A Multifunction Hydrogel-Coating Engineered Implant for Rescuing Biofilm Infection and Boosting Osseointegration by Macrophage-Related Immunomodulation.

Innovative methodologies combined with scavenging reactive oxygen species (ROS), alleviating oxidative stress damage and promoting macrophage polarization to M2 phenotype may be ideal for remodeling implant-infected bone tissue. Herein, a functionalization strategy for doping Tannic acid-d-tyrosine nanoparticles with photothermal profile into the hydrogel coating composed of konjac gum and gelatin on the surface of titanium (Ti) substrate is accurately constructed. The prepared hydrogel coating exhibits excellent properties of eliminating biofilm and killing planktonic bacteria, which is based on increasing susceptibility to bacteria by the photothermal effect, biofilm-dissipation effect of D-tyrosine, as well as the bactericidal effect of tannic acid. In addition, the modified Ti substrate has effectively alleviated proinflammatory responses by scavenging intracellular excessive ROS and guiding macrophages polarization toward M2. More interesting, conditioned medium from macrophage indicates that paracrine is conducive to osteogenic proliferation and differentiation of mesenchymal stem cells. Results from rat model of femur infection in vivo demonstrate that the modified Ti implant significantly eliminates the residual bacteria, relieves inflammation, mediates macrophage polarization, and accelerates osseointegration. Altogether, this study exhibits a new perspective for the development of advanced functional implant with great application potential in bone tissue regeneration and repair.

Enhanced Immunogenic Cell Death and Antigen Presentation via Engineered Bifidobacterium bifidum to Boost Chemo-immunotherapy.

The immunogenic cell death (ICD) of tumor cells has aroused great interest in the field of immunotherapy, mainly due to the production of plentiful tumor-associated antigens (TAAs) and damage-associated molecule patterns. However, doxorubicin (DOX)-induced tumor-specific T-cell-mediated immune response is usually very weak because of antigen presentation deficiency and the immunosuppressive tumor microenvironment (ITME). Herein, the probiotic Bifidobacterium bifidum (Bi) was covalently modified with DOX-loaded CaP/SiO2 nanoparticles (DNPs@Bi) for tumor therapy. On one hand, the pH-responsive release of DOX could induce chemotherapy and ICD in the ITME. On the other hand, tumor-targeting Bi is able to significantly enhance the presentation of TAAs from B16F10 cells to DCs via Cx43-dependent gap junctions. Due to the combination of enhanced ICD and TAAs presentation, the maturation of DCs and the infiltration of cytotoxic T lymphocytes in the ITME were stimulated. As a result, in vivo antitumor experiments demonstrated that DNPs@Bi prolonged the survival rate and significantly inhibited the tumor progression and metastasis. This strategy of bacterial-driven hypoxia-targeting delivery systems offers a promising approach to tumor chemo-immunotherapy.

Fabrication of a New Hyaluronic Acid/Gelatin Nanocomposite Hydrogel Coating on Titanium-Based Implants for Treating Biofilm Infection and Excessive Inflammatory Response.

Persistent inflammation caused by implant-associated biofilm infections has emerged as a significant clinical issue. While many methods have been developed to give implants great anti-biofilm benefits, the post-inflammatory microenvironment is frequently disregarded. Oxidative stress (OS) due to excessive reactive oxygen species (ROS) is considered to be one of the specific physiological signals of the inflammation microenvironment. Herein, ZIF-90-Bi-CeO2 nanoparticles (NPs) were incorporated into a Schiff-base chemically crosslinked hydrogel composed of aldehyde-based hyaluronic acid and gelatin. Through chemical crosslinking between polydopamine and gelatin, the hydrogel coating adhered to the Ti substrate. The modified Ti substrate gained multimodal antibacterial and anti-biofilm functions, which were attributed to the photothermal effect of Bi NPs, and the release of Zn ions and CeO2 NPs. Notably, CeO2 NPs endowed the system with dual-enzyme (SOD- and CAT-like) catalytic activities. In a rat implant-associated infection (IAI) model, the dual-functional hydrogel had a biofilm-removal ability and regulated OS and inflammatory responses to facilitate osseointegration. The photothermal therapy combined with a host inflammation-microenvironment regulation strategy might provide a novel treatment for biofilm infection and the accompanying excessive inflammation.

