Responsive Hydrogels Research Articles

Guar gum-based stimuli responsive hydrogels for sustained release of diclofenac sodium

In the current study, hydrogels for the controlled release of diclofenac sodium were synthesized from graphene oxide-reinforced guar gum and poly (N-vinyl-2-pyrrolidone) using the Solution Casting Technique. Varying concentrations of 3-Glycidyloxypropyl trimethoxysilane (GLYMO) were employed for the crosslinking of hydrogels. Further, the characterization of hydrogels was carried out using different techniques such as Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction, thermal analysis and scanning electron microscope. The FTIR investigations reveals particular functionalities and development of hydrogel interfaces. While thermal analysis prophesied that, improvement in forces among hydrogel components is directly proportional to the GLYMO concentration. In-vitro biodegradation test and cell viability assay against HEK-293 cell lines confirmed their biodegradable and biocompatible nature. GPG-32 demonstrated maximum antibacterial activity against P.aeruginosa and E.coli strains. The maximum swelling 2001 % and 1814 % in distilled water were recorded for GPG (control) and GPG-8 respectively that obeyed Fick's law. Hydrogels displayed high swelling responses at pH 6 in buffer and non-buffer solutions. In 2.5 h, 88.7 % diclofenac sodium was released which was determined by UV visible spectrophotometer. In conclusion, guar gum-based non-toxic, biocompatible and biodegradable hydrogels would be a model platform for targeting inflammation and pains. Furthermore, improved mechanical and viscoelastic behavior of hydrogels could also be explored for making drug loaded dressings for wound healing applications.

Functional drug-delivery hydrogels for oral and maxillofacial wound healing.

The repair process for oral and maxillofacial injuries involves hemostasis, inflammation, proliferation, and remodeling. Injury repair involves a variety of cells, including platelets, immune cells, fibroblasts, and various cytokines. Rapid and adequate healing of oral and maxillofacial trauma is a major concern to patients. Functional drug-delivery hydrogels play an active role in promoting wound healing and have shown unique advantages in wound dressings. Functional hydrogels promote wound healing through their adhesive, anti-inflammatory, antioxidant, antibacterial, hemostatic, angiogenic, and re-epithelialization-promoting properties, effectively sealing wounds and reducing inflammation. In addition, functional hydrogels can respond to changes in temperature, light, magnetic fields, pH, and reactive oxygen species to release drugs, enabling precise treatment. Furthermore, hydrogels can deliver various cargos that promote healing, including nucleic acids, cytokines, small-molecule drugs, stem cells, exosomes, and nanomaterials. Therefore, functional drug-delivery hydrogels have a positive impact on the healing of oral and maxillofacial injuries. This review describes the oral mucosal structure and healing process and summarizes the currently available responsive hydrogels used to promote wound healing.

Microenvironment responsive nanocomposite hydrogel with NIR photothermal therapy, vascularization and anti-inflammation for diabetic infected wound healing.

Bacterial infection, excessive inflammation and damaging blood vessels network are the major factors to delay the healing of diabetic ulcer. At present, most of wound repair materials are passive and can't response to the wound microenvironment, resulting in a low utilization of bioactive substances and hence a poor therapeutic effect. Therefore, it's essential to design an intelligent wound dressing responsive to the wound microenvironment to achieve the release of drugs on-demand on the basis of multifunctionality. In this work, metformin-laden CuPDA NPs composite hydrogel (Met@ CuPDA NPs/HG) was fabricated by dynamic phenylborate bonding of gelatin modified by dopamine (Gel-DA), Cu-loaded polydopamine nanoparticles (CuPDA NPs) with hyaluronic acid modified by phenyl boronate acid (HA-PBA), which possessed good injectability, self-healing, adhesive and DPPH scavenging performance. The slow release of metformin was achieved by the interaction with CuPDA NPs, boric groups (B-N coordination) and the constraint of hydrogel network. Metformin had a pH and glucose responsive release behavior to treat different wound microenvironment intelligently. Moreover, CuPDA NPs endowed the hydrogel excellent photothermal responsiveness to kill bacteria of >95% within 10min and also the slow release of Cu2+ to protect wound from infection for a long time. Met@ CuPDA NPs/HG also recruited cells to a certain direction and promoted vascularization by releasing Cu2+. More importantly, Met@CuPDA NPs/HG effectively decreased the inflammation by eliminating ROS and inhibiting the activation of NF-κB pathway. Animal experiments demonstrated that Met@CuPDA NPs/HG significantly promoted wound healing of diabetic SD rats by killing bacteria, inhibiting inflammation, improving angiogenesis and accelerating the deposition of ECM and collagen. Therefore, Met@CuPDA NPs/HG had a great application potential for diabetic wound healing.

