, therapy, and theranostics. Various chemical stimuli will be described in the context of stimuli-responsive nanosystems. Accordingly, the functional chemical groups responsible for the responsiveness and the strategies to incorporate these groups into the polymer will be discussed in detail. With the research on this topic expending at a fast pace, some innovative concepts, such as sequential and cascade drug release, NIR-II imaging, and multifunctional formulations, have emerged as popular strategies for enhanced performance, which will also be included here with up-to-date illustrations. We hope that this review will offer valuable insights for the selection and optimization of stimuli-responsive polymers to help accelerate their future applications in cancer diagnosis and treatment.

Smart Responsive Microneedles for Controlled Drug Delivery.

As an emerging technology, microneedles offer advantages such as painless administration, good biocompatibility, and ease of self-administration, so as to effectively treat various diseases, such as diabetes, wound repair, tumor treatment and so on. How to regulate the release behavior of loaded drugs in polymer microneedles is the core element of transdermal drug delivery. As an emerging on-demand drug-delivery technology, intelligent responsive microneedles can achieve local accurate release of drugs according to external stimuli or internal physiological environment changes. This review focuses on the research efforts in smart responsive polymer microneedles at home and abroad in recent years. It summarizes the response mechanisms based on various stimuli and their respective application scenarios. Utilizing innovative, responsive microneedle systems offers a convenient and precise targeted drug delivery method, holding significant research implications in transdermal drug administration. Safety and efficacy will remain the key areas of continuous efforts for research scholars in the future.

Recent advances in tailoring stimuli-responsive hybrid scaffolds for cardiac tissue engineering and allied applications.

To recapitulate bio-physical properties and functional behaviour of native heart tissues, recent tissue engineering-based approaches are focused on developing smart/stimuli-responsive materials for interfacing cardiac cells. Overcoming the drawbacks of the traditionally used biomaterials, these smart materials portray outstanding mechanical and conductive properties while promoting cell-cell interaction and cell-matrix transduction cues in such excitable tissues. To date, a large number of stimuli-responsive materials have been employed for interfacing cardiac tissues alone or in combination with natural/synthetic materials for cardiac tissue engineering. However, their comprehensive classification and a comparative analysis of the role played by these materials in regulating cardiac cell behaviour and in vivo metabolism are much less discussed. In an attempt to cover the recent advances in fabricating stimuli-responsive biomaterials for engineering cardiac tissues, this review details the role of these materials in modulating cardiomyocyte behaviour, functionality and surrounding matrix properties. Furthermore, concerns and challenges regarding the clinical translation of these materials and the possibility of using such materials for the fabrication of bio-actuators and bioelectronic devices are discussed.

Strategy for Nonenzymatic Harvesting of Cells via Decoupling of Adhesive and Disjoining Domains of Nanostructured Stimulus-Responsive Polymer Films.

The nanostructured polymer film introduces a novel mechanism of nonenzymatic cell harvesting by decoupling solid cell-adhesive and soft stimulus-responsive cell-disjoining areas on the surface. The key characteristics of this architecture are the decoupling of adhesion from detachment and the impermeability to the integrin protein complex of the adhesive domains. This surface design eliminates inherent limitations of thermoresponsive coatings, namely, the necessity for the precise thickness of the coating, grafting or cross-linking density, and material of the basal substrate. The concept is demonstrated with nanostructured thermoresponsive films made of cell-adhesive epoxy photoresist domains and cell-disjoining poly(N-isopropylacrylamide) brush domains.

Designing Multimodal ON-OFF Nanoswitches of DNA-Functionalized Nanoparticles by Stimuli-Responsive Polymers.

It is a challenging task to realize highly reversible ON-OFF nanoswitches over a wide range of temperatures, which emerge as a versatile toolbox for use in nanobiotechnology. Herein, nanoparticles (NPs) bifunctionalized by DNA strands and stimuli-responsive polymers are proposed to construct multimodal ON-OFF nanoswitches by the coarse-grained model. The successful achievement of multimodal ON-OFF nanoswitches for bifunctionalized NPs at lower temperatures is attributed to the synergistic effects of the contraction and expansion configurations of stimuli-responsive polymers, combined with the hybridization-dehybridization event of DNA strands. Importantly, our simulations isolate the conditions of programmable self-assembly of bifunctionalized NPs to realize the multimodal ON-OFF nanoswitches by the changes of temperature and chain rigidity. In addition, it is found that the bifunctionalized NPs in the ON state display anisotropic and patchy features due to an introduction of stimuli-responsive polymers. Our simulation results provide fundamental insights on qualitative predictions of ON/OFF states of DNA-based NPs, which can aid in realizing a set of ON-OFF nanoswitches by the rational design of functionalization molecules.

Diffusion-Limited Processes in Hydrogels with Chosen Applications from Drug Delivery to Electronic Components.