Doxorubicin-loaded polypyrrole nanovesicles for suppressing tumor metastasis through combining photothermotherapy and lymphatic system-targeted chemotherapy.

The lymphatic system provides a main route for the dissemination of most malignancies, which was related to high mortality in cancer patients. Traditional intravenous chemotherapy is of limited effectiveness on lymphatic metastasis due to the difficulty in accessing the lymphatic system. Herein, a novel lymphatic-targeting nanoplatform is prepared by loading doxorubicin (DOX) into sub-50 nm polypyrrole nanovesicles (PPy NVs). The PPy NVs possessed hollow spherical morphologies and a negative surface charge, leading to high drug loading capacity. These vesicles can also convert near-infrared (NIR) light into heat and thus can be used for tumor thermal ablation. DOX loaded PPy NVs (PPy@DOX NVs) along with NIR illumination are highly effective against 4T1 breast cancer cells in vitro. More importantly, following subcutaneous (SC) injection, a direct lymphatic migration of PPy@DOX NVs is confirmed through fluorescence observation of the isolated draining nodes. The acidic conditions in metastatic nodes might subsequently trigger the release of the encapsulated DOX NVs based on their pH-sensitive release profile. In a mouse model bearing 4T1 breast cancer, lymphatic metastases, as well as lung metastases, are significantly inhibited by nanocarrier-mediated trans-lymphatic drug delivery in combination with photothermal ablation. In conclusion, this platform holds great potential in impeding tumor growth and metastasis.

Fabrication of a pH-responsive core-shell nanosystem with a low-temperature photothermal therapy effect for treating bacterial biofilm infection.

Recently, photothermal therapy (PTT) has been recognized as a viable alternative strategy against bacterial biofilm infection. However, the hyperthermia required for PTT to ablate a biofilm usually induces damage in normal tissues/organs nearby. Herein, we developed zeolite-based imidazole framework (ZIF-8)-coated mesoporous polydopamine (MPDA) core-shell nanoparticles and then loaded Pifithrin-µ (PES), a natural inhibitor of heat-shock protein (HSP) that plays an essential role in bacteria resisting heating-induced damage. The ZIF-8 shell of the MPDA@ZIF-8/PES nanoplatform enabled a rapid degradation in response to the acidic environment in bacterial biofilm infection, which triggered the controlled release of PES and Zn ions. As a result, HSP was remarkably suppressed for enhancing PTT efficacy upon mild near-infrared light irradiation. In addition, the release of Zn2+ also had an antibacterial/antibiofilm effect. Thus, the fabricated nanosystem was able to induce the effective elimination of the bacterial biofilm, realizing low-temperature PTT (∼45 °C) with excellent antibacterial efficacy. This work presented here not only provides a facile approach to fabricate the MPDA@ZIF-8/PES nanosystem with the responsiveness of the bacterial infection environment, but also proposes a promising low-temperature PTT strategy to treat bacterial biofilm-infection effectively.

Polydopamine Nanosheets Doped Injectable Hydrogel with Nitric Oxide Release and Photothermal Effects for Bacterial Ablation and Wound Healing.

