Stimuli-responsive nano-reserveriors drug delivery systems based on inorganic nanoparticles

The convergence of nanotechnology,material science,biology and medicine promotes the rapid development of nano-biomedicine,which plays an important role in relieving the pain of patients and improving the health of human,in particular of cancer therapy.Construction of stimuli-responsive controlled release system for targeted drug delivery to specific cells is essentially important for cancer therapy since most chemotherapeutics are severely toxic[1].During past decades,magnetic nanoparticles（MNPs）and mesoporous silica nanoparticles（MSNs）attracted much attention in the related field,due to their good biocompatibility。

Mesoporous Silica Nanoparticles/Magnetic Iron Nanoparticles Based Nanocarriers for Stimuli-Responsive Targeted Tumor Therapy

Construction of stimuli-responsive controlled release system for targeted drug delivery to specific cells is essentially important for cancer therapy since most chemotherapeutics are severely toxic[1].Surface-functionalized magnetic nanoparticles(MNPs)and end-capped mesoporous silica nanoparticles(MSNs)presented themselves as ideal stimuli-responsive carriers for controlled drug and/or gene delivery,owing to their good biocompatibility,

Surface modification of titanium implant for repairing/improving microenvironment of bone injury and promoting osseointegration

Bone injury and implantation operation are often accompanied by microenvironment damage of bone tis-sue,which seriously affects the process of osseointegration of implants,especially for titanium(Ti)-based bioinert materials.Thus,repairing or improving the microenvironment of damaged bone tissue is of great significance for bone rescue,reconstruction,and regeneration,which is still a major medical challenge.Oxidative stress(OS)and oxygen(O_(2))deficiency are considered to be specific physiological signals of the bone-injury microenvironment.From the above background,a coating consisting of manganese dioxide(MnO_(2))nanoenzyme and strontium(Sr)ions was fabricated on the surface of the Ti implant via a one-step hydrothermal treatment.MnO_(2) nanoenzyme presented in the coating alleviated OS and O_(2) deficiency at the injury site by catalyzing the decomposition of abundant endogenous H_(2)O_(2) around the modified Ti implants into O_(2).In addition,Sr ions were released from the surface of the implant at a certain rate in a body-fluid environment,further promoting the adhesion,growth,and osteogenic differentiation of mesenchymal stem cells.More importantly,a Sprague Dawley rat femur model demonstrated that the modified Ti implant showed significant potential to accelerate bone tissue reconstruction in vivo.In sum-mary,the present system provides a new idea for the treatment of bone injury and the development of new orthopedic implants.

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.

Design of manganese ion coated Prussian blue nanocarrier for the therapy of refractory diffuse large B-cell lymphoma based on a comprehensive analysis of ferroptosis regulators from clinical cases

Diffuse large B-cell lymphoma(DLBCL)is a prevalent human malignancy,and understanding its biology will help identify problems in refractory patients and customize alternative therapies for them.We found that DLBCL can be stratified into two independent subtypes with different clinical characteristics and outcomes by consensus clustering of expression of ferroptosis regulatory genes,which proves that ferroptosis is effective in treating refractory cases.In this work,we constructed a novel ferroptosis nanocarrier(PBPMn@PEG)by coating Prussian blue nanoparticles with manganese ions and encapsulating them with poly(ethyleneglycol).The low efficiency of the Fenton reaction of Prussian blue nanoparticles can be improved greatly by manganese coating,and can effectively generate hydroxyl radicals,and induce ferroptosis of lymphoma cells(SU-DHL-10 cells)by down-regulating ferroptosis suppressor genes and up-regulating ferroptosis driver genes.It also induces effective cell apoptosis,which is synergistic with ferroptosis for DLBCL therapy.In vivo experiments also prove that PBPMn@PEG achieved a better anti-tumor effect by up-regulating COX2,HO-1/hemeoxygenase-1(HMOX1),and NADPH oxidase-4(NOX4),and downregulating FSP1 and GPX4,with lower biotoxicity.As a novel and potential DLBCL drug carrier,our discovery served as a foundation for the treatment of the refractory DLBCL by inducing ferroptosis for DLBCL treatment in addition to the therapeutic effect of drugs.

