Tea polyphenol modified, photothermal responsive and ROS generative black phosphorus quantum dots as nanoplatforms for promoting MRSA infected wounds healing in diabetic rats.

BACKGROUND: Healing of MRSA (methicillin-resistant Staphylococcus aureus) infected deep burn wounds (MIDBW) in diabetic patients remains an obstacle but is a cutting-edge research problem in clinical science. Surgical debridement and continuous antibiotic use remain the primary clinical treatment for MIDBW. However, suboptimal pharmacokinetics and high doses of antibiotics often cause serious side effects such as fatal complications of drug-resistant bacterial infections. MRSA, which causes wound infection, is currently a bacterium of concern in diabetic wound healing. In more severe cases, it can even lead to amputation of the patient's limb. The development of bioactive nanomaterials that can promote infected wound healing is significant. RESULTS: The present work proposed a strategy of using EGCG (Epigallocatechin gallate) modified black phosphorus quantum dots (BPQDs) as therapeutic nanoplatforms for MIDBW to achieve the synergistic functions of NIR (near-infrared)-response, ROS-generation, sterilization, and promoting wound healing. The electron spin resonance results revealed that EGCG-BPQDs@H had a more vital photocatalytic ability to produce singlet oxygen than BPQDs@H. The inhibition results indicated an effective bactericidal rate of 88.6% against MRSA. Molecular biology analysis demonstrated that EGCG-BPQDs significantly upregulated CD31 nearly fourfold and basic fibroblast growth factor (bFGF) nearly twofold, which were beneficial for promoting the proliferation of vascular endothelial cells and skin epidermal cells. Under NIR irradiation, EGCG-BPQDs hydrogel (EGCG-BPQDs@H) treated MIDBW area could rapidly raise temperature up to 55 °C for sterilization. The MIBDW closure rate of rats after 21 days of treatment was 92.4%, much better than that of 61.1% of the control group. The engineered EGCG-BPQDs@H were found to promote MIDBW healing by triggering the PI3K/AKT and ERK1/2 signaling pathways, which could enhance cell proliferation and differentiation. In addition, intravenous circulation experiment showed good biocompatibility of EGCG-BPQDs@H. No significant damage to major organs was observed in rats. CONCLUSIONS: The obtained results demonstrated that EGCG-BPQDs@H achieved the synergistic functions of photocatalytic property, photothermal effects and promoted wound healing, and are promising multifunctional nanoplatforms for MIDBW healing in diabetics.

Biodegradable hollow mesoporous bimetallic nanoreactors to boost chemodynamic therapy.

As an endogenous catalytic treatment, chemodynamic therapy (CDT) was attracting considerable attention, but the weak catalytic efficiency of Fenton agents and the non-degradation of nanocarriers severely limited its development. In this work, a biodegradable bimetallic nanoreactor was developed for boosting CDT, in which Fe-doped hollow mesoporous manganese dioxide (HMnO2) was selected as nanocarrier, and the Fe/HMnO2@DOX-GOD@HA nanoprobe was constructed by loading doxorubicin (DOX) and modifying glucose oxidase (GOD) and hyaluronic acid (HA). The glutathione (GSH) responsive degradation of HMnO2 promoted the release of DOX, by which the release rate significantly increased to 96.6%. Moreover, by the GSH depletion, the reduction of Mn2+/Fe2+ achieved strong bimetallic Fenton efficiency, and the hydroxyl radicals (·OH) generation was further enhanced using the self-supplying H2O2 of GOD. Through the active targeting recognition of HA, the bimetallic nanoreactor significantly enriched the tumor accumulation, by which the enhanced antitumor efficacy was realized. Thus, this work developed biodegradable bimetallic nanoreactor by consuming GSH and self-supplying H2O2, and provided a new paradigm for enhancing CDT.

Preparation of pro-angiogenic, antibacterial and EGCG-modified ZnO quantum dots for treating bacterial infected wound of diabetic rats.