The development of wound dressings with combined antibacterial activities and pro-healing functions has always been an intractable medical task for treating bacterial wound infection. Herein, a novel injectable hybrid hydrogel dressing is developed, which is doped with nitric oxide (NO) donor (N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine, BNN6) loaded two-dimensional polydopamine nanosheets (PDA NS). The hydrogel matrix is in situ formed through dynamic Schiff base crosslinking between hydrazide-modified γ-polyglutamic acid (γ-PGA-ADH) and aldehyde-terminated Pluronic F127 (F127-CHO). Under 808 nm irradiation, the embedded PDA NS exhibits outstanding photothermal transform properties (56.1%) and on-demand NO release. The combination of photothermal and NO gas therapy with a synergistic antibacterial effect works on both Escherichia coli and Staphylococcus aureus in vitro. Furthermore, a full-thickness skin defect model also demonstrates that the hybrid hydrogel shows outstanding antibacterial properties and effectively accelerates the wound healing process. Overall, this study provides a facile and promising method for the fabrication of PDA NS based multifunctional hydrogel dressing for the application of infectious skin wound healing.

Mitochondrial Metabolism Targeted Nanoplatform for Efficient Triple-Negative Breast Cancer Combination Therapy.

Tumor reprogram pathway of mitochondrial metabolism is an emerging approach for malignant tumor treatment, such as triple-negative breast cancer. In this study, a tumor/mitochondria cascaded targeting, adenosine-triphosphate (ATP) responsive nanocarrier of zeolitic imidazolate framework-90 (ZIF-90) for breast cancer combination therapy is reported. Atovaquone (AVO) and hemin are loaded into ZIF-90, then a peptide iRGD with tumor-targeting ability is modified on the ZIF-90 nanoplatform. Hemin can specifically degrade BTB and CNC homology1 (BACH1), resulting in the changes of mitochondrial metabolism, and AVO acts as the inhibitor of the electron transport chain (ETC). The degradation of BACH1 using hemin can effectively improve the anti-tumor efficiency of mitochondrial metabolism inhibitor AVO, by increasing dependency on mitochondrial respiration. This nanoplatform displays both tumor-targeting and mitochondria-targeting capacity with high level of ATP responsive drug release behavior. The specific characteristic of mitochondria-targeting ability of this nanoplatform can increase the accumulation of AVO in the mitochondria, and in turn, can effectively improve the inhibition of the ETC. Both in vitro and in vivo results reveal that this composite nanocarrier has excellent tumor inhibition ability with limited side effects. Accordingly, this study provides an attractive strategy in the mitochondrial metabolism for cancer targeted therapy.

Functionalized Tumor-Targeting Nanosheets Exhibiting Fe(II) Overloading and GSH Consumption for Ferroptosis Activation in Liver Tumor.

Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX4) is down-regulated by consumption intracellular GSH content via converting GSH into glutathione oxidized (GSSG), which is named the classical mode. The intracellular Fe2+ content is overloaded by the significant up-regulation of HMOX1 expression, which is denoted as nonclassical mode. The synergistic effect of classical and nonclassical mode increased the intracellular lipid reactive oxide species, induced the occurrence of ferroptosis and up-regulated the expression of BH3 interacting domain death agonist (BID), apoptosis-inducing factor (AIF), and endonuclease G proteins (EndoG). The synergistic strategy demonstrate the excellent ferroptosis induction ability and antitumor efficacy in vivo, which provides great potential for the clinical transformation of ferroptosis.

Recent Progress in the Development of Multifunctional Nanoplatform for Precise Tumor Phototherapy.

Phototherapy, including photodynamic therapy and photothermal therapy, mainly relies on phototherapeutic agents (PAs) to produce heat or toxic reactive oxygen species (ROS) to kill tumors. It has attracted wide attention due to its merits of noninvasive properties and negligible drug resistance. However, the phototoxicity of conventional PAs is one of the main challenges for its potential clinical application. This is mainly caused by the uncontrolled distribution of PA in vivo, as well as the inevitable damage to healthy cells along the light path. Ensuring the generation of ROS or heat specific at tumor site is the key for precise tumor phototherapy. In this review, the progress of targeted delivery of PA and activatable phototherapy strategies based on nanocarriers for precise tumor therapy is summarized. The research progress of passive targeting, active targeting, and activatable targeting strategies in the delivery of PA is also described. Then, the switchable nanosystems for tumor precise phototherapy in response to tumor microenvironment, including pH, glutathione (GSH), protein, and nucleic acid, are highlighted. Finally, the challenges and opportunities of nanocarrier-based precise phototherapy are discussed for clinical application in the future.