Development and characterization of pH responsive sodium alginate hydrogel containing metal-phenolic network for anthocyanin delivery

Favorable hydrogels can be used as a material to deliver bioactive molecules and improve the stability of bioactive substances, while their safety needs to be improved. In this study, protocatechuic acid (PCA) and Fe3+ were rapidly self-assembled to form a metal-phenolic network under different pH conditions, and then sodium alginate (SA) was added to prepare the SA/PCA/Fe hydrogel without adding other chemical reagents. The structural characteristic of SA/PCA/Fe hydrogel was characterized by infrared spectroscopy, X-ray diffraction analysis and scanning electron microscopy. The results showed that the structures of SA/PCA/Fe hydrogels prepared at different pH values were significantly different. The texture analysis, water-holding measurement and rheological analysis indicated that the SA/PCA/Fe hydrogel showed higher gel strength, water holding capacity and storage modulus. Thermogravimetric analysis illuminated that the SA/PCA/Fe hydrogel enhanced the thermal stability of free anthocyanins through encapsulating anthocyanins. Moreover, in vitro simulated digestion experiment revealed that SA/PCA/Fe hydrogel could control the release of anthocyanins in the simulated gastrointestinal tract. To sum up, this present study might provide a safer and feasible way for the delivery of bioactive substances.

Environment-Interactive Programmable Deformation of Electronically Innervated Synergistic Fluorescence-Color/Shape Changeable Hydrogel Actuators.

Utilization of life-like hydrogels to replicate synergistic shape/color changeable behaviors of living organisms has been long envisaged to produce robust functional integrated soft actuators/robots. However, it remains challenging to construct such hydrogel systems with integrated functionality of remote, localized and environment-interactive control over synergistic discoloration/actuation. Herein, inspired by the evolution-optimized bioelectricity stimulus and multilayer structure of natural reptile skins, electronically innervated fluorescence-color switchable hydrogel actuating systems with bio-inspired multilayer structure comprising of responsive fluorescent hydrogel sheet and conductive Graphene/PDMS film with electrothermal effect is presented. Such rational structure enables remote control over synergistic fluorescence-color and shape changes of the systems via the cascading "electrical trigger-Joule heat generation-hydrogel shrinkage" mechanism. Consequently, local/sequential control of discoloration/actuation are achieved due to the highly controllable electrical stimulus in terms of amplitude and circuit design. Furthermore, by joint use with acoustic sensors, soft chameleon robots with unprecedented environment-interactive adaptation are demonstrated, which can intelligently sense environment signals to adjust their color/shape-changeable behaviors. This work opens previously unidentified avenues for functional integrated soft actuators/robots and will inspire life-like intelligent systems for versatile uses.

Spatiotemporally Responsive Hydrogel Dressing with Self-Adaptive Antibacterial Activity and Cell Compatibility for Wound Sealing and Healing.

Adhesive hydrogels containing quaternary ammonium salt (QAS) moieties have shown attractive advantages in treatment for acute wounds, attributed to their high performances in wound sealing and sterilization. However, the introduction of QAS commonly leads to high cytotoxicity and adhesive deterioration. Herein, aimed to solve these two issues, a self-adaptive dressing with delicate spatiotemporal responsiveness is developed by employing cellulose sulfate (CS) as dynamic layers to coat QAS-based hydrogel. In detail, due to the acid environment of wound in the early stages of healing, the CS coating will quickly detach to expose the active QAS groups for maximum disinfectant efficacy; meanwhile, as the wound gradually heals and recovers to a neutral pH, the CS will remain stable to keep QAS screened, realizing a high cell growth-promoting activity for epithelium regeneration. Additionally, attributed to the synergy of temporary hydrophobicity by CS and slow water absorption kinetics of the hydrogel, the resultant dressing possesses outstanding wound sealing and hemostasis performance. At last, this work anticipates this approach to intelligent wound dressings based on dynamic and responsive intermolecular interaction can also be applied to a wide range of self-adaptive biomedical materials employing different chemistries for applications in medical therapy and health monitoring.

