A guanosine/konjac glucomannan supramolecular hydrogel with antioxidant, antibacterial and immunoregulatory properties for cutaneous wound treatment.

Developing naturally-derived wound dressing materials with intrinsic therapeutic effects is desirable for the clinical applications. Recently, guanosine-based supramolecular G-quadruplex (G4) hydrogel exhibited great potential in preparing biological materials due to its simple fabrication method and responsive gel networks. However, the weak mechanical properties and the consequent burst release of bioactive molecules restrict its clinical applications. Herein, we found that konjac glucomannan (KGM) with immunoregulatory effect did not affect the self-assembly of G-quadruplexes and thus effectively enhancing the mechanical properties of G4 hydrogel. Aloin, as a model drug, was in situ loaded into gel networks, finally obtaining the G4/Aloin-KGM hydrogel. This hydrogel exhibited porous morphology, swelling ability and hemostatic capability. Boronate bonds in G4 networks and aloin collectively endowed the hydrogel with excellent antioxidant performance. Meanwhile, aloin also provided outstanding in vitro and in vivo bactericidal ability. The wounds treated with this biocompatible hydrogel demonstrated faster regeneration of epithelial and dermal tissues, and the whole wound healing stages were accelerated by promoting collagen deposition, facilitating macrophage polarization towards M2 phenotype, down-regulating the expression level of IL-6, and up-regulating the expression level of IL-10, CD31 and α-SMA.

A Bionic Yeast Tumor Vaccine Using the Co-Loading Strategy to Prevent Post-Operative Tumor Recurrence.

Immunotherapy is an effective adjunct to surgery for preventing tumor recurrence and metastasis in postoperative tumor patients. Although mimicking microbial invasion and immune activation pathways can effectively stimulate the immune system, the limited capacity of microbial components to bind antigens and adjuvants restricts the development of this system. Here, we construct bionic yeast carriers (BYCs) by in situ polymerization of mesoporous silica nanoparticles (MSNs) within the yeast capsules (YCs). BYCs can mimic the yeast infection pathway while utilizing the loading capacity of MSNs for multiple substances. Pore size and hydrophobicity-modified BYC can be loaded with both antigen and adjuvant R848. Oral or subcutaneous injection uptake of coloaded BYCs demonstrated positive therapeutic effects as a tumor therapeutic vaccine in both the transplantation tumor model and the metastasis tumor model. 57% of initial 400 mm3 tumor recurrence models are completely cured with coloaded BYCs via combination therapy with surgery, utilizing surgically resected tumors as antigens. The BYCs construction and coloading strategy will provide insights and optimistic approaches for the development of effective and controllable cancer vaccine carriers.

Body temperature-induced adhesive hyaluronate/gelatin-based hybrid hydrogel dressing for promoting skin regeneration.

Skin wound management faces significant clinical challenges, including continuous bacterial infection and inflammation. Therefore, developing removable hydrogel dressings with intrinsic multifunctional properties is highly desirable. In this study, a body temperature-induced adhesive and removable hydrogel was designed to treat skin defect wounds. The HA/Gel-R-Ag hybrid gel was prepared by incorporating a silver ion-crosslinked sulfhydryl hyaluronate/gelatin-based polymeric gel network into a supramolecular rhein gel network, thereby significantly enhancing its mechanical properties. Temperature-responsive gelatin chains give the hybrid gel reversible tissue adhesiveness and detachment, thus avoiding secondary injury to wounds when changing the hydrogels. The hybrid gel exhibited excellent bactericidal ability owing to the antibacterial capacity of the silver ions and rhein. Moreover, both HA and rhein endowed the hybrid gel with immunoregulatory effects by promoting macrophage polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In a full-thickness skin defect mouse mode, this porous, degradable, and biocompatible HA/Gel-R-Ag hybrid gel boosted skin regeneration by inhibiting inflammation and promoting collagen deposition and angiogenesis. It is thus a simple method for widening the application range of mechanically weak rhein gels and providing a promising wound dressing material with multiple intrinsic functions for treating skin wounds.

Cascade enzymatic preparation of carboxymethyl chitosan-based multifunctional hydrogels for promoting cutaneous wound healing.