Effects of Y on the Microstructure, Mechanical and Bio-corrosion Properties of Mg-Zn-Ca Bulk Metallic Glass

The micro-alloying effects of Y on the microstructure, mechanical properties, and bio-corrosion behavior of Mg69-xZn27Ca4Yx（x= 0, 1, 2 at.%） alloys were investigated through X-ray diffraction, compressive tests,electrochemical treatments, and immersion tests. The Mg69Zn27Ca4 alloy was found to be absolutely amorphous, and its glass-forming ability decreased with the addition of Y. The Mg68Zn27Ca4Y1 alloy exhibited an ultrahigh compressive strength above 1010 MPa as well as high capacity for plastic strain above 3.1%.Electrochemical and immersion tests revealed that these Y-doped MgeZ neC a alloys had good bio-corrosion resistance in simulated body fluid（SBF） at 37℃. The results of the cytotoxicity test showed high cell viabilities for these alloys, which means good bio-compatibility.

Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant

A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation.Over-active and continuous inflammation,however,impairs fracture healing and leads to excessive tissue damage.Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site.In the present study,we achieved an enriched concentration of PD-L1 from exosomes(Exos)of a genetically engineered Human Umbilical Vein Endothelial Cell(HUVECs),and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface,suppressing the activation of T cells.Furthermore,exosomal PD-L1 induced Mesenchymal Stem Cells(MSCs)towards osteogenic differentiation when pre-cultured with T cells.Moreover,embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner.Additionally,exosomal PD-L1,embedded in a hydrogel,markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase.Importantly,our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites,while T cells in distant immune organs such as the spleen were not affected.In summary,this study provides the first example of using PD-L1-enriched Exos for bone fracture repair,and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.

基于仿生微纳技术抗肿瘤策略研究进展

恶性肿瘤作为全球危害人类健康最主要的杀手之一,给人类生命健康带来极大危害.传统肿瘤的治疗手段主要为手术、化学药物治疗、放射治疗,均存在靶向性不足、造成一定的机体伤害等问题.因此,研究人员试图寻找出新型安全、有效、低成本的肿瘤诊疗方法.随着仿生学、分子科学、基因技术和纳米科学的发展,基于仿生微纳技术的肿瘤仿生治疗技术已成为当前诊疗研究的热点.研究人员从大自然中获取灵感,开发设计了众多仿生材料,并用于新型抗肿瘤策略研发.相较于传统肿瘤诊疗药物,其具有良好的生物相容性、优异的抗肿瘤效果、更低的成本.本文从改善肿瘤微环境角度出发,介绍了4类肿瘤仿生治疗策略及其应用优势,分析仿生抗肿瘤材料的治疗效果,总结仿生抗肿瘤材料研发面临的问题,并对后续应用进行展望.

Antibacterial surface design of biomedical titanium materials for orthopedic applications

Titanium(Ti)and titanium alloys have become widely used as biomedical materials in orthopedics because of their good machinability,corrosion resistance,low elastic modulus and excellent biocompatibility.However,when Ti-based implants are used for bone repair and replacement,they are easy to cause bacteria adhesion and aggregation,which leads to postoperative infection.In addition,Ti and its alloys,as bio-inert materials,cannot induce desirable tissue responses such as osseointegration after implantation,which will eventually lead to implant loosening.Postoperative bacterial infection and lack of osseointegration directly lead to the failure of implantation surgery and are not conductive to the long-term service of titanium-based implants.Recently,researchers have made many attempts to focus on the surface modification of multifunctional Ti-based implants to endow them with both antibacterial activity and simultaneous osteoinductive property.In this review,we primarily highlighted the recent progresses in the surface design of Ti implants with both antimicrobial and osteoinductive properties for orthopedic applications.First,the challenges for treating implant-associated infections were briefly introduced such as the emergence of antibiotic resistance,the formation of biofilms,and the construction of cell-selective surfaces.Some of the essential fundamentals were concisely introduced to address these emerging challenges.Next,we intended to elaborate the potential strategies of multifunctional surface design to endow good osseointegration for antibacterial Ti implants and highlighted the recent advances of the implants.We hope that this review will provide theoretical basis and technical support for the development of new Ti implant with antibacterial and osteogenic functions.