Thermal responsive smart lanthanide luminescent hydrogel actuator

Among stimuli-responsive soft materials, thermal responsive hydrogels are the most attractive one because temperature is the most easily regulated external stimuli. We here report a thermal responsive bilayer smart luminescent hydrogel actuator with tough mechanical strength and thermal reversible deformation behavior. The bilayer hydrogel is composed of Poly(N-isopropylacrylamide)-Laponite-Tb complex (PNIPAM-Lap-Tb·L3) layer and Poly(N,N-dimethylacrylamide)-Laponite-Eu complex (PDMA-Lap-Eu·L3) layer. Upon alternative heating and cooling, the PNIPAM-Lap-Tb·L3 layer undergoes reversible shrink and expansion, while the PDMA-Lap-Eu·L3 layer is not affected, leading to asymmetric deformation behavior. The luminescent intensity of the bilayer hydrogel was enhanced by heating, and the maximum bending angle was 371° in 15 min. By processing the bilayer hydrogel into complex 2D and 3D structure, we further demonstrate their great potential as smart soft actuators.

Surface-Active Thermally Responsive Hydrogels by Emulsion Sedimentation for Smart Window Applications

Surface-Active Thermally Responsive Hydrogels by Emulsion Sedimentation for Smart Window Applications

PH and temperature dual-responsive hydrogel actuator with bidirectional bending behavior and ultra large bending angle

Smart hydrogels have received attentions for the great potentials in biomedical and robots applications. However, the deformation performance of hydrogels still needs to be improved, especially for the pH and thermal dual responsive hydrogels. In this study, a pH and temperature dual-responsive poly(acrylamide-acrylic acid-3-acrylamidophenylboronic acid)/Poly(N-isopropylacrylamide) (P(AAm-AAc-3-AAPBA)/PNIPAM) bilayer structures have been prepared by UV polymerization. The PNIPAM layer shrinks/swells when the temperature is higher/lower than the low critical solution temperature, while P(AAm-AAc-3-AAPBA) layer will swell/shrink when pH is too high/low. The volume change trend of the two layer is different, resulting in the bending behaviors of P(AAm-AAc-3-AAPBA)/PNIPAM hydrogel actuator. The bidirectional bending performance can be reversibly, repeatedly, and precisely controlled by pH and temperature-induced cooperative swelling-shrinking properties from both layers. The bending angle of the bilayer structure achieves about 1420° at the environment of pH 2 and 55 ℃. It takes about 70 s to convert the bending angle of the bilayer structures from 355° (10 ℃, pH 2) to −360° (55 ℃, pH 12). In addition, three kinds of biomimetic hydrogel structures, such as mechanical gripper, bionic flower and bionic hand, have been prepared and demonstrated good performance. The obtained P(AAm-AAc-3-AAPBA)/PNIPAM hydrogels exhibit excellent pH and thermal responsive bending properties, which enable them as an ideal smart hydrogel system.

Bilayer Hydrogel Composed of Elastin-Mimetic Polypeptides as a Bio-Actuator with Bidirectional and Reversible Bending Behaviors.

Biologically derived hydrogels have attracted attention as promising polymers for use in biomedical applications because of their high biocompatibility, biodegradability, and low toxicity. Elastin-mimetic polypeptides (EMPs), which contain a repeated amino acid sequence derived from the hydrophobic domain of tropoelastin, exhibit reversible phase transition behavior, and thus, represent an interesting starting point for the development of biologically derived hydrogels. In this study, we succeeded in developing functional EMP-conjugated hydrogels that displayed temperature-responsive swelling/shrinking properties. The EMP-conjugated hydrogels were prepared through the polymerization of acrylated EMP with acrylamide. The EMP hydrogel swelled and shrank in response to temperature changes, and the swelling/shrinking capacity of the EMP hydrogels could be controlled by altering either the amount of EMP or the salt concentration in the buffer. The EMP hydrogels were able to select a uniform component of EMPs with a desired and specific repeat number of the EMP sequence, which could control the swelling/shrinking property of the EMP hydrogel. Moreover, we developed a smart hydrogel actuator based on EMP crosslinked hydrogels and non-crosslinked hydrogels that exhibited bidirectional curvature behavior in response to changes in temperature. These thermally responsive EMP hydrogels have potential use as bio-actuators for a number of biomedical applications.

