Tumor-activated IL-2 mRNA delivered by lipid nanoparticles for cancer immunotherapy.

Interleukin-2 (IL-2) exhibits the unique capacity to modulate immune functions, potentially exerting antitumor effects by stimulating immune responses, making it highly promising for immunotherapy. However, the clinical use of recombinant IL-2 protein faces significant limitations due to its short half-life and systemic toxicity. To overcome these challenges and fully exploit IL-2's potential in tumor immunotherapy, this study reports the development of a tumor-activated IL-2 mRNA, delivered via lipid nanoparticles (LNPs). Initially, ionizable lipid U-101 derived nanoparticles (U-101-LNP) were prepared using microfluidic technology. Subsequent in vitro and in vivo delivery tests demonstrated that U-101-LNP achieved more effective transfection than the approved ALC-0315-LNP. Following this, IL-2F mRNAs, encoding fusion proteins comprising IL-2, a linker, and CD25 (IL-2Rα), were designed and synthesized through in vitro transcription. A cleavable linker, consisting of the peptide sequence SGRSEN↓IRTA, was selected for cleavage by matrix metalloproteinase-14 (MMP-14). IL-2F mRNA was then encapsulated in U-101-LNP to create U-101-LNP/IL-2F mRNA complexes. After optimization, assessments of expression efficiency, masking, and release characteristics revealed that IL-2F with linker C4 demonstrated superior performance. Finally, the antitumor activity of IL-2F mRNA was evaluated. The results indicated that U-101-LNP/IL-2F mRNA achieved the strongest antitumor effect, with an inhibition rate of 70.3%. Immunohistochemistry observations revealed significant expressions of IL-2, IFN-γ, and CD8, suggesting an up-regulation of immunomodulation in tumor tissues. This effect could be ascribed to the expression of IL-2F, followed by the cleavage of the linker under the action of MMP-14 in tumor tissue, which sustainably releases IL-2. H&E staining of tissues treated with U-101-LNP/IL-2F mRNA showed no abnormalities. Further evaluations indicated that the U-101-LNP/IL-2F mRNA group maintained proper levels of inflammatory factors without obvious alterations in liver and renal functions. Taken together, the U-101-LNP/IL-2F mRNA formulation demonstrated effective antitumor activity and safety, which suggests potential applicability in clinical immunotherapy.

Wet-Driven Bionic Actuators from Wool Artificial Yarn Muscles.

Nature-similar muscle is one of the ultimate goals of advanced artificial muscle materials. Currently, a variety of chemical and natural materials have been gradually developed for the preparation of artificial muscles. However, due to the scarcity, biological exclusion, and poor flexibility of the abovementioned materials, it is still a challenging process to maximize the imitation of behaviors shown by real muscles and commercial development. Here, this article presents multidimensional wool yarn artificial muscles, and the wet response behavior of fibers is induced in yarn muscles successfully by virtue of weakening the water-repellent effect of wool scales. Wool artificial muscles are cost-effective and widely available and have good biocompatibility. In addition, wool fiber assemblies are structurally stable, soft, and flexible to be processed into artificial muscles with torsional, contractile, and even multilayered structures, enabling various wet-driven behaviors. On the basis of the theoretical model and numerical simulation, we explained and verified the working mechanism employed in wool artificial yarn muscles. Finally, the yarn muscle was integrated into a wool muscle group through the textile technology, followed by the application to robot bionic arms, displaying the great potential of wool artificial yarn muscles in bionic drivers and the intelligent textile industry.

Injectable polylysine and dextran hydrogels with robust antibacterial and ROS-scavenging activity for wound healing.

Cutaneous wound management remains a major concern due to uncontrolled inflammation and bacterial infection in clinical care. A desirable hydrogel dressing with antibacterial and antioxidative properties can drive wound healing by inhibiting infection and inflammation. Herein, a multifunctional hydrogel based on polylysine-graft-cysteine (EPL-SH)/oxidized dextran (ODex) was fabricated for promoting skin tissue regeneration. The engineered hydrogel possessed versatile properties including tunable gelation time (60-300 s), typical rheological behavior, suitable swelling and degradation progress, injectable and self-healing ability. The unique hydrogels also displayed promising tissue adhesiveness, high cell affinity, excellent antioxidant and antimicrobial activity. Furthermore, the in vivo full-thickness skin defect experiment demonstrated the simple-to-implement injectable hydrogels could significantly promoting wound healing by improving the collagen deposition and angiogenesis. The manufacture of our multifunctional hydrogels dressing affords a new strategy for improving efficacy of cutaneous wound treatment.

Bio-fabricated nanocomposite hydrogel with ROS scavenging and local oxygenation accelerates diabetic wound healing.