Diffusion is one of the key nature processes which plays an important role in respiration, digestion, and nutrient transport in cells. In this regard, the present article aims to review various diffusion approaches used to fabricate different functional materials based on hydrogels, unique examples of materials that control diffusion. They have found applications in fields such as drug encapsulation and delivery, nutrient delivery in agriculture, developing materials for regenerative medicine, and creating stimuli-responsive materials in soft robotics and microrobotics. In addition, mechanisms of release and drug diffusion kinetics as key tools for material design are discussed.

Stimuli-Responsive Polymer Nanoprobes Intended for Fluorescence-Guided Surgery of Malignant Head-and-Neck Tumors and Metastases.

Nano-sized carriers are widely studied as suitable candidates for the advanced delivery of various bioactive molecules such as drugs and diagnostics. Herein, the development of long-circulating stimuli-responsive polymer nanoprobes tailored for the fluorescently-guided surgery of solid tumors is reported. Nanoprobes are designed as long-circulating nanosystems preferably accumulated in solid tumors due to the Enhanced permeability and retention effect, so they act as a tumor microenvironment-sensitive activatable diagnostic. This study designs polymer probes differing in the structure of the spacer between the polymer carrier and Cy7 by employing pH-sensitive spacers, oligopeptide spacers susceptible to cathepsin B-catalyzed enzymatic hydrolysis, and non-degradable control spacer. Increased accumulation of the nanoprobes in the tumor tissue coupled with stimuli-sensitive release behavior and subsequent activation of the fluorescent signal upon dye release facilitated favorable tumor-to-background ratio, a key feature for fluorescence-guided surgery. The probes show excellent diagnostic potential for the surgical removal of intraperitoneal metastasis and orthotopic head and neck tumors with very high efficacy and accuracy. In addition, the combination of macroscopic resection followed by fluorescence-guided surgery using developed probes enable the identification and resection of most of the CAL33 intraperitoneal metastases with total tumor burden reduced to 97.2%.

A Novel Smart CFRP Cable Based on Optical Electrical Co-Sensing for Full-Process Prestress Monitoring of Structures.

Carbon-fiber-reinforced polymer (CFRP) is a type of composite material with many superior performances, such as high tensile strength, light weight, corrosion resistance, good fatigue, and creep performance. As a result, CFRP cables have great potential to replace steel cables in prestressed concrete structures. However, the technology to monitor the stress state in real-time throughout the entire life cycle is very important in the application of CFRP cables. Therefore, an optical-electrical co-sensing CFRP cable (OECSCFRP cable) was designed and manufactured in this paper. Firstly, a brief description is outlined for the production technology of the CFRP-DOFS bar, CFRP-CCFPI bar, and CFRP cable anchorage technology. Subsequently, the sensing and mechanical properties of the OECS-CFRP cable were characterized by serious experiments. Finally, the OECS-CFRP cable was used for the prestress monitoring of an unbonded prestressed RC beam to verify the feasibility of the actual structure. The results show that the main static performance indexes of DOFS and CCFPI meet the requirements of civil engineering. In the loading test of the prestressed beam, the OECS-CFRP cable can effectively monitor the cable force and the midspan defection of the beam so as to obtain the stiffness degradation of the prestressed beam under different loads.

Fabrication of Dual-Stimuli-Responsive Polymer Vesicles for Regulation of Enzymolysis Efficiency in A Cascade Reaction.

Enzymatic cascade reactions in confined microenvironments play important roles in cellular chemical transformation. Controlling enzymatic efficiency and eliminating substrate interference in cascade reactions is of great significance. To this end, a vesicle composed of poly(styrene-maleic anhydride-N-isopropylacrylamide)(P(S-M-NIP)) and functionalized with 1,2-bis(10,12- tricosadiynoyl)-sn-glycero-3-phosphocholine (DC89 PC) was designed herein. Based on the thermo-sensitive property of P(S-M-NIP) and the photo-responsive property of DC89 PC, a serial of dual-stimuli-responsive nanoreactors was constructed via enzymes encapsulation to tune their enzymolysis efficiencies. A kinetics study of the glucose oxidase-encapsulated nanoreactor indicated that its enzymolysis velocity increased 2.1- and 1.6-fold under heating and the ultraviolet (UV)-light irradiation, respectively. Consequently, an enzymatic cascade reaction in the proposed enzyme reactor encapsulated with ß-galactosidase and glucose oxidase was investigated. The results revealed a 2.9-fold enhancement in enzymolysis efficiency by changing the ambient temperature under UV irradiation. The dual-stimuli-responsive polymer vesicles could also eliminate H2 O2 interference during the enzymatic cascade reaction. The vesicles demonstrated potential for switch-membrane-permeability, while, the confined microenvironment played a key role in regulating the reactions upon the temperature change and the presence of UV light. Our synthetic multi-organelle-like system provides a new way to mimic the control of cascade reaction catalytic processes by programming the "open/close" sates of the nanocapsules.

Visualizing Drug Release from a Stimuli-Responsive Soft Material Based on Amine-Thiol Displacement.