RETRACTED ARTICLE: A pH/enzyme dual responsive PMB spatiotemporal release hydrogel promoting chronic wound repair

Suppressing persistent multidrug-resistant (MDR) bacterial infections and excessive inflammation is the key for treating chronic wounds. Therefore, developing a microenvironment-responsive material with good biodegradability, drug-loading, anti-infection, and anti-inflammatory properties is desired to boost the chronic wounds healing process; however, using ordinary assembly remains a defect. Herein, we propose a pH/enzyme dual-responsive polymyxin B (PMB) spatiotemporal-release hydrogel (GelMA/OSSA/PMB), namely, the amount of OSSA and PMB released from GelMA/OSSA/PMB was closely related the wound pH and the enzyme concentration changing. The GelMA/OSSA/PMB showed better biosafety than equivalent free PMB, owing to the controlled release of PMB, which helped kill planktonic bacteria and inhibit biofilm activity in vitro. In addition, the GelMA/OSSA/PMB exhibited excellent antibacterial and anti-inflammatory properties. A MDR Pseudomonas aeruginosa caused infection was effectively resolved by the GelMA/OSSA/PMB hydrogel in vivo, thereby significantly boosting wound closure during the inflammatory phase. Furthermore, GelMA/OSSA/PMB accelerated the sequential phases of wound repair.

Construction of organic–inorganic hybrid heterostructure towards solvent responsive hydrogel with high stiffness

Solvent responsive hydrogel is a kind of intelligent soft material, which can be used in soft robots. Currently, most of the solvent responsive hydrogels are based on pure organic materials which has limited stiffness for actuations. Herein, a novel organic–inorganic composite hydrogel is designed and prepared. Calcium phosphate oligomers nanoclusters are incorporated in polymer solution containing polyvinyl alcohol (PVA) and sodium alginate to form organic–inorganic hybrid copolymer suspensions. The solvent responsive hydrogel is simply prepared using co-evaporation method by optimizing the components in the colloid system. The inorganic nanoparticles work as the scaffold in the porous PVA network and the evaporation caused nonuniformity distribution further induces the formation of heterostructure, which has different shrinkage ratios along the thickness direction. The prepared hydrogel demonstrates excellent shape memory property by changing the environmental solvents between water and ethanol and its repeatability is also verified. The stiffness of hydrogel is enhanced and it has large deformation after incorporation of calcium phosphate nanoparticles. The bending angle of hydrogel can be well controlled by different water to ethanol ratios, allowing for underwater actuation. The functionality of an artificial gripper based on responsive hydrogel with high stiffness is demonstrated to transfer objects in ethanol. The design of organic–inorganic composite hydrogel with high stiffness may provide new insights for preparation of intelligent soft materials for underwater applications.

PH-temperature Responsive Hydrogel-Mediated Delivery of Exendin-4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72h compared to free EX solution. The findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.

Removal of Calcareous Concretions from Marine Archaeological Ceramics by Means of a Stimuli-Responsive Hydrogel

The presence of calcareous concretions on the surface of marine archaeological ceramics is a frequently observed phenomenon. It is necessary to remove these materials when the deposits obscure the feature of ceramics. Unfortunately, calcareous concretions provide distinctive documentation of the burning history of ceramics. The interaction of acid solution or detachment of the deposit layers in physical ways leads to the loss of archeological information. To prevent the loss of archeological information and to achieve precise and gentle concretion removal, responsive hydrogel cleaning systems have been developed. The hydrogels synthesized are composed of networks of poly(vinyl acetate)/sodium alginate that exhibit desirable water retention properties, are responsive to Ca2+ ions, and do not leave any residues after undergoing cleaning treatment. Four distinct compositions were selected. The study of water retention properties involved quantifying the weight changes. The composition was obtained from Fourier transform infrared spectra. The microstructure was obtained from scanning electron microscopy. The mechanical properties were obtained from rheological measurements. To demonstrate both the efficiency and working mechanism of the selected hydrogels, a representative study of mocked samples is presented first. After selecting the most appropriate hydrogel composite, a cleaning process was implemented on the marine archaeological ceramics. This article demonstrates the advantages of stimuli-responsive hydrogels in controlling the release of acid solution release, thereby surpassing the limitations of traditional cleaning methods.