Chronic wounds, especially diabetic wounds, involve abnormally long inflammatory periods due to their pathological microenvironment of high reactive oxygen species (ROS) levels and lack of blood vessels. Here, via a mild, simple and feasible fabrication approach, a sustained oxygenation system is proposed, consisting of MnO2 nanosheets and a dual-network hydrogel fabricated from natural biomaterials including silk fibroin (SF) and carboxymethyl cellulose (CMC). Compared with the initial value (61.09 kPa), the compression modulus of the dual-network hydrogel increased by 116.2% through the coordination of strong covalent bonds and sacrificial coordination bonds constructed by enzymatic crosslinking and UV-irradiation crosslinking; the intrinsic shear-thinning effect endows the dual-network hydrogel with satisfactory injectable properties to be customized as a predetermined shape to accommodate the irregular wounds of diabetes. The encapsulated MnO2 nanosheets can catalyze the excessive ROS into necessary O2in situ and, after co-incubating with the SF/CMC@MnO2 hydrogels, cells in oxidative stress show significantly lower ROS (3 times) and higher O2 (17 times) levels that are conductive to relieving oxidative stress, promoting angiogenesis and reducing inflammation in vivo. Meanwhile, these SF-based hydrogels can offset the overexpression of matrix metalloproteinases (MMPs) in diabetic wounds (more than 80%) and promote remodeling of the extracellular matrix. Eventually, wound healing rates >76% in 7 days and 100% in 14 days were achieved by the bio-fabricated nanocomposite hydrogel and are remarkably faster than the commercial dressing healing rates (<30% in 7 days and <80% in 14 days). These results indicate that this bio-fabricated hydrogel system with multiple and customizable functions has great promise in the personalized clinical care of chronic wounds.

Ascidian-inspired aciduric hydrogels with high stretchability and adhesiveness promote gastric hemostasis and wound healing.

Adhesives for gastric hemorrhage are of great clinical significance. However, it remains a major challenge in clinics due to its poor stability under acidic environments and low adhesion to wet tissues. Herein, inspired by the high adhesiveness of the ascidian secretory protein, we designed a series of aciduric bionic hydrogel adhesives (PDTAs) based on poly(γ-glutamic acid) (γ-PGA) and tannic acid (TA). The formation of hydrogel adhesives was attributed to the abundant hydrogen bonds between amide groups of PGA-DA and polyphenol groups of TA. These hydrogel adhesives exhibited enhanced wet tissue adhesion (400%), higher stretchability (800% elongation), and aciduric stability (7 days) compared with commercial fibrin glue. Rodent wound models indicated that the hydrogel adhesives demonstrated significant healing promotion due to ameliorating collagen deposition and angiogenesis. These hydrogel adhesives show great potential in treating gastric hemorrhages and promoting wound healing.

Dynamic regulable sodium alginate/poly(γ-glutamic acid) hybrid hydrogels promoted chondrogenic differentiation of stem cells.

Traditional hydrogels often fail to match the dynamic interactions between mechanical and cellular behaviors exhibited by the natural cartilage extracellular matrix. In this research, we constructed a novel hybrid hydrogels system based on sodium alginate and polyglutamic acid. By controlling the grafting rate and concentration of polymer, the gelation time and mechanical strength can be adjusted between range of 8-28 s and 60-144 kPa. By adding microcrystalline cellulose into the system, so that the degradation time was prolonged (125%) and the swelling rate was reduced (470%). Additionally, the presence of hydrazone bonds gives the system some dynamic response characteristics, and the hydrogel exhibits excellent self healing and injectable ability. It was found that the system had positive cytocompatibility (80%), which accelerated regulatory gene expression in cartilage tissue. In conclusion, this injectable hydrogel with self-healing and customizable mechanical strength will have broad application prospects in future biomedical engineering.

Mechanoadaptive injectable hydrogel based on poly(γ-glutamic acid) and hyaluronic acid regulates fibroblast migration for wound healing.

Injectable hydrogels have shown therapeutic effects on wound repair, but most of them exhibit poor mechanical strength. The impacts of stiff injectable hydrogels on cell behavior and wound healing remain unclear. Herein, an injectable hydrogel was developed based on thiolated poly(γ-glutamic acid) (γ-PGA-SH) and glycidyl methacrylate-conjuated oxidized hyaluronic acid (OHA-GMA). Thiol-methacrylate Michael chemistry-mediated post-stabilization and increase of polymer concentration were found to improve the mechanical strength of γ-PGA-SH/OHA-GMA hydrogel. Moreover, in vitro studies confirmed its biodegradability, biocompatibility, and self-healing property. Using the mechanically-tunable hydrogel, it further showed that fibroblasts migrated faster on the surface of stiffer hydrogel, but infiltrated slowly inside it compared with softer hydrogel. In animal experiments, the injectable hydrogel could promote wound healing by increasing collagen deposition and vascularization. In summary, γ-PGA-SH/OHA-GMA hydrogel is able to regulate migration and infiltration of fibroblasts by altering stiffness and offers effective in situ forming scaffolds towards skin tissue regeneration.