The complex wound environment and abnormalities in self-metabolism of diabetic skin defects lead to impaired angiogenesis, which can easily lead to bacterial infection and increased inflammation. Therefore, there is an urgent need for multifunctional composites with antimicrobial and pro-angiogenic properties to improve the current therapeutic outcomes of diabetic wounds. In this study, we described an EGCG-modified zinc oxide quantum dots (ZnO QDs) hydrogel (ZnO-EGCG@H) for the treatment of delayed diabetic wounds. In vitro antimicrobial assays showed that ZnO-EGCG@H effectively cleared 95.6% of MRSA and 97% of AmprE. coli with good bactericidal activity. Western blotting assay analysis showed that ZnO-EGCG@H downregulated trauma inflammatory factors (TNF-α, IL-6) by 46.9% and 57%, respectively, while upregulating 1.7-fold VEGF and 2-fold EGF, accelerating wound healing by reducing inflammatory response and promoting proliferation of vascular endothelial cells and skin epidermal cells. After 15 days of ZnO-EGCG@H treatment, the rate of skin lesion closure in rats was 96.3%, which was much better than that of 65.4% in the control group. Safety experiments showed that ZnO-EGCG@H was reassuringly biocompatible and harmless to vital organs. The obtained results suggested that ZnO-EGCG@H had the potential to be a safe and effective treatment method with a promising future as a diabetic wound treatment material.

Electrospinning of antibacterial and anti-inflammatory Ag@hesperidin core-shell nanoparticles into nanofibers used for promoting infected wound healing.

Bacterial infection and excessive inflammation are still the main obstacles to wound repair. Thus, antibacterial and anti-inflammation nanomaterials are always attracting for infected wound healing. In this work, ultra-uniform (∼20 nm) and colloidally stable Ag nanoparticles (Ag-Hes NPs) with core-shell structure were prepared by using hesperidin as reducing and capping agent. The obtained Ag-Hes NPs present effective antibacterial properties on both Staphylococcus aureus and Escherichia coli. Ag-Hes NPs also got high 1,1-diphenyl-1-picrylhydrazyl scavenging capability of 69%. Under the package of polyvinyl alcohol and sodium alginate, Ag-Hes NPs were encapsulated into electro spun nanofibers to form hydrogel (Ag-Hes@H). This strategy provides a moisture environment which could enrich and release Ag-Hes NPs gradually. Cell experiments and animal wound healing investigation proved that Ag-Hes@H could promote the proliferation and migration of human umbilical vein endothelial cells and accelerate infected wound healing. Meanwhile, Ag-Hes@H significantly reduced the expression of inflammatory cytokines, including IL-6, MMP9 and TNF-α. Immunohistochemistry data further suggested that Ag-Hes@H accelerated wound closure by promoting collagen deposition and skin cell proliferation. The designed antibacterial and anti-inflammatory Ag-Hes@H has great potential for promoting infected wound healing.

Preparation of epigallocatechin gallate decorated Au-Ag nano-heterostructures as NIR-sensitive nano-enzymes for the treatment of osteoarthritis through mitochondrial repair and cartilage protection.

Osteoarthritis (OA), a widespread degenerative disease characterized by cartilage destruction, has emerged as a public health challenge in the current aging society. In addition to applied steroids and surgery, near-infrared (NIR) sensitive nano-enzyme for the treatment of osteoarthritis through mitochondrial repair and cartilage protection is attractive and promising. In this study, a NIR sensitive multifunctional heterostructure (EGCG (Epigallocatechin gallate) decorated Au-Ag nano-jars (E@Au-Ag)) was introduced as an enzyme-sensitive active nanoplatform for the treatment of osteoarthritis. Molecular biology results indicated that E@Au-Ag possesses intrinsic properties of anti-oxidative stress and was able to reduce the apoptosis rate of chondrocytes by 83.3%. The area of the intra-articular joint cavity injected with E@Au-Ag can be elevated to 46.6 °C under NIR to promote the release of EGCG further to induce cartilage regeneration. X-ray radiography and section staining showed that E@Au-Ag reduced cartilage damage and decreased OARSI scores by approximately 52% after 8 weeks of treatment in a surgically induced OA model. The results demonstrated that this multifunctional enzyme-like nanoplatform with a synergistic NIR sensitive property to facilitate cartilage migration and regeneration repair provides a promising OA treatment strategy. STATEMENT OF SIGNIFICANCE: 1. NIR-sensitive nano-enzyme is gaining much attention in the field of biomedical materials. 2. EGCG decorated Au-Ag nano-heterostructures were utilized as NIR-sensitive nano-enzymes for the treatment of osteoarthritis through mitochondrial repair and cartilage protection. 3. The obtained multifunctional Au-Ag nano-heterostructures are promising for osteoarthritis treatment.

