Neutrophil-Mimicking Nanozyme with Cascade Catalytic Releasing Nitric Oxide and Signet Oxygen Property for Synergistic Bimodal Therapy of Methicillin-Resistant Staphylococcus Aureus Infections.

Recently, chloroperoxidase (CPO)-mediated enzyme dynamic therapy (EDT) by mimicking the antipathogen function of neutrophils via generating highly active signet oxygen (1O2) has attracted great interest in biomedical applications. However, the therapeutic efficiency of EDT is largely restricted by the low CPO delivery efficiency and insufficient hydrogen peroxide (H2O2) supply. In the present work, a neutrophil-mimicking nanozyme of MGBC with high CPO delivery efficiency, H2O2 self-supply, and enzyme-cascade catalytic properties is designed for high-efficient treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. In the infection microenvironment, MGBC can effectively catalyze glucose to self-supply substantial H2O2, which enables long-lasting 1O2 generation via the CPO-mediated catalytic reaction. At the meantime, MGBC can also catalyze H2O2 to sustainably release NO for gas therapy (GT), which synergistically strengthens the therapeutic effect of EDT. As a result, MGBC displayed effective MRSA-killing and MSRA biofilms-eradicating properties, and high efficiency in treating both MRSA infected full-thickness excision wounds and subcutaneous MRSA infection by exerting the synergistic bimodal EDT/GT therapeutic effects. In-depth mechanism study revealed that the synergistic EDT/GT antibacterial effects of MGBC can attenuate the drug resistance and toxicity of MRSA by significantly downregulating quorum sensing, multidrug efflux, virulence, and biofilm formation-related genes.

CD-MOF-1 Growth on Polysaccharide Gels through Only C2-OH/C3-OH or C5-O/C6-OH Group Formed Four-Coordinated K+ Ions for Developing Porous Biogels.

The γ-cyclodextrin (γ-CD) metal-organic frameworks (CD-MOF-1) consist of γ-CD and potassium (K+) ions through coordinating an eight-coordinated K+ ion with two C5-linked oxygen and C6-linked hydroxyl (C5-O/C6-OH) groups in the primary faces of adjacent γ-CD units and two C2- and C3-linked hydroxyl (C2-OH/C3-OH) groups in the secondary faces. Herein, we found polysaccharide gels with only C2-OH/C3-OH or C5-O/C6-OH groups in pyranoid rings can form four-coordinated K+ ions and then coordinate γ-CD in a KOH solution for CD-MOF-1 growth. Exposure of C2-OH/C3-OH or C5-O/C6-OH groups in polysaccharide gels is important to form active four-coordinated K+ ions. Mechanism supporting this work is that four-coordinated K+ ion sites are first formed after coordinating C2-OH/C3-OH groups in pectin and then coordinating C5-O/C6-OH groups in the primary faces of γ-CD units. Alternatively, four-coordinated K+ ions with C5-O/C6-OH groups in chitosan can coordinate the C2-OH/C3-OH groups in the secondary faces of γ-CD units. Mechanism of CD-MOF-1 growing on pectin and chitosan gels through the proposed four-coordinated K+ ions is also universally applicable to other polysaccharide gels with similar C2-OH/C3-OH or C5-O/C6-OH groups such as alginate gel. Based on this mechanism, we developed pectin and chitosan gel-based CD-MOF-1 composites and exemplified applications of them in antibacterial and organic dye removal. To help future research and applications of this mechanism, we share our theoretical assumption for further investigations that any matrices with an ortho-hydroxyl carbon chain or ortho-hydroxyl ether structures may form four-coordinated K+ ions for CD-MOF-1 growth. The proposed mechanism will broaden the development of novel CD-MOF-1 composites in various fields.

A Rapid Method for Antigen-Specific Hybridoma Clone Isolation.