In this research, we developed a photoluminescent platform using amine-coupled fluorophores, generated from a single conjugate acceptor containing bis-vinylogous thioesters. Based on the experimental and computational results, the fluorescence turn-on mechanism was proposed to be charge separated induced energy radiative transition for the amine-coupled fluorophore, while the sulfur-containing precursor was not fluorescent since the energy internal conversion occurred through vibrational 2RS- (R represents alkyl groups) as energy acceptor(s). Further utilizing the conjugate acceptor, we establish a new fluorogenic approach via a highly cross-linked soft material to selectively detect cysteine under neutral aqueous conditions. Turn-on fluorescence emission and macroscopic degradation occurred in the presence of cysteine as the stimuli, which can be visually tracked due to the generation of an optical indicator and the cleavage of linkers within the matrix. Furthermore, a novel drug delivery system was constructed, achieving controlled release of sulfhydryl drug (6-mercaptopurine) which was tracked by photoluminescence and high-performance liquid chromatography. The photoluminescent molecules developed herein are suitable for visualizing polymeric degradation, making them suitable for additional "smart" material applications.

Novel electrochemical sensing platform basing on di-functional stimuli-responsive imprinted polymers for simultaneous extraction and determination of metronidazole.

A novel magnetic-controlled electrochemical sensor has been fabricated by combined photo-responsive surface molecular imprinted polymers (P-SMIPs) and electrochemical sensor. In particular, the P-SMIPs were obtained by living radical polymerization of photo-responsive functional monomer onto the magnetic Fe3O4 modified multi-walled carbon nanotubes nanocomposites. The magnetic glassy carbon electrode was introduced to make the anchoring and removal of P-SMIPs onto the magnetic-controlled glassy carbon electrode easy to manipulate. Driven by UV/vis light, the platform performs releasing and absorption of metronidazole basing on conformational variations of the photo-responsive monomer at the receptor sites part in the P-SMIPs. This process can be tested by the photo-responsive variations of metronidazole electrochemical signal. As the consequence, extracting of P-SMIPs sensor can be conveniently triggered by the controllable UV light intervention measure, leading to effectively improve in both analytes mass transfer rate to the receiving media and extraction efficiency. The experimental result indicated that the excellent recoveries of metronidazole were varied between 77.9% and 89.9% with RSDs ≤4.87% in the biological samples. Therefore, the P-SMIPs sensor shows satisfactory potential in reusable extractions that can be recycled several times with no significant loss of activity, and this utilization strategy can be extended to other analytes, achieving manifold applications of pharmaceutical and environmental.

Smart stimuli-responsive chitosan hydrogel for drug delivery: A review.

Smart stimuli-responsive materials can respond to different signals (pH, temperature, light, electricity, etc.), and they have become a hot research topic for drug delivery. As a polysaccharide polymer with excellent biocompatibility, chitosan can be obtained from diverse natural sources. Chitosan hydrogels with different stimuli-response capabilities are widely applied in the drug delivery field. This review highlights and discusses the research progress on chitosan hydrogels concerning their stimuli-responsive capabilities. The feature of various stimuli-responsive kinds of hydrogels is outlined, and their potential use of drug delivery is summarized. Furthermore, the questions and future development chances of stimuli-responsive chitosan hydrogels are analyzed by comparing the current published literature, and the directions for the intelligent development of chitosan hydrogels are discussed.

Conductive polymers and composites-based systems: An incipient stride in drug delivery and therapeutics realm.

Novel therapies and drug delivery systems (DDS) emphasis on localized, personalized, triggered, and regulated drug administration have heavily implicated electrically responsive DDS. An ideal DDS must deliver drugs to the target region at therapeutically effective concentrations to elicit a pharmacological response, resulting in better prophylaxis of the disease and the treatment. Biodegradable polymers are frequently employed for in-vivo long-term release; however, dose dumping can be anticipated. As a result, current DDSs can be tagged as dubbed "Smart Biomaterials" since they only focus on an on-demand cargo release in response to a trigger or stimulation. These organic materials have been recognized for their metal-like conductivity, as well as their mechanical stability and ease of production. These biomaterials can be programmed to respond to both internal and external stimuli. External pulsed triggers are required for extrinsic stimuli-responsive materials, whereas intrinsic stimuli-responsive materials rely on localized changes in the tissue environment. Furthermore, these materials have the ability to deliver active pharmaceutical agents at a varied concentration levels and across a broad spectrum of action. Drug delivery, biomedical implant technology, biosensor technology, and tissue engineering can be listed as a few prominent applications that have sparked immense interest for conductive polymers-based research and advancements in academia as well as in industry. This review comprehensively covers a cutting-edge collection of electrically conductive polymers and composites, and provide detailed insights of recent trends and advancements allied to conductive polymers for their potential applicability in an array of diverse meadows primarily focusing on drug delivery, biosensing and therapeutics. Furthermore, progressions in their synthesis, structural and functional properties have been presented in conjunction with futuristic directions for the smooth clinical translations.