Designing wound dressings with inherent multifunctional therapeutic effects is desirable for clinical applications. Herein, a series of multifunctional carboxymethyl chitosan (CMCS)-based hydrogels were fabricated by the facile urate oxidase (UOX)-horseradish peroxidase (HRP) cascade enzymatic crosslinking system. For the first time, the cascade enzymatic crosslinking system was not only used for preparing hydrogel wound dressings but also for accelerating wound healing due to the activity retention of the self-compartmental enzymes. A CMCS derivative (HCMCS-mF) synthesized by successively grafting 4-hydroxybenzaldehyde (H) and 5-methylfurfural (mF) on CMCS and a quaternary ammonium crosslinker (QMal) with terminal grafting maleimide (Mal) groups were combined with enzymatic system for the facile preparation of hydrogels. The mild Diels-Alder (DA) crosslinking reaction between mF and Mal groups constructed the first network of hydrogels. The cascade UOX-HRP system mediated the oxidative crosslinking of phenols thus forming the second gel network. Self-entrapped UOX maintained its enzymatic activity and could continuously catalyze the oxidation of uric acid, generating therapeutic allantoin. These porous, degradable, mechanically stable hydrogels with excellent antioxidant performance and enhanced antibacterial capacity could effectively accelerate skin wound repair by simultaneously reducing oxidative stress, relieving inflammation, promoting collagen deposition and upregulating the expression level of CD31.

Schiff base modified starch: A promising biosupport for palladium in Suzuki cross-coupling reactions.

Starch can be used in diverse fields because it is a readily available, non-toxic polysaccharide with adaptable functionality and biodegradability. In this study, taking the aforementioned characteristics into consideration, we designed a modified starch (Starch-SB), which serves as supporting material for palladium stabilization. This new air and moisture-stable robust palladium composite [Starch-SB-Pd(II)] was characterized by FT-IR, XRD, TGA, XPS, SEM, EDX, TEM, CP/MAS 13C NMR, and ICP-MS analytical techniques. The catalytic studies exhibit high activity (up to 99 %) and stability in Suzuki cross-coupling reactions for this starch supported catalytic system under mild conditions (lower reaction temperature and green solvents) because of the cooperative interactions of multifunctional capturing sites on starch (Schiff base, hydroxy and amine groups) with palladium species. The experiments on reusability demonstrate that Starch-SB-Pd(II), which was prepared from functionalized starch, could be readily recycled several cycles through centrifugation. Moreover, we proposed a possibly multifunctional complex structure. This work presents an appealing and intriguing pathway for the utilization of polysaccharide as crucial support in green chemical transformations.

Honokiol@PF127 crosslinked hyaluronate-based hydrogel for promoting wound healing by regulating macrophage polarization.

Bacterial infection, oxidative stress and inflammation are the main obstacles in wound healing. Hydrogels with moist and inherent properties are beneficial to wound healing. Here, we fabricated a honokiol-laden micelle-crosslinked hyaluronate-based hydrogel by simply mixing honokiol-laden PF127-CHO micelles, 3,3'-dithiobis(propionohydrazide) grafted hyaluronic acid and silver ions. PF127 could not only effectively load hydrophobic small molecules but also be macromolecular crosslinker for preparing hydrogels. Hyaluronic acid plays an essential role in wound healing processes including regulating macrophage polarization towards M2 phenotype. The chemical dynamic acylhydrazone crosslinking and physical crosslinking among PF127-CHO micelles constructed hydrogel's networks, which endowed hydrogel with excellent self-healing properties. PF-HA-3 hydrogel also exhibited outstanding antioxidant and antibacterial capabilities. In a full-thickness skin defect model, this degradable and biocompatible hydrogel could promote wound healing by remodeling wound tissues, regulating M2 polarization and angiogenesis. In summary, this inherent multifunctional hydrogel will provide a promising strategy for designing bioactive compounds-based wound dressings.

The combination of in situ photodynamic promotion and ion-interference to improve the efficacy of cancer therapy.