Highly stretchable, self-healable and adhesive, thermal responsive conductive hydrogel loading nanocellulose complex for a flexible sensor

Currently, with the widespread concerns of smart soft sensors in wearable electronics, human health detection and electronic skin, flexible conductive hydrogels have been extensively studied. However, it remains a great challenge to develop hydrogels that have both satisfactory mechanical performance with stretchable and compressible and high conductive. Herein, based on synergistic dynamic hydrogen and metal coordination bonds, polyvinyl alcohol (PVA)/poly (2-hydroxyethyl methacrylate) (PHEMA) hydrogels doped with polypyrrole decorated cellulose nanofibers (CNFs@PPy) are developed via free radical polymerization. The loading versatile CNFs@PPy highlighted the complex hydrogels super-stretchability (approximately 2600 % elongation) and excellent toughness (2.74 MJ/m3) properties to tensile deformation, strong compressive strength (1.96 MPa), fast temperature responsiveness and outstanding strain sensing capability (GF = 3.13). Moreover, the PHEMA/PVA/CNFs@PPy hydrogels possessed rapid self-healing and powerful adhesive abilities to various interfaces without extra assistance, as well as distinguished fatigue resistance performance. Such advantages make the nanocomposite hydrogel displayed high stability and repeatable to both pressure and strain in a wide range of deformations, enabling a promising candidate in the fields of motion monitoring and healthcare management.

All-in-one dual responsive hydrogels for thermoelectrochromic (TEC) devices

The development of new functional materials plays a pivotal role in creating novel materials for devices such as displays or smart windows, offering new possibilities for indoor comfort and energy saving. Most devices only respond to a single external stimulus (electrical, light, thermal) missing on the potential of incorporating multiple responses. Herein, all-in-one thermo- and electrochromic hydrogels for dual responsive displays are presented. In these multifunctional materials, different viologens and thermoresponsive polymers (poly(N-isopropylacrylamide) or poly(N-vinylcaprolactam)) were incorporated simultaneously into hydrogels. By applying these hydrogels on simple sandwich type FTO based devices, it was possible to create single layered dual responsive devices. These devices could change their opacity and color due to their thermochromic (TC) and electrochromic (EC) properties, being able to combine both changes at the same time. The devices showed high optical contrasts, from their almost fully transparent bleached state to their TC and EC states (<5% and ≈70% transmittance at 600 nm, respectively). All phase changes were proven to be reversible by cycling between the bleached, TC, EC and dual TEC states for consecutive times. Therefore, these hydrogels can offer new simple smart window or display designs.

Thermo-aqueous coupling behaviors for shape memory hydrogels: A statistical–mechanical model and simulations faced with experiments

The shape memory behavior of hydrogels endows themselves with the capacities of shape programming and shape recovering, which have great potential in many fields, such as drug release and soft robotics. In thermally responsive hydrogel, particularly, there are two critical factors, temperature and water, that can induce the shape memory effect(SME). Temperature-induced SME has been extensively studied, while water-induced SME has been rarely investigated. In our work, the combined effect of water and temperature on shape memory behavior of hydrogels is experimentally studied and deeply analyzed from a physical perspective. We found that the shape fixed ratio of shape memory hydrogels (SMHs) increases monotonically with temperature, but first increases and then decreases with water content. Moreover, it exits a nonlinear coupling between the water and temperature effects on the SME. On the basis of these findings, a constitutive model is developed to capture this thermo-aqueous coupling using the statistical theory of transient networks, from which we obtain an explicit evolution equation of deformation gradient. In the proposed theory, the temperature-induced SME is investigated through the temperature-water responsive association and dissociation of dynamic bonds while the water-induced SME is explained by the variation of the glass transition temperature according to the Fox–Flory model. Finally, and to provide a final test of the theoretical work, it is implemented into a user element (UEL) subroutine which provide simulations in agreement with our experiments. Our work is expected to provide guidance for future application of SMHs.

