Double-network hydrogel enhanced by SS31-loaded mesoporous polydopamine nanoparticles:Symphonic collaboration of near-infrared photothermal antibacterial effect and mitochondrial maintenance for full-thickness wound healing in diabetes mellitus

Diabetic wound healing has become a serious healthcare challenge.The high-glucose environment leads to persistent bacterial infection and mitochondrial dysfunction,resulting in chronic inflammation,abnormal vascular function,and tissue necrosis.To solve these issues,we developed a double-network hydrogel,constructed with pluronic F127 diacrylate(F127DA)and hyaluronic acid methacrylate(HAMA),and enhanced by SS31-loaded mesoporous polydopamine nanoparticles(MPDA NPs).As components,SS31,a mitochondria-targeted peptide,maintains mitochondrial function,reduces mitochondrial reactive oxygen species(ROS)and thus regulates macrophage polarization,as well as promoting cell proliferation and migration,while MPDA NPs not only scavenge ROS and exert an anti-bacterial effect by photothermal treatment under near-infrared light irradiation,but also control release of SS31 in response to ROS.This F127DA/HAMA-MPDA@SS31(FH-M@S)hydrogel has characteristics of adhesion,superior biocompatibility and mechanical properties which can adapt to irregular wounds at different body sites and provide sustained release of MPDA@SS31(M@S)NPs.In addition,in a diabetic rat full thickness skin defect model,the FH-M@S hydrogel promoted macrophage M2 polarization,collagen deposition,neovascularization and wound healing.Therefore,the FH-M@S hydrogel exhibits promising therapeutic potential for skin regeneration.

Elimination of methicillin‑resistant Staphylococcus aureus biofilms on titanium implants via photothermally‑triggered nitric oxide and immunotherapy for enhanced osseointegration

Background:Treatment of methicillin-resistant Staphylococcus aureus(MRSA)biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium(Ti)implants.There is a need to explore more effective approaches for the treatment of MRSA biofilm infections.Methods:Herein,an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles(PDA),nitric oxide(NO)release donor sodium nitroprusside(SNP)and osteogenic growth peptide(OGP)onto Ti implants,denoted as Ti-PDA@SNP-OGP.The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy,X-ray photoelectron spectroscope,water contact angle,photothermal property and NO release behavior.The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2′,7′-dichlorofluorescein diacetate probe,1-N-phenylnaphthylamine assay,adenosine triphosphate intensity,O-nitrophenyl-β-D-galactopyranoside hydrolysis activity,bicinchoninic acid leakage.Fluorescence staining,assays for alkaline phosphatase activity,collagen secretion and extracellular matrix mineralization,quantitative real‑time reverse transcription‑polymerase chain reaction,and enzyme-linked immunosorbent assay(ELISA)were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells(MSCs),RAW264.7 cells and their co-culture system.Giemsa staining,ELISA,micro-CT,hematoxylin and eosin,Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms,inhibition of inflammatory response,and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo.Results:Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light(NIR)irradiation,and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species(ROS)-mediated oxidative stress,destroying bacterial membrane integrity and causing leakage of intracellular components(P<0.01).In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs,but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype(P<0.05 or P<0.01).The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways(P<0.01).In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model(P<0.01).Conclusions:Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Polydopamine nanoparticle-mediated mild photothermal therapy for inhibiting atherosclerotic plaque progression by regulating lipid metabolism of foam cells

Since apoptosis of foam,cells can induce plaque instability,reducing intracellular lipid content while protecting foam cells from apoptosis is beneficial for the safe and efficient therapy of atherosclerosis.In this study,osteopontin-coupled polydopamine(PDA-OPN)nanoparticles were synthesized and applied to target mild photothermal therapy(PTT)of atherosclerosis.The results from laser confocal microscopy indicate that PDA-OPN nanoparticles can be specially recognized and absorbed by foam cells.Under near-infrared laser irradiation,the mild photothermal generated by PDA-OPN decreases intracellular lipid accumulation but does not induce cell apoptosis.In vivo treatments demonstrate that mild PTT can substantially reduce plaque area and improve plaque stability by upregulating the expression of plaque fibrosis in ApoE^(−/−)mice.Our findings reinforce that the PDA-OPN nanoparticle-mediated mild PTT can inhibit atherosclerotic progression,which provides new insights for developing safe and effective treatment methods for atherosclerosis.

Molecular engineering of antibodies for site-specific conjugation to lipid polydopamine hybrid nanoparticles

Conjugation of antibodies to nanoparticles allows specific cancer targeting,but conventional conjugation methods generate heterogeneous conjugations that cannot guarantee the optimal orientation and functionality of the conjugated antibody.Here,a molecular engineering technique was used for sitespecific conjugation of antibodies to nanoparticles.We designed an anti-claudin 3(CLDN3)antibody containing a single cysteine residue,h4 G3 cys,then linked it to the maleimide group of lipid polydopamine hybrid nanoparticles(LPNs).Because of their negatively charged lipid coating,LPNs showed high colloidal stability and provided a functional surface for site-specific conjugation of h4 G3 cys.The activity of h4 G3 cys was tested by measuring the binding of h4 G3 cys-conjugated LPNs(C-LPNs)to CLDN3-positive tumor cells and assessing its subsequent photothermal effects.C-LPNsspecifically recognized CLDN3-overexpressing T47 D breast cancer cells but not CLDN3-negative Hs578 T breast cancer cells.High binding of C-LPNs to CLDN3-overexpressing T47 D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy.Consistent with this,intravenous injection of C-LPNsin a T47 D xenograft mouse model followed by NIR irradiation caused remarkable tumor ablation compared with other treatments through high temperature increases.Our results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.