Preparation of Photocatalytic and Antibacterial MOF Nanozyme Used for Infected Diabetic Wound Healing.

Bacterial infection has been a considerable obstacle for diabetic wound healing. A multifunctional nanoplatform used as nanozyme for bacterial infected diabetic wound is extremely attractive. Therefore, gold nanoclusters modified zirconium-based porphyrin metal-organic frameworks (Au NCs@PCN) were constructed by an in situ growth method. Through SEM, TEM, and EDS mapping, the surface of ellipsoid-shaped particles around 190 nm was observed to be evenly interspersed with 5-8 nm gold nanoclusters. Notably, Au NCs@PCN exhibits excellent performance in exciting ROS generation and photothermal effects. Under near-infrared (NIR) laser irradiation, Au NCs@PCN can be heated to 56.2 °C and produce ROS, showing an effective killing effect on bacteria. Antibacterial studies showed that Au NCs@PCN inhibited MRSA and Ampr E. coli by destroying membrane structure and inducing protein leakage up to 95.3% and 90.6%, respectively. Animal experiments showed that Au NCs@PCN treated diabetic rats had reduced wound coverage to 2.7% within 21 days. The immunoblot analysis showed that proangiogenic and proepithelial cell proliferation factors were expressed significantly up-regulated. These results prove that Au NCs@PCN with photocatalytic and nanozyme activity has a broad application prospect for promoting diabetic infected wound healing.

Preparation of NIR-responsive, ROS-generating and antibacterial black phosphorus quantum dots for promoting the MRSA-infected wound healing in diabetic rats.

Multidrug-resistant (MDR) bacteria-induced infection is becoming a huge challenge for clinical treatment, especially for non-healing diabetic wound infections, which increase patient mortality. MRSA infections and delayed wound healing (methicillin-resistant Staphylococcus aureus) accounted for a higher proportion. Although surgical debridement and continuous use of antibiotics are still the main clinical treatments, new multifunctional therapeutic nanoplatform are attractive for MIDW. Thus, in the present study, black phosphorus quantum dots (BPQDs) encapsulated in hydrogel (BPQDs@NH) were utilized as nanoplatforms for MIDW treatment to achieve the multifunctional properties of NIR (near infrared) responsiveness, ROS (reactive oxygen species) generation and antibacterial activity. Upon NIR irradiation, the temperature of the BPQDs@NH-treated MIDW area rapidly increased up to 55 °C for sterilization. In vitro experiments showed that BPQDs@NH exerted a synergistic effect on inhibiting MRSA by producing of ROS, lipid peroxidation, glutathione, adenosine triphosphate accumulation and bacterial membrane destruction upon NIR irradiation. The resulting BPQDs@NH achieved an effective sterilization rate of approximately 90% for MRSA. Furthermore, animal experiments revealed that BPQDs@NH achieved an effective closure rate of 95% for MIDW after 12 days by reducing the inflammatory response and regulating the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Meanwhile, intravenous circulation experiments showed good biocompatibility of BPQDs, and no obvious damage to rat major organs was observed. The obtained results indicated that BPQDs@NH achieved the synergistic functions of NIR-responsiveness, ROS generation, and antibacterial activity and promoted wound healing, suggesting that they are promising multifunctional nanoplatforms for MIDW healing. STATEMENT OF SIGNIFICANCE: 1. NIR-triggered ROS-generating and antibacterial nanoplatforms are attractive in the wound healing field. 2. In this work, black phosphorus quantum dots encapsulated in a hydrogel were used as a nanoplatform for treating MRSA infected wounds. 3. The obtained materials have achieved an effective sterilization rate for MRSA and effective wound closure rate.

Modulation of Rat Kidney Stone Crystallization and the Relative Oxidative Stress Pathway by Green Tea Polyphenol.