Photodynamic therapy (PDT) is proved to be a promising modality for clinical cancer treatment. However, it also suffers from a key obstacle in association with its oxygen-dependent nature which greatly limits its effective application against hypoxic tumors. Herein, on the basis of the unique property of calcium peroxide (CaO2), we propose an O2-self-supply strategy for the promotion of PDT by combining the in situ O2-generation characteristic of calcium peroxide with the photosensitive nature of porphyrin. A shell of ZIF-8 was synthesized surround the CaO2 core to prevent the CaO2 from premature decomposition and increased the loading of THPP efficiently. Depending on the in situ self-supply of O2, the photosensitizer was able to exhibit an enhanced PDT effect that significantly inhibit the growth of tumor. Moreover, the enrichment of free calcium ions derived from the decomposition of CaO2 under acidic tumor microenvironment also shows the unique ion-interference effect and contributes to the obvious inhibition against tumor growth. This work presents a synergistic strategy for the construction of a photodynamic promotion/ion-interference combined nano-platform which can also serve as an inspiration for the future design of effective nanocomposites in tumor treatment.

Enzymatic one-pot preparation of carboxylmethyl chitosan-based hydrogel with inherent antioxidant and antibacterial properties for accelerating wound healing.

Facile preparation of multifunctional hydrogel wound dressings with inherent versatile properties is highly desirable in practical healthcare. Here, a biocompatible hydrogel was designed and fabricated via mild enzymatic crosslinking and polymerization. We first designed an enzymatic system containing horseradish peroxidase (HRP), H2O2, and the macromolecular initiator-acetoacetyl polyvinyl alcohol (PVA-ACAC), which can generate active PVA-ACAC carbon radicals via HRP-mediated oxidation by H2O2. Trimethylammonium chloride (Q), methacryloyl (MA) and phenol (Ph)-grafted carboxymethyl chitosan (Ph-QCMCS-MA) was then synthesized. HRP catalyzes the oxidation of phenol groups to achieve the fast phenol crosslinking, and PVA-ACAC carbon radicals initiate the polymerization of MA groups simultaneously, finally obtaining the target PPQM gel. The quaternary ammonium and phenol groups endow the PPQM gel with excellent antibacterial and antioxidant properties, respectively. This multifunctional hydrogel, which has additional adhesive and hemostatic properties, could promote wound healing processes in an in vivo full-thickness skin defect experiment by reducing the generation of pro-inflammatory cytokines (IL-6) and upregulating anti-inflammatory factors (IL-10) and angiogenesis-related cytokines (VEGF and α-SMA). As a result, it could be used as competitive wound dressings.

Facile preparation of polyphenol-crosslinked chitosan-based hydrogels for cutaneous wound repair.

The design and facile preparation of the smart hydrogel wound dressings with inherent excellent antioxidant and antibacterial capacity to effectively promote wound healing processes is highly desirable in clinical applications. Herein, a series of multifunctional hydrogels were prepared by the dynamic Schiff base and boronate ester crosslinking among phenylboronic acid (PBA) grafted carboxymethyl chitosan (CMCS), polyphenols and Cu2+-crosslinked polyphenol nanoparticles (CuNPs). The dynamic crosslinking bonds endowed hydrogels with excellent self-healing and degradable properties. Three polyphenols including tannic acid (TA), oligomeric proanthocyanidins (OPC) and (-)-epigallocatechin-3-O-gallate (EGCG) contributed to the outstanding antibacterial and antioxidant abilities of these hydrogels. The tissue adhesive capacity of hydrogels gave them good hemostatic effect. Through a full-thickness skin defect model of mice, these biocompatible hydrogels could accelerate wound healing processes by promoting granulation tissue formation, collagen deposition, M2 macrophage polarization and cytokine secretion, demonstrating that these natural-derived hydrogels with inherent physiological properties and low-cost preparation approaches could be promising dressing materials.

Mimic enzymatic preparation of conductive supramolecular-polymeric hydrogels with antibacterial and antioxidant properties for accelerating wound healing.