Injectable adaptive self-healing hyaluronic acid/poly (γ-glutamic acid) hydrogel for cutaneous wound healing.

The most significant challenge in designing wound dressings is to mimic the tissue microenvironment because of the pro-regenerative structural and functional properties of skin. Herein, we developed a type of bionic extracellular matrix (ECM) hydrogels based on thiol-modified poly (γ-glutamic acid) (γ-PGA-SH) and oxidized hyaluronic acid (HA-CHO). The rapid and reversible thiol-aldehyde addition reaction of thiols in γ-PGA-SH and aldehyde groups in HA-CHO provided hydrogels with a dynamic covalent network and endowed them with properties of adaptability and self-healing capability, which are conducive for initial wound coverage and for prolonging the lifespan of the dressing. Interestingly, these hydrogels also showed typical viscoelastic characteristics similar to those of natural ECM, degradation property in vitro and in vivo, and free radical scavenging capability. In addition, the gelation time, rheological behavior, mechanical property, porous structure, and degradation process of the hydrogels could be tuned by adjusting polymer content. Furthermore, the ECM-inspired hydrogels significantly enhanced the wound healing process in vivo in a full-thickness skin defect model compared to those by commercial dressing (Tegaderm™) by facilitating angiogenesis and promoting collagen deposition. The successful application of the multifunctional hydrogel as an antioxidant wound dressing for wound treatment significantly exhibited its great application potential for biomedical areas. STATEMENT OF SIGNIFICANCE: The application of tissue engineering techniques to repair full-thickness skin wounds remains a great challenge in clinical trials. Among the recent approaches used for wound healing, in situ forming injectable hydrogels have gained much attention, and few of them have shown satisfactory overall performance, such as integration into the wound bed, biodegradability, immunocompatibility, vascularization, and recapitulation of the structure and function of skin. In the present study, we designed a simple and convenient in situ forming injectable adaptable self-healing hydrogels with biodegradability and antioxidative properties, which could substantially improve wound healing quality at an affordable cost. The hydrogel-based wound dressing is expected to solve the abovementioned problems and help in promoting cutaneous wound healing.

Bioinspired mineral-polymeric hybrid hyaluronic acid/poly (γ-glutamic acid) hydrogels as tunable scaffolds for stem cells differentiation.

Aiming at the difficulty of integrated repair of osteochondral tissue, we designed a hybrid hydrogel scaffold that mimicked the microenvironment of osteochondral niches. Besides, the nano-hydroxyapatite (nHAP) was specially introduced into the hydrogel for its natural ability to promote bone regeneration. The hydrogel also exhibited good toughness (7500 KJ/m3), strength (1000 kPa), viscoelasticity, and in vitro cell experiments showed that hydrogels had quite good cytocompatibility (near 100 % viability). The results of the three-dimensional (3D) cell culture also proved that the survival rate of the cells in the hybrid hydrogels doped with nHAP and dispersion were the highest. In vitro RT-qPCR experiments proved that after being cultured in hydrogel scaffolds doped with nHAP, bone mesenchymal stem cells (BMSCs) could express genes related to osteoblasts and chondrocytes. As a result, this hydrogel provides a general for developing alternative materials applicable for stem cells differentiation and even osteochondral tissue engineering.

A Numerical and Experimental Study on a Pre-Twisted Ring Spinning System.

The ring spinning process is the most widely used method in the spinning industry. Nowadays, the labor cost become more and more expensive, and it is essential to improve productivity. For increasing the productivity, a modification of adding a pre-twister and holding roller on the traditional ring spinning system have been discussed in this paper. The computational fluid dynamics (CFD) are introduced to study the effects of pre-twister and spinning tests are implemented for verification. The numerical simulations show that the cavity conical degree and nozzle numbers of the pre-twister are the key parameters which affect the airflow fluctuation in the cavity, and have obvious effects on the resultant yarn twist. By contrast, the axial angle and tangential angle of the nozzle have less effect on the resultant yarn twist. When the fiber bundles pass by the front nip, they are affected by the vortex and result in a partially strengthened and wrapped structure which could be subsequently twisted less by the traveler and ring, so the productivity could be potentially increased. According to the spinning tests, an evident productivity increase by nearly 30% for medium cotton yarns can be achieved, and the yarns have an acceptable reduction in nearly all properties.