Using an enzyme-linked immunosorbent assay (ELISA) and limited dilution methods to screen and clone antigen-specific hybridoma cells is extremely time-consuming and labor-intensive. This work features a simple and rapid cell surface fluorescence immunosorbent assay (CSFIA), designed for the detection and isolation of antigen-specific hybridoma clones. In this assay, antigens are first anchored to the hybridoma cell surface through a dual-functioning molecular Oleyl-PEG4000-NHS. Specific antibodies secreted from hybridoma cells are then captured by the antigens on the cell surface. Positive hybridoma cells are stained using a fluorescently labeled anti-mouse IgG-Fc antibody. After the addition of a methylcellulose semisolid medium, positive clones are easily picked using a pipet. These positive cell clones can be used to produce monoclonal antibodies after direct expansion. Using this method, positive hybridoma clones against both malachite green and porcine epidemic diarrhea virus are selected with high efficiency. Compared to the ELISA-based method, the CSFIA-based method achieved the capability of isolating >2-fold more hybridoma clones in <25% of the corresponding processing time. In brief, the CSFIA-based method is highly efficient and inexpensive with a simple and direct operation, which is an excellent candidate method for antigen-specific positive clone isolation in a monoclonal antibody preparation.

d-Amino Acid Position Influences the Anticancer Activity of Galaxamide Analogs: An Apoptotic Mechanism Study.

Galaxamide, an extract from Galaxaura filamentosa, is a cyclic pentapeptide containing five l-leucines. Due to the particular cyclic structure and the excellent anticancer activity, synthesis of Galaxamide and its analogs and their subsequent bio-applications have attracted great attention. In the present work, we synthesized six Galaxamide analogs by replacing one of the l-leucines with phenylalanine and varying the d-amino acid position. The anticancer effect of the synthesized Galaxamide analogs was tested against four in vitro human cancer cell lines, human hepatocellular cells (HepG2), human breast cancer cell (MCF-7), human breast adenocarcinoma cells (MDA-MB-435) and a human cervical carcinoma cell line (Hela). Results showed that Galaxamide analogs with different d-amino acid positions displayed distinct anticancer potential. The Galaxamide analog containing d-amino acid at position 5 (Analog-6) presented the strongest anticancer activity. The mechanism study revealed that Analog-6 could cause the early apoptosis of HepG2 cells by inhibiting their growth in the sub-G1 stage of the cell cycle and induce the chromatin condensation and fragmentation, which can be seen as 68% of HepG2 cells inhibited in the sub-G1 stage. Moreover, a mitochondria-mediated pathway was found to be involved in the apoptotic process of Analog-6 on HepG2 cells.

Posterolateral Approach With Buttress Plates and Cannulated Screw Fixation for Large Posterior Malleolus Fractures.

The present study retrospectively reviewed the clinical efficacy of open reduction and internal fixation with buttress plates and cannulated screws via a posterolateral approach for the treatment of large posterior malleolus fractures. From July 2009 to April 2012, 34 patients (15 males and 19 females; mean age 41.2 years) with posterior malleolus fractures involving >25% of the distal articular tibia, were treated by cannulated screw and buttress plate fixation. All the patients were followed for ≥24 months. The outcome measures included the radiographic appearance of the reduction and bone union and the Baird-Jackson score. The average operation time was 105.6 (range 78 to 145) minutes. Radiologic examination showed all fractures achieved anatomic reduction and primary bone union at a mean of 3.8 (range 3 to 7) months after surgery. After an average follow-up period of 32.7 (range 24 to 44) months, no displacement, loosening, or breakage of internal fixation was observed. However, mild posttraumatic arthritis was present in 3 patients. According to the Baird-Jackson scoring system, the outcomes were rated as excellent in 11 cases, good in 17, fair in 5, and poor in only 1 case, for an excellent and good rate of 82.3%. An association analysis indicated age and injury mechanism might be factors influencing the intraoperative and postoperative outcomes. A posterolateral approach with buttress plate and cannulated screw internal fixation could be an effective technique for reduction and fixation of large posterior malleolus fragments.

Utilizing machine learning algorithms to identify biomarkers associated with diabetic nephropathy: A review.