Supramolecular-polymeric hydrogels by combining low-molecular-weight gelators (LMWGs) with polymers have attracted great attention due to their unique double networks. Polymers are generally introduced into an LMWG matrix, thus enhancing the mechanical performance and broadening of the application fields of supramolecular hydrogels. Herein, a series of supramolecular-polymer hydrogels with inherent multiple properties were fabricated as wound dressings. An enzyme-like supramolecular H/G4 hydrogel co-assembled by hemin and guanosine-quartet motifs was successively integrated with hyaluronic acid (HA) and polyaniline (PANI), yielding a supramolecular-polymeric composite hydrogel (namely H/G4-HA(Cu)/PANI). The introduction of Cu2+-crosslinked hydrazide-grafted HA polymeric networks not only enhanced the viscoelasticity of the H/G4 supramolecular hydrogel but also endowed composite hydrogels with bioactive properties as wound healing dressings. The enzyme-like nanofibril H/G4 hydrogel could catalyse the oxidative polymerization of aniline, thus introducing PANI into gel networks. The porous H/G4-HA(Cu)/PANI exhibited a certain degree of swelling ratio under physiological conditions. H/G4-HA(Cu)/PANI also showed degradability, conductivity and appropriate mechanical properties. Through a full-thickness skin defect model of mice, this haemostatic, antioxidant, antibacterial and drug-free H/G4-HA(Cu)/PANI could accelerate wound healing processes by promoting wound closure, collagen deposition and upregulation of the CD31 expression level, which indicates that H/G4-HA(Cu)/PANI could be a promising wound dressing material.

Research Progress on Nanoplatforms and Nanotherapeutic Strategies in Treating Glioma.

Glioma is the most common and aggressive primary intracranial tumor within the central nervous system. The blood-brain barrier (BBB) has been a great hurdle for an effective glioma treatment. To effectively treat glioma, various strategies have been applied to deliver drugs to the brain by crossing the BBB. Nanocarrier-mediated drug delivery is emerging as an effective and noninvasive system to treat glioma, showing great potential in glioma therapy. In this review, we will provide a comprehensive overview on nanocarrier-mediated drug delivery and related glioma therapy. Following an initial overview of the BBB and blood-brain-tumor barrier (BBTB) structure and characteristics, nanocarrier-mediated drug delivery strategies (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, biomimetic nanoparticles, and exosomes) for crossing the BBB are discussed. Finally, nanotherapeutic techniques (imaging-mediated chemotherapy, photothermal therapy, photodynamic therapy, gene therapy, immunotherapy, ferroptosis therapy, sonodynamic therapy, chemodynamic therapy, and combination therapy) in treating glioma are summarized. In addition, this review provides some perspectives on the clinical applications of nanomedicines.

EGCG-crosslinked carboxymethyl chitosan-based hydrogels with inherent desired functions for full-thickness skin wound healing.

Hydrogel wound dressings have attracted intense and increasing interest for their extracellular matrix like properties and bioactive material delivery ability. Various functional hydrogels loaded with metals (and their oxides), antibiotics and anti-inflammatory agents have been prepared to realize antioxidant, bactericidal and anti-inflammatory effects, accelerating wound healing. Nevertheless, it is still a big challenge to facilely fabricate hydrogel wound dressings with inherent desirable properties to promote wound healing and avoid some drawbacks such as toxicity of metals and drug resistance. Herein, we facilely prepared a series of (-)-epigallocatechin-3-O-gallate (EGCG)-crosslinked carboxymethyl chitosan-based hydrogels (EP gels) with inherent antioxidant, bactericidal and adhesive properties. Gluconate-terminated polyethylene glycol (PEG-glu) was introduced into gel networks to enhance the mechanical properties. The hydrogels are constructed via borate ester crosslinking between phenylboronic acid (PBA) groups of PBA-grafted carboxymethyl chitosan (CMCS-PBA) and diol groups of EGCG and PEG-glu. The hydrogels exhibited excellent self-healing properties, desirable mechanical and adhesive strength, free radical scavenging capability and outstanding bactericidal ability against S. aureus and E. coli. In the subsequent full-thickness skin defect model of mice, EP1 gel could promote the proliferation and remodeling process such as the regeneration of epidermis, dermis, and skin appendages, deposition of collagen, and upregulation of the VEGF level, thereby accelerating the healing of damaged skin. Overall, we facilely prepared polysaccharide-based hydrogels with inherent desirable properties as promising dressings for wound repair.

Research progress on self-assembled nanodrug delivery systems.