Enzymatically-degradable hydrogel coatings on titanium for bacterial infection inhibition and enhanced soft tissue compatibility via a self-adaptive strategy

Ideal percutaneous titanium implants request both antibacterial ability and soft tissue compatibility.ZnO structure constructed on titanium has been widely proved to be helpful to combat pathogen contamination,but the biosafety of ZnO is always questioned.How to maintain the remarkable antibacterial ability of ZnO and efficiently reduce the corresponding toxicity is still challenging.Herein,a hybrid hydrogel coating was constructed on the fabricated ZnO structure of titanium,and the coating was proved to be enzymatically-degradable when bacteria exist.Then the antibacterial activity of ZnO was presented.When under the normal condition(no bacteria),the hydrogel coating was stable and tightly adhered to titanium.The toxicity of ZnO was reduced,and the viability of fibroblasts was largely improved.More importantly,the hydrogel coating provided a good buffer zone for cell ingrowth and soft tissue integration.The curbed Zn ion release was also proved to be useful to regulate fibroblast responses such as the expression of CTGF and COL-I.These results were also validated by in vivo studies.Therefore,this study proposed a valid self-adaptive strategy for ZnO improvement.Under different conditions,the sample could present different functions,and both the antibacterial ability and soft tissue compatibility were finely preserved.

Constructions of ROS-responsive titanium-hydroxyapatite implant for mesenchymal stem cell recruitment in peri-implant space and bone formation in osteoporosis microenvironment

To solve the issue of unsatisfactory recruitment of mesenchymal stem cells(MSCs)around implant in osteoporotic fractures,we fabricated a ROS-responsive system on titanium surface through hydroxyapatite coating and biomolecule grafting.The porous hydroxyapatite and phosphorylated osteogenic growth peptides(p-OGP)were introduced onto titanium surface to synergistically improve osteogenic differentiation of MSCs.After the p-OGPpromoted expression of osteogenic related proteins,the calcium and phosphate ions were released through the degradation of hydroxyapatite and integrated into bone tissues to boost the mineralization of bone matrix.The ROS-triggered release of DNA aptamer(Apt)19S in the osteoporotic microenvironment guides MSC migration to implant site due to its high affinity with alkaline phosphatase on the membrane of MSCs.Once MSCs reached the implant interface,their osteogenic differentiation potential was enhanced by p-OGP and hydroxyapatite to promote bone regeneration.The study here provided a simple and novel strategy to prepare functional titanium implants for osteoporotic bone fracture repair.

Surface modification of titanium substrate via combining photothermal therapy and quorum-sensing-inhibition strategy for improving osseointegration and treating biofilm-associated bacterial infection

Insufficient osseointegration and biofilm-associated bacterial infection are important challenges for clinical application of titanium(Ti)-based implants.Here,we constructed mesoporous polydopamine(MPDA)nanoparticles(NPs)loaded with luteolin(LUT,a quorum sensing inhibitor),which were further coated with the shell of calcium phosphate(CaP)to construct MPDA-LUT@CaP nanosystem.Then,MPDA-LUT@CaP NPs were immobilized on the surface of Ti implants.Under acidic environment of bacterial biofilm-infection,the CaP shell of MPDA-LUT@CaP NPs was rapidly degraded and released LUT,Ca^(2+)and PO_(4)^(3-)from the surface of Ti implant.LUT could effectively inhibit and disperse biofilm.Furthermore,under near-infrared irradiation(NIR),the thermotherapy induced by the photothermal conversion effect of MPDA destroyed the integrity of the bacterial membrane,and synergistically led to protein leakage and a decrease in ATP levels.Combined with photothermal therapy(PTT)and quorum-sensing-inhibition strategy,the surface-functionalized Ti substrate had an antibacterial rate of over 95.59%against Staphylococcus aureus and the elimination rate of the formed biofilm was as high as 90.3%,so as to achieve low temperature and efficient treatment of bacterial biofilm infection.More importantly,the modified Ti implant accelerated the growth of cell and the healing process of bone tissue due to the released Ca^(2+)and PO_(4)^(3-).In summary,this work combined PTT with quorum-sensing-inhibition strategy provides a new idea for surface functionalization of implant for achieving effective antibacterial and osseointegration capabilities.