Diabetic nephropathy (DN), a multifaceted disease with various contributing factors, presents challenges in understanding its underlying causes. Uncovering biomarkers linked to this condition can shed light on its pathogenesis and support the creation of new diagnostic and treatment methods. Gene expression data were sourced from accessible public databases, and Weighted Gene Co-expression Network Analysis (WGCNA)was employed to pinpoint gene co-expression modules relevant to DN. Subsequently, various machine learning techniques, such as random forest, lasso regression algorithm (LASSO), and support vector machine-recursive feature elimination (SVM-REF), were utilized for distinguishing DN cases from controls using the identified gene modules. Additionally, functional enrichment analyses were conducted to explore the biological roles of these genes. Our analysis revealed 131 genes showing distinct expression patterns between controlled and uncontrolled groups. During the integrated WCGNA, we identified 61 co-expressed genes encompassing both categories. The enrichment analysis highlighted involvement in various immune responses and complex activities. Techniques like Random Forest, LASSO, and SVM-REF were applied to pinpoint key hub genes, leading to the identification of VWF and DNASE1L3. In the context of DN, they demonstrated significant consistency in both expression and function. Our research uncovered potential biomarkers for DN through the application of WGCNA and various machine learning methods. The results indicate that 2 central genes could serve as innovative diagnostic indicators and therapeutic targets for this disease. This discovery offers fresh perspectives on the development of DN and could contribute to the advancement of new diagnostic and treatment approaches.

Copper peroxide nanodot-decorated gold nanostar/silica nanorod Janus nanostructure with NIR-II photothermal and acid-triggered hydroxyl radical generation properties for the effective treatment of wound infections.

Recently, bacterial infections have become a global crisis, greatly threatening the health of human beings. The development of a non-antibiotic biomaterial is recognized as an alternative way for the effective treatment of bacterial infections. In the present work, a multifunctional copper peroxide (CP) nanodot-decorated gold nanostar (GNS)/silica nanorod (SiNR) Janus nanostructure (GNS@CP/SiNR) with excellent antibacterial activity was reported. Due to the formation of the Janus nanostructure, GNS@CP/SiNR displayed strong plasmonic resonance absorbance in the near infrared (NIR)-II region that enabled the nanosystem to achieve mild photothermal therapy (MPTT). In acidic conditions, CP decorated on GNS@CP/SiNR dissociated rapidly by releasing Cu2+ and H2O2, which subsequently transformed to ˙OH via the Fenton-like reaction for chemodynamic therapy (CDT). As a result, GNS@CP/SiNR could effectively inhibit both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus), and eradicate the associated bacterial biofilms by exerting the synergistic MPTT/CDT antibacterial effect. Moreover, GNS@CP/SiNR was also demonstrated to be effective in treating wound infections, as verified on the S. aureus-infected full thickness excision wound rat model. Our mechanism study revealed that the synergistic MPTT/CDT effect of GNS@CP/SiNR firstly caused bacterial membrane damage, followed by boosting intracellular ROS via the severe oxidative stress effect, which subsequently caused the depletion of intracellular GSH and DNA damage, finally leading to the death of bacteria.

The m6A-ncRNAs axis in diabetes complications: novel mechanism and therapeutic potential.

Diabetes, a multifaceted metabolic disorder, poses a significant global health burden with its increasing prevalence and associated complications, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, and diabetic angiopathy. Recent studies have highlighted the intricate interplay between N6-methyladenosine (m6A) and non-coding RNAs (ncRNAs) in key pathways implicated in these diabetes complications, like cell apoptosis, oxidative stress, and inflammation. Thus, understanding the mechanistic insights into how m6A dysregulation impacts the expression and function of ncRNAs opens new avenues for therapeutic interventions targeting the m6A-ncRNAs axis in diabetes complications. This review explores the regulatory roles of m6A modifications and ncRNAs, and stresses the role of the m6A-ncRNA axis in diabetes complications, providing a therapeutic potential for these diseases.

The regulatory role of miRNA and lncRNA on autophagy in diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes that causes glomerular sclerosis and end-stage renal disease, leading to ascending morbidity and mortality in diabetic patients. Excessive accumulation of aberrantly modified proteins or damaged organelles, such as advanced glycation end-products, dysfunctional mitochondria, and inflammasomes is associated with the pathogenesis of DN. As one of the main degradation pathways, autophagy recycles toxic substances to maintain cellular homeostasis and autophagy dysregulation plays a crucial role in DN progression. MicroRNA (miRNA) and long non-coding RNA (lncRNA) are non-coding RNA (ncRNA) molecules that regulate gene expression and have been implicated in both physiological and pathological conditions. Recent studies have revealed that autophagy-regulating miRNA and lncRNA have been involved in pathological processes of DN, including renal cell injury, mitochondrial dysfunction, inflammation, and renal fibrosis. This review summarizes the role of autophagy in DN and emphasizes the modulation of miRNA and lncRNA on autophagy during disease progression, for the development of promising interventions by targeting these ncRNAs in this disease.

Anticancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer.

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery.

Revealing the antibacterial power of hydrogen-releasing PdH nanohydride against drug resistant Staphylococcus aureus: an in-depth mechanism study.

Currently, multidrug resistant (MDR) bacterial infections are a great threat to public health, and the development of novel strategies for high efficiency combatting of MDR bacteria is in urgent demand. Hydrogen (H2) is a small gas with a high reducing ability, and plenty of recent studies have demonstrated its therapeutic effect on many diseases. However, the antibacterial effectiveness and mechanism of H2 against MDR bacteria are still unknown. In the present work, using PdH nanohydride with a temperature responsive H2-releasing property as the H2 source, we demonstrated that H2 was not only able to inhibit the growth of normal Staphylococcus aureus (S. aureus), but could also effectively eliminate single drug resistant S. aureus (CRSA) and multidrug resistant S. aureus (MRSA), as well as the biofilms formed by those bacteria. Moreover, an in-depth mechanism regarding the anti-antibiotic-resistance activity of H2 was elucidated by us, in which H2 exerted its antibacterial effect by firstly causing severe membrane damage, followed by boosting generation of intracellular ROS, which subsequently triggered DNA damage and finally led to bacterial death. The proposed mechanism was further verified by genomic analysis, where a cluster of genes related to bacterial membrane integrity, biofilm formation, metabolism and DNA functions was significantly perturbed by the released H2. In particular, H2 boosted intracellular ROS generation by destroying the redox homeostasis of bacterial metabolism. More importantly, we revealed that H2 was able to alleviate the antibiotic resistance of CRSA and MRSA by significantly down-regulating the expression of many drug-resistant genes, e.g. the norG gene of CRSA, and fmtA, gpsB, sarA and marR genes of MRSA, as well as reducing the minimal inhibitory concentration (MIC) of ciprofloxacin/ampicillin against CRSA/MRSA. The findings in our work suggested that H2 therapy is a promising tool for combating antibiotic-resistant bacteria.

Ursolic acid inhibits cigarette smoke extract-induced human bronchial epithelial cell injury and prevents development of lung cancer.

Cigarette smoking is the main cause of chronic obstructive pulmonary disease and lung cancer. The present study was aimed to explore the chemopreventive effect of ursolic acid (UA) on these diseases. In the CSE treated normal human bronchial epithelial cell model, UA alleviated cytotoxicity caused by CSE, recovered the intracellular redox balance, and relieved the stimulation of external deleterious factors as well. UA mitigated CSE-induced DNA damage through the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway. Moreover, UA inhibited lung cancer development in the model established by A549 cells in nude mice in vivo. For the first time, our results indicate that UA could be developed as a potential lung cancer chemopreventive agent.

[FTIR analysis of the impact of covalent coupling on the secondary structure of antibody protein].

The immunolatex was prepared by covalent coupling. FTIR technology combined with substractive spectroscopy, deconvolution, derivation and curve-fitting methods were used to study the structure of the antibody protein on the immunolatex. The result demonstrates that the alpha-helix strcture of antibody increases with the increase in the pH value and the concentration of latex. So it is concluded that covalent coupling has a great impact on the secondary structure of antibody protein.

[Interaction between latex microspheres and antibody proteins revealed by fluorescence spectroscopy].