A nanoplatform based on mesoporous silica-coated gold nanorods for cancer triplex therapy.

To enhance the efficacy of nanoparticle-based cancer therapy with reduced side effects and promote its clinical translation, a biocompatible nanocomposite based on mesoporous silica-coated gold nanorods (AuNR@MSN) for triple tumor therapy is reported in this study. The gold core served as a hyperthermia agent, while the MSN shell acted as a reservoir of chemotherapeutics owing to its excellent loading capacity. Cytochrome c with the apoptosis inducing function was anchored on the surface of AuNR@MSN to prevent drug leakage through redox-responsive disulfide bonds. The successful construction of a nanocomposite was confirmed by characterization of the physicochemical properties. In vitro and in vivo studies demonstrated that the nanocomposite displayed an optimizing anti-tumor effect with a synergistic strategy of excellent photothermal therapy, chemotherapy and protein therapy. Therefore, this cooperative strategy paves the way for high-efficiency oncotherapy with reduced side effects.

Engineering of a Core-Shell Nanoplatform to Overcome Multidrug Resistance via ATP Deprivation.

Inhibiting the function of P-glycoprotein (P-gp) transporter, which causes drug efflux through adenosine triphosphate (ATP)-dependent manner, has become an effective strategy to conquer multidrug resistance (MDR) of cancer cells. However, there remains challenges for effective co-delivery, sequential release of P-gp modulator and chemotherapeutic agent. In this work, a novel type of core-shell nanoparticle is reported. It can independently encapsulate a high amount (about 683 µg mg-1 ) of chemotherapeutic agent doxorubicin (DOX) in the mesoporous polydopamine (MPDA) core and glucose oxidase (GOx) in the zeolite imidazolate frameworks-8 (ZIF-8) shell, namely MPDA@ZIF-8/DOX+GOx. The fast release of GOx triggered by acid-sensitive degradation of the ZIF-8 shell consumes glucose to starve cancer cells for ATP deprivation and effective suppress ATP-dependent drug efflux in advance, and then effectively facilitates the accumulation of DOX in MCF-7/ADR cancer cells. Experiments in vitro and in vivo demonstrate that the fabricated nanosystem can dramatically improve anticancer effects for MDR through sequential release property and exhibit excellent biocompatibility. Overall, this work reveals new insights in the use of GOx for MDR treatment.

Lymph node-targeted immune-activation mediated by imiquimod-loaded mesoporous polydopamine based-nanocarriers.

Toll-like receptor (TLR) agonists are the potent stimulants of innate immune system and hold promises as an adjuvant for anticancer immunotherapy. Unfortunately, most of them are limited by a prompt dissemination, and thus caused "wasted inflammation". Hence, how to restrict their action radius into lymphoid tissues is of great relevance to enhance their efficacy and concomitantly alleviates the side effects. Here, imiquimod (R837), a TLR 7 agonist, was loaded into mesoporous polydopamine (MPDA) nanocarriers with high efficiency. Moreover, its surface was modified by polyvinyl pyrrolidone (PVP) to enhance their lymphatic drainage ability. These nano-adjuvants have obvious advantages in promoting dendritic cell (DC) maturation in comparison to free R837. Moreover, their transportation and retention ability in proximal lymph nodes (LNs) were also confirmed, by which lymphatic drug exposure can be maximized to a great extent. Consequently, effective DC activation and CD8+ T cell responses were observed as expected by R837 released in draining LNs. This effect was further enhanced by the presence of endogenous tumor antigens from apoptosis debris induced by MPDA-based photothermal effect, and thus led to the growth inhibition of subcutaneous B16 melanomas. The results demonstrated the great potency against melanoma of the designed PVP-MPDA@R837 nano-adjuvants by combining photothermal conversion property of MPDA with lymphatic-focused immune-activation.