The role of tea polyphenol (TP) in modulating kidney stone crystallization and regulating the relative nephropathy pathway of rats was investigated. Calcium oxalate (CaOx) crystallization and oxidative stress are essential for kidney stone diseases. The kidney stone model in a rat was established by using ethylene glycol to affect the oxalic acid metabolism. The crystallization process of CaOx in the rat kidney was modulated by different TP intakes. At the same time, the effects of different types of CaOx, extracted from the rat kidney, on the proliferation and differentiation of HK-2 cells were also studied. The results showed that calcium oxalate monohydrate crystals were obtained in the blank control and the low-dose TP groups. However, CaOx crystals extracted from higher-TP-intake groups were mainly calcium oxalate dihydrate. Moreover, the size of the CaOx crystals produced in TP intake groups was much smaller than that of the blank control group. Cell experiment results show that TP can effectively reduce the damage of CaOx crystals to HK-2 cells. Further research found that TP can significantly improve oxidative stress in cases of kidney stones. TP has been proven to control CaOx crystallization in vitro, but the in vivo research results obtained through the rat stone model in this paper are novel and originally important for researching the relationship between tea drinking and preventive treatment of kidney stone diseases.

Preparation of exosomes encapsulated nanohydrogel for accelerating wound healing of diabetic rats by promoting angiogenesis.

Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) were helpful for injury repair, but whether HUCMSCs-derived exosomes could be encapsulated in a novel nanohydrogel to regulate diabetic wound healing was unclear. Here, HUCMSCs-derived exosomes encapsulated in a bioactive scaffold composed of polyvinyl alcohol (PVA)/alginate (Alg) nanohydrogel (exo@H) was applied to wound healing of diabetic rats. Results found that exo@H could facilitate the proliferation, migration and angiogenesis of HUVECs and sped up the process of diabetic wound healing. We confirmed that exo@H contributed to the expression of the molecules related to wound healing, including SMA, SR-B1 and CD31. Besides, we also found that exo@H up-regulated VEGF level via regulating ERK1/2 pathway. These data demonstrated that exo@H significantly accelerated healing of diabetic wounds in rats by promoting angiogenesis.

Preparation of EGCG decorated, injectable extracellular vesicles for cartilage repair in rat arthritis.

Arthritis is a kind of chronic inflammatory autoimmune disease, which can destroy joint cartilage and bone, leading to joint pain, joint swelling, and limited mobility. Traditional therapies have many side effects or focus too much on anti-inflammation while neglecting joint repair. In this experiment, we combined Epigallocatechin gallate (EGCG) with extracellular vesicles derived from macrophages to treat rheumatoid arthritis. Sustained-release resulted in a significant decrease in chondrocyte expression of hypoxia-inducible factor 1-alpha, a decrease in apoptosis-related proteins Cytochrome C, Caspase-3, Caspase-9, and Bax. Molecular biological analysis showed that extracellular vesicles-encapsulated EGCG (EVs-EGCG) more significantly upregulated type II collagen expression by about 1.8-fold than EGCG alone, which was more beneficial for arthritis repair. Animal experiments revealed that these EGCG-coated extracellular vesicles significantly reduced swelling, decreased synovial hyperplasia, repaired cartilage, and attenuated arthritis-related pathology scores in arthritic rats. Measurement data showed that EVs-EGCG treatment reduced joint swelling by approximately 39.5% in rheumatoid rats. In vitro studies have shown that this EVs-EGCG can increase the expression of cartilage type II collagen and reduce apoptosis of chondrocytes. Moreover, it was demonstrated in vivo experiments to reduce cartilage destruction in rheumatoid arthritis rats, providing a solution for the treatment of rheumatoid arthritis.

Preparation of ROS active and photothermal responsive hydroxyapatite nanoplatforms for anticancer therapy.

Photothermal responsive nanoplatforms are attracting for photothermal therapy (PTT) of cancer. Herein, we propose a strategy to prepare IR-780 modified hydroxyapatite (HAP) nanorods as photothermic agents (HAP@IR-780). The results demonstrated that the obtained HAP@IR-780 was photothermal responsive under near-infrared laser irradiation the photothermal conversion efficiency was 69.3%, and it remained photostability after 4 cycles of irradiation. This advantage overcomes the optical instability of IR780. MTT and cellular uptake research proved that HAP@IR-780 was biocompatible in appropriate concentration range (0-20 µg/mL) without laser irradiation. Concentration-dependent internalization and reactive oxygen species (ROS) related apoptosis of HAP@IR-780 for MCF-7 cells were observed. Animal experiments showed that the gathered HAP@IR-780 at the tumor site reached a photothermal responsive temperature up to 57.9 °C, which could almost ablate the tumor with volumes as large as 1500 mm3. In general, our photothermal material has good photothermal conversion characteristics, and may have the least safety problems while showing excellent therapeutic effects. Therefore, HAP@IR-780 has a brilliant prospect in the field of tumor photothermal therapy.