Polydopamine nanoparticle-dotted food gum hydrogel with excellent antibacterial activity and rapid shape adaptability for accelerated bacteria-infected wound healing

Most commonly used wound dressings have severe problems,such as an inability to adapt to wound shape or a lack of antibacterial capacity,affecting their ability to meet the requirements of clinical applications.Here,a nanocomposite hydrogel(XKP)is developed by introducing polydopamine nanoparticles(PDA NPs)into a food gum matrix(XK,consisting of xanthan gum and konjac glucomannan,both FDA-approved food thickening agents)for skin wound healing.In this system,the embedded PDA NPs not only interact with the food gum matrix to form a hydrogel with excellent mechanical strength,but also act as photothermal transduction agents to convert near-infrared laser radiation to heat,thereby triggering bacterial death.Moreover,the XKP hydrogel has high elasticity and tunable water content,enabling it to adapt to the shape of the wound and insulate it,providing a moist environment suitable for healing.In-vivo skin wound healing results clearly demonstrate that XKP can significantly accelerate the healing of wounds by reducing the inflammatory response and promoting vascular reconstruction.In summary,this strategy provides a simple and practical method to overcome the drawbacks of traditional wound dressings,and provides further options when choosing suitable wound healing materials for clinical applications.

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 10 min and also the slow release of Cu^(2+)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 Cu^(2+).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.

A HAase/NIR responsive surface on titanium implants for treating bacterial infection and improving osseointegration

Bacterial infection and insufficient osseointegration are critical factors affecting the long-term success of titanium-based implants.Unfortunately,the direct application of antibiotic on Ti implants easily leads to poor cytocompatibility,as well as the production of drug-resistant bacteria.So,in this work,we designed a prospective antibacterial strategy by combining photothermal and ciprofloxacin(CIP).The synergistic effect of photothermal and antibiotic may provide an effective bacteriostatic efficacy without sacrificing osteogenesis at a mild condition of moderate temperature and less antibiotic.Herein,CIP was loaded into mesoporous polydopamine(MPDA)nanoparticles(MPDA@CIP),which were anchored on the surface of titanium and finally covered with sodium hyaluronate-catechol(HAc)coating.The hydrophilic HAc layer could inhibit the early adhesion of bacteria,and some bacteria could secrete bacterial hyaluronidase to accelerate the degradation of HAc.This enabled smart enzyme-triggered release of antimicrobials at the site of infection on-demand and avoided unwanted side effects on normal tissues.In addition,NIR light irradiation had a positive influence on both CIP release and MPDA nanoparticle’s photothermal effect.Moreover,before anchoring MPDA@CIP,by the construction of hydroxyapatite microstructure on Ti sur-face with micro-arc oxidation and alkali heat treatment,the ability of bone formation of Ti could be promoted also.Both in vitro as well as in vivo assays demonstrated that functional Ti has an excellent antibacterial effect and osteogenic ability.

Mesoporous polydopamine nanoplatforms loaded with calcium ascorbate for amplified oxidation and photothermal combination cancer therapy

Destruction of cellular redox homeostasis to induce cancer cell apoptosis is an emerging tumor therapeutic strategy. To achieve this goal, elevating exogenous oxidative stress or impairing the antioxidant defense system of cancer cells is an effective method. Herein, we firstly report a biocompatible and versatile nanoplatform based on mesoporous polydopamine (MpDA) nanoparticles and a phase-change material (PCM) for delivering calcium ascorbate (Vc-Ca), simultaneously enabling combination therapy of hyperthermia, reactive oxygen species (ROS) generation, and suppression of tumor antioxidant capability. In this design, Vc-Ca encapsulated in MpDA using PCM is controllably released due to the melting of PCM matrix in response to photothermal heating upon near-infrared irradiation. Vc-Ca is proved to be a prooxidant that can promote the production of ROS (H2O2) in the tumor site. Remarkably, MpDA can not only act as a photothermal agent but also can break the redox balance of cancer cells through depleting the primary antioxidant glutathione, thus amplifying Vc-Ca-mediated oxidative therapy. Both in vitro and in vivo results demonstrate the significantly enhanced antitumor activity of boosted ROS combined with local hyperthermia. This study highlights the potential applications of Vc-Ca in cancer treatment, and the prepared multifunctional nanoplatform provides a novel paradigm for highefficiency oxidation-photothermal therapy.

pH Readout enhanced ELISA for point-of-care testing of cardiac troponin I

Enzyme-linked immunosorbent assay（ELISA） as a conventional method for protein quantification has its characteristic properties,however,it is challenging to implement excellent portability and sensitivity at the same time.In this study,we described a pH ELISA using synthetic melanin nanoparticles（SMNPs） for the co-immobilization of glucose oxidase（GOx） and second antibody（Ab_2） as signal labels,portable pH meter as signal readout device for point-of-care testing（POCT） of cardiac troponin I（cTnI）.In accordance with the varying amount of cTnI,following sandwich type immunoassay,proportional SMNPs-GOx-Ab_2 were immobilized specifically resulting in corresponding decrease of pH values owing to GOx loaded on SMNPs can high-efficiency convert glucose into gluconic acid.This assay is easy-to-use,portable,sensitive and able to realize POCT,affording a linear range from 0.5 pg/m L to 10 ng/m L and low limit of detection（LOD） of 0.15 pg/m L towards cTnI,which was demonstrated the significant promising in the early diagnosis and screening of acute myocardial infarction.