Redox-responsive amphiphilic camptothecin prodrug nanoparticles for targeted liver tumor therapy.

Tumor cell-targeting drug delivery systems are of great importance to anti-tumor therapy in clinics. Owing to the overexpression of the asialoglycoprotein receptor (ASGPR) on the membrane of hepatoma carcinoma cells, the conjugation of lactose on the surface of drug delivery systems has already shown significant advantages for targeting tumor cells. In this study, a disulfide bond-conjugated prodrug targeting delivery system consisting of camptothecin (CPT) and lactose (LA) was synthesized, which was denoted as CPT-S-S-LA. Camptothecin and lactose act as the chemotherapy drug and targeting ligand in the drug delivery system, respectively. Since CPT-S-S-LA is an amphiphilic compound, it can self-assemble into nanoparticles with a diameter of around 110 nm. The CPT-S-S-LA nanoparticles displayed controllable drug release behavior in the physiological environment. Unlike the free CPT, the CPT-S-S-LA nanoparticles firstly assembled at the tumor sites via the enhanced permeability and retention (EPR) effect, and then were phagocytized by the tumor cells with ASGP receptor-mediated endocytosis. Finally, the antitumor agent CPT was released for killing tumor cells, which have a high glutathione (GSH) concentration environment. The nanoparticles displayed favorable ability to target hepatoma carcinoma cells rather than the normal HUVEC cells in vitro. Both the in vitro and in vivo studies demonstrated that the CPT-S-S-LA nanoparticles display enhanced antitumor ability and reduced side effects. Thus, active targeting prodrug delivery systems should be a promising strategy for liver tumor therapy.

Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy.

Biofilm formation is a main challenge in treatment of bone-implant-associated infections, resulting in tolerance to immune system and antibiotics. However, smart non-surgical or non-invasive treatment methods of combating established biofilm on an implant have been less reported. Herein, a therapeutic system consisting of mesoporous polydopamine nanoparticles (MPDA) to combat biofilm is reported for the first time. We develop a synergistic photothermal/photodynamic therapy (PTT/PDT) strategy aiming for biofilms eradication on titanium (Ti) implant, which is integrated with MPDA loading with photosensitizer Indocyanine Green (ICG) by π-π stacking. Specifically, MPDA is functionalized with RGD peptide to endow the modified Ti sample (Ti-M/I/RGD) with good cytocompatibility. More importantly, Ti-M/I/RGD implant remarkably kills Staphylococcus aureus (S. aureus) biofilm with an efficiency of 95.4% in vivo upon near infrared (NIR). After biofilm eradication, implant still displays great performance regarding osteogenesis and osseointegration. Overall, this study provides a PTT/PDT strtategy for the development of antibacterial Ti implants for potential orthpediac application.

Spin splitting modulated by uniaxial stress in InAs nanowires.

We theoretically study the electronic structure, spin splitting, effective mass, and spin orientation of InAs nanowires with cylindrical symmetry in the presence of an external electric field and uniaxial stress. Using an eight-band k·p theoretical model, we deduce a formula for the spin splitting in the system, indicating that the spin splitting under uniaxial stress is a nonlinear function of the momentum and the electric field. The spin splitting can be described by a linear Rashba model when the wavevector and the electric field are sufficiently small. Our numeric results show that the uniaxial stress can modulate the spin splitting. With the increase of wavevector, the uniaxial tensile stress first restrains and then amplifies the spin splitting of the lowest electron state compared to the no strain case. The reverse is true under a compression. Moreover, strong spin splitting can be induced by compression when the top of the valence band is close to the bottom of the conductance band, and the spin orientations of the electron stay almost unchanged before the overlap of the two bands.