In recent years, nanodrug delivery systems have attracted increasing attention due to their advantages, such as high drug loading, low toxicity and side effects, improved bioavailability, long circulation time, good targeting and controlled drug release efficiency. Self-assembly technology has developed rapidly in recent decades and plays an important role in the research and development of nanoscience. The combination of nanometer drug delivery and self-assembly technology can realize the self-delivery process of drugs. The facile synthesis process and strong biological affinity can both effectively enhance the therapeutic efficacy and reduce the toxicity of drugs. This combination of technologies has received wide attention in the field of nanobiomedicine. In this review, we summarize the research progress and applications of different types of self-assembled nanodrug delivery systems (amphiphilic block copolymer-based self-assembled drug delivery system, carrier-free nanodrugs, peptide-based self-assembled delivery system, metal-polyphenol self-assembly and natural small-molecule self-assembled nanodrug delivery systems), which are expected to have potential therapeutic value in the field of biomedicine in the future.

Photo-induced adhesive carboxymethyl chitosan-based hydrogels with antibacterial and antioxidant properties for accelerating wound healing.

Designing adhesive hydrogel wound dressings with inherent antibacterial and antioxidant properties is desirable to treat cutaneous full-thickness injuries in clinical care. Herein, a series of photo-induced Schiff base crosslinking-based adhesive hydrogels with promising traits are designed and prepared through Diels-Alder (DA) reactions between functional groups-grafted carboxymethyl chitosan (CMCS) and a photo-responsive polyethylene glycol (PEG) crosslinker. The quaternary ammonium and phenol groups in modified CMCS endows hydrogels excellent antibacterial and antioxidant properties. Upon UV (365 nm) irradiation, the generated o-nitrosobenzaldehyde from the photo-isomerization of o-nitrobenzyl in PEG derivative can subsequently crosslink with amino groups on tissue interfaces via Schiff base, endowing the hydrogel with well adhesiveness. Additionally, the hydrogel exhibits good BSA adsorption capacity, cytocompatibility and hemostatic property. The in vivo full-thickness skin defect study on mice indicates that the multi-functional hydrogel with considerable collagen deposition and vascularization capacities can be an effective and promising adhesive dressing for improving wound healing.

Facile preparation of polysaccharides-based adhesive hydrogel with antibacterial and antioxidant properties for promoting wound healing.

Infection, oxidative stress, and inflammation are the major obstacles to cutaneous wound healing. Designing adhesive wound dressings with inherent antibacterial and antioxidant properties are highly desirable. Herein, a series of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-doped multifunctional hydrogels were facilely prepared by combining quaternized carboxymethyl chitosan (QCMCS) and oxidized hyaluronate (HA-CHO). Schiff base crosslinking between amino groups in QCMCS and aldehyde groups in HA-CHO not only constructed hydrogel networks but also endowed hydrogels with good self-healing property. The hydrogel exhibited adjustable tissue adhesiveness, degradability, and rheological properties by changing the content of TEMPO groups. Moreover, the hydrogels presented excellent inherent antibacterial and antioxidant properties, along with the porous structures, swelling ability, good cytocompatibility and low hemolysis ratio, which are beneficial to promoting wound healing process. Overall, the TEMPO hydrogel showed excellent therapeutic effect in mice skin defect model, giving the hydrogel with fitness as wound dressings for treating skin wounds.

Research on endoplasmic reticulum-targeting fluorescent probes and endoplasmic reticulum stress-mediated nanoanticancer strategies: A review.

Subcellular localization of organelles can achieve accurate drug delivery and maximize drug efficacy. As the largest organelle in eukaryotic cells, the endoplasmic reticulum (ER) plays an important role in protein synthesis, folding, and posttranslational modification; lipid biosynthesis; and calcium homeostasis. Observing the changes in various metal ions, active substances, and the microenvironment in the ER is crucial for diagnosing and treating many diseases, including cancer. Excessive endoplasmic reticulum stress (ERS) can have a killing effect on malignant cells and can mediate cell apoptosis, proper modulation of ERS can provide new perspectives for the treatment of many diseases, including cancer. Therefore, the ER is used as a new anticancer target in cancer treatment. This review discusses ER-targeting fluorescent probes and ERS-mediated nanoanticancer strategies.

Tissue Fluid Triggered Enzyme Polymerization for Ultrafast Gelation and Cartilage Repair.