Self‐healing injectable stimuli responsive polysaccharide hydrogel constructed with dynamic covalent bonds

AbstractHydrogels based on dynamic covalent bonds have unique properties and are competent in many biomedical fields. However, critical issues such as biocompatibility, mechanical properties, and stimulus responsiveness are required to be solved. It is also expected to develop a simple preparation method with mild conditions. Based on these objectives, chitosan (CS), sodium alginate (SA) and 2‐formylphenylboronic acid (2‐FPBA) are used to prepare the dynamic covalent bond hydrogels within minutes neither chemical medications nor severe conditions. Benefiting from the imine borate and boronic ester bonds both formed in the hydrogels, the hydrogels are stable, injectable, and of efficient self‐healing properties. The damage‐recovery process can be repeated for more than 6 cycles. The microstructure of the hydrogels recoded by atomic force microscopy (AFM) is consistent with the mechanical properties and both of them could be affected by the concentrations of SA and 2‐FPBA. Moreover, the dynamic hydrogels are responsive to pH values and oxidative environment. When the model drug 5‐fluorouracil (5‐FU) is loaded in the dynamic hydrogels, the release profiles are sustainable and present significant differences with various stimuli. These dynamic covalent bond hydrogels have a promising prospect in tissue engineering and drug delivery.

Self-regulating bioinspired supramolecular photonic hydrogels based on chemical reaction networks for monitoring activities of enzymes and biofuels

Inspired by the way many living organisms utilize chemical/biological reactions to regulate their skin and respond to stimuli in the external environment, we have developed a self-regulating hydrogel design by incorporating chemical reaction networks (CRNs) into biomimetic photonic crystal hydrogels. In this hydrogel system, we used host–guest supramolecular non-covalent bonds between beta-cyclodextrin (β-CD) and ferrocene (Fc) as partial crosslinkers and designed a CRN involving enzyme-fuel couples of horseradish peroxidase (HRP)/H2O2 and glucose oxidase (GOD)/d-glucose, by which the responsive hydrogel was transformed into a glucose-driven self-regulating hydrogel. Due to the biomimetic structural color in the hydrogel, the progress of the chemical reaction was accompanied by a change in the color of the hydrogel. Based on this principle, the designed supramolecular photonic hydrogel (SPH) can not only achieve naked-eye detection of H2O2 and glucose concentrations with the assistance of a smartphone but also monitor the reactions of HRP and GOD enzymes and determine their activity parameters. The sensitivity and stability of the sensor have been proven. In addition, due to the reversibility of the chemical reaction network, the sensor can be reused, thus having the potential to serve as a low-cost point-of-care sensor. The SPH was ultimately used to detect glucose in human plasma and H2O2 in liver tumor tissue. The results are comparable with commercial assay kits. By redesigning the chemical reaction network in the hydrogel, it is expected to be used for detecting other enzymes or fuels.

CO enhances agomir transfection under pathological conditions to inhibit MMP overexpression

Cellular uptake of exogenous nucleic acids is inhibited in pathological tissues accompanied by excessive expression of matrix metalloproteinases (MMPs). We show that CO, as a regulator of membrane function, can reactivate uptake of agomir (Ago) in pathological condition via RAB5-mediated endocytic pathway. Herein, a responsive nanoparticle-crosslinked injectable hydrogel (CO-Ago gel) was engineered as a prototype for co-delivering CO and Ago to inhibit MMP overexpression in accordance with the disease severity. Compared to a typical matrix-enhanced gene therapy (Ago gel), CO-Ago gel significantly promoted Ago uptake, achieving an order of magnitude improvement of targeted gene expression under pathological conditions (11.2-fold for cardiomyocyte and 15.3-fold for primary fibroblasts). The therapeutic effect of CO-Ago gel on MMP overexpression was assessed in rat models of myocardial ischemia reperfusion and diabetic skin wound healing. The results suggest CO-enhanced transfection could contribute to the development of next-generation adjuvants for gene-based therapies and vaccines in vivo.