Exo/endogenous factors co-activatable nanodevice for spatiotem-porally controlled miRNA imaging and guided tumor ablation

Remote activation of biomarker sensing holds a great promise of shifting the success of in vitro diagnostics to spatiotemporally controlled in vivo visualization of tumor,and in turn,imaging guided therapy.Herein,a"dual-key-one-lock"nanodevice was designed and built by assembling thermo-activatable probe of trimeric DNA hybrids into a mesoporous polydopamine nanoparticle-based multifunctional nanotransducer(probe host,fluorescence quencher,and photothermal conversion agent),enabling precisely switchable theranostic operations under the co-activation of exo/endogenous stimulations(near-infrared(NIR)light and microRNA(miRNA)).By this design,the NIR irradiation-induced local heat through the porous nanotransducer can be transferred to the DNA nanothermometer for triggering the exposure of the miRNA recognition segment,as well as the subsequent fluorescence activation by strand displacement reactions(SDR).A programmable application of short-(3 min)and long-duration(10 min)NIR irradiation was administered sequentially to induce a milder and a stronger hyperthermia,respectively,to activate the localized miRNA imaging,and in turn,tumor thermoablation under the fluorescence guidance in vivo.By reducing nonspecific activation,dual factor co-activatable nanodevices exhibited a high tumor-to-background ratio(TBR)value of 8.9,as well as a significantly lower(6-9-fold)normal tissue fluorescence as compared with those sensing miRNA solely.The in vivo results show that the tumors were significantly suppressed after the photothermal therapy with the assistance of the accurate miRNA diagnosis.This rationally integrated nanoplatform may pave a new avenue for advanced theranostic systems with high spatiotemporal precision by activatable designs.

Moderated crevice corrosion susceptibility of Ti6Al4V implant material due to albumin-corrosion interaction

Localized corrosion of metallic biomaterials is a concerning problem for implant applications.In the present work,the interaction between localized corrosion of Ti6Al4V implant material and adsorption of bovine serum albumin(BSA)was investigated by electrochemical tests,surface morphological and compositional analysis.The artificial crevice was set up on the Ti6Al4V surface to simulate the crevice corrosion of metallic implants.The results show that the BSA adsorption is regulated by the heterogeneous metallic ion release resulted from the crevice corrosion.The negatively charged BSA prefers to aggregate at the interior of artificial crevice due to electrostatic interaction with the concentrated metallic cations in the crevice.In return,the non-uniform BSA adsorption can decrease the crevice corrosion susceptibility of the Ti6Al4V implant material,even though the presence of BSA accelerates the dissolution of passive films.For the Ti6Al4V alloys with artificial crevice,stable localized corrosion occurs after 96 h of immersion in the PBS free of BSA while no stable localized corrosion can be determined in the presence of 4%BSA.It is deduced that the presence of BSA can reduce the surface potential discrepancy between the crevice interior and the crevice exterior.The disclosed mechanism of albumin-corrosion interaction is vital to the localized corrosion control of metallic implants in clinical use.

Phenylboronic acid-modified hollow silica nanoparticles for dual-responsive delivery of doxorubicin for targeted tumor therapy

This work reports a multifunctional nanocarrier based on hollow mesoporous silica nanoparticles(HMSNs)for targeting tumor therapy.Doxorubicin(DOX)was loaded into HMSNs and blocked with cytochrome C conjugated lactobionic acid(CytC–LA)via redox-cleavable disulfide bonds and pH-disassociation boronate ester bonds as intermediate linkers.The CytC–LA was used both as sealing agent and targeting motif.A series of characterizations demonstrated the successful construction of the drug delivery system.The system demonstrated pH and redox dual-responsive drug release behavior in vitro.The DOX loading HMSNs system displayed a good biocompatibility,which could be specifically endocytosed by HepG2 cells and led to high cytotoxicity against tumor cells by inducing cell apoptosis.In vivo data(tumor volume,tumor weight,terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining)proved that the system could deliver DOX to tumor site with high efficiency and inhibit tumor growth with minimal toxic side effect.