The in situ gelation of injectable precursors is desirable in the field of tissue regeneration, especially in the context of irregular defect filling. The current driving forces for fast gelation include the phase-transition of thermally sensitive copolymers, click chemical reactions with tissue components, and metal coordination effect. However, the rapid formation of tough hydrogels remains a challenge. Inspired by aerobic metabolism, we herein propose a tissue-fluid-triggered cascade enzymatic polymerization process catalyzed by glucose oxidase and ferrous glycinate for the ultrafast gelation of acryloylated chondroitin sulfates and acrylamides. The highly efficient production of carbon radicals and macromolecules contribute to rapid polymerization for soft tissue augmentation in bone defects. The copolymer hydrogel demonstrated the regeneration-promoting capacity of cartilage. As the first example of using artificial enzyme complexes for in situ polymerization, this work offers a biomimetic approach to the design of strength-adjustable hydrogels for bio-implanting and bio-printing applications.

Photo-induced programmable degradation of carboxymethyl chitosan-based hydrogels.

Hydrogels are widely used in the biomedical field, due to their high similarity to native extracellular matrix (ECM). Most responsive hydrogels could only passively receive stimuli and independently change their properties. In this study, a photosensitive o-nitrobenzyl (NB) ester linker of polyethylene glycol (PEG) with maleimido (Mal) as terminal groups (PEG-NB-Mal) and a 5-methylfurfuryl (mF) grafted carboxymethyl chitosan (CMCS) derivative (CMCS-mF) were synthesized and used to prepare functional hydrogels via Diels-Alder (DA) reactions. The hydrogel exhibited programmable degradation properties after sequential exposure to UV light and acid treatments. It can maintain high integrity upon the single stimuli, the cascade acid and UV light treatments or the cascade UV light and alkaline treatments. Moreover, the hydrogel exhibited well controlled release profile of rhodamine B (RB). In summary, such CMCS-based hydrogels show great potential in biomedical applications. In addition, the usage of photo-induced cascade reaction in sequential degradation hydrogels can be extended to design other types of programmable smart materials.

Research progress on nanotechnology for delivery of active ingredients from traditional Chinese medicines.

There is growing acceptance of traditional Chinese medicines (TCMs) as potential sources of clinical agents based on the demonstrated efficacies of numerous bioactive compounds first identified in TCM extracts, such as paclitaxel, camptothecin, and artemisinin. However, there are several challenges to achieving the full clinical potential of many TCMs, particularly the generally high hydrophobicity and low bioavailability. Recently, however, numerous studies have attempted to circumvent the limited in vivo activity and systemic toxicity of TCM ingredients by incorporation into nanoparticle-based delivery systems. Many of these formulations demonstrate improved bioavailability, enhanced tissue targeting, and greater in vivo stability compared to the native compound. This review summarizes nanoformulations of the most promising and extensively studied TCM compounds to provide a reference for further research. Combining these natural compounds with nanotechnology-based delivery systems may further improve the clinical utility of these agents, in turn leading to more intensive research on traditional medicinal compounds.

One-pot preparation of double network hydrogels via enzyme-mediated polymerization and post-self-assembly for wound healing.

Hybrid hydrogels combining polymers and low-molecular-weight gelators (LMWGs) are promising soft materials. Self-assembled LMWG-based supramolecular networks via noncovalent interactions exhibit excellent reversible thixotropy, which are usually incorporated into polymer gel networks generating functional double network hybrid hydrogels. In this study, we used enzyme-mediated polymerization and post-self-assembly for the one-pot preparation of LMWG-based hybrid hydrogels which consist of a covalently cross-linked polyacrylamide as the first chemical network and post-self-assembled DBS-COOH as the second supramolecular network. The gelation processes are monitored by the EPR measurement and 1H NMR characterization. The DBS-COOH gel network endows the hybrid gel with a well-controlled release behaviour of an anti-inflammatory drug-diclofenac sodium (DCF). Further in vivo wound healing experiments elucidated that the hybrid gel is a promising candidate material for biomedical applications. The enzymatic one-pot preparation principle will provide a unique viewpoint for fabricating functional LMWG/polymer hybrid hydrogels.