Latex-antibody complexes were prepared by the method of covalent coupling and the properties of the complexes were studied by fluorescence spectrophotometric method for the purpose of revealing the interaction between latex microspheres and antibody proteins. Analysis of intrinsic fluorescence spectra showed that after being coupled with latex microspheres, the emission maximum of antibody protein showed an obvious blue shift, the intensity of emission maximum decreased significantly, the tertiary structure of antibody protein changed to some extent, the interaction between latex microspheres and antibody proteins had a great quenching effect on the intrinsic fluorescence spectra of antibody proteins, the quenching effect was enhanced along with the increasing pH value and latex concentration, and the quenching mechanism was static quenching. Results of exogenous fluorescence spectra showed that the fluorescence intensity of emission maximum was enhanced significantly after being coupled with latex microspheres, the hydrophobicity of antibody protein was decreasing with the increase in the pH values, however, due to the increasing latex concentration, the hydrophobicity antibody protein was increasing.

[Protective effect and mechanism of Ecliptae Herba on cigarette smoke extract-induced cytotoxicity of NHBE cells].

OBJECTIVE: To investigate the protective effect and mechanism of Ecliptae Herba extract on cigarette smoke extract-induced cytotoxicity. METHOD: The effect of Ecliptae Herba extract on CSE-induced NHBE cell proliferation was detected by MTT assay. GSH content was determined by DTNB colorimetry. GST activity was measured by CDNB colorimetric assay. NQO1 activity was detected by NADPH and DCIP. The protein expression was determined by Western blot assay. RESULT: Ecliptae Herba extract reduced CSE's inhibitory effect on NHBE cells, recover the decrease in intracellular GSH caused by CSE and reduce the CSE-induced activity of GST and NQO1 and NQO1 protein expression. CONCLUSION: Ecliptae Herba extract can reduce CSE-induced injury on NHBE cells, which may be related to phase II detoxification enzymes.

Near-infrared laser-controlled nitric oxide-releasing gold nanostar/hollow polydopamine Janus nanoparticles for synergistic elimination of methicillin-resistant Staphylococcus aureus and wound healing.

Recently, nitric oxide (NO) has received increasing interest in combat against bacteria-induced infections because of its ability to sensitize and enhance the antibacterial effectiveness of many therapeutic approaches such as antibiotics. However, high-efficient loading and controlled release of NO remain a big challenge. In the present work, a type of gold nanostar/hollow polydopamine Janus nanostructure (GNS/HPDA JNPs) with precise near infrared (NIR)-controlled NO release property was fabricated using a facile seed-mediated method. Upon NIR laser irradiation, the NO-releasing GNS/HPDA JNPs (GNS/HPDA-BNN6) exhibited a synergistic photothermal and NO antibacterial effect by significantly inhibiting the growth and biofilm formation of both Gram-negative and Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An in-depth mechanism study revealed that two pathways were mainly involved in the synergistic photothermal and NO antibacterial effect. In one pathway, the synergistic effect severely destroyed the bacterial membrane by causing leakage of intracellular components such as DNA. In another pathway, the synergistic effect largely disturbed bacterial metabolism by regulating relative metabolic genes, followed by enhancing ROS generation to cause intracellular GSH depletion and DNA damage. More importantly, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of the drug-resistant gene mecA and some relative multidrug efflux pumps (e.g., SepA and Tet38). An in vivo evaluation using a rat model with MRSA-infected wounds indicated that the synergistic photothermal and NO effect of GNS/HPDA-BNN6 can effectively eliminate MRSA from wounds, thereby alleviating inflammation and promoting wound healing. STATEMENT OF SIGNIFICANCE: Multidrug-resistant (MDR) bacteria have become a big threat to mankind, and therefore, the development of innovative antibacterial agents with high antibacterial efficiency is urgently required. Nanomaterial-mediated nitric oxide (NO) therapy is a promising strategy to effectively combat MDR bacteria through a synergistic antibacterial effect. Here, a gold nanostar/hollow polydopamine Janus nanostructure with precise near infrared (NIR) light-controlled NO release property (GNS/HPDA-BNN6) was developed. Both in vitro and in vivo evaluations demonstrated that GNS/HPDA-BNN6 could effectively eliminate methicillin-resistant Staphylococcus aureus (MRSA) from infected wounds and promote wound healing through a synergistic photothermal and NO therapeutic effect. Remarkably, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of some drug-resistant genes and multidrug efflux pumps.

Hierarchically Hybrid Porous Co3O4@NiMoO4/CoMoO4 Heterostructures for High-Performance Electrochemical Energy Storage.

Hierarchical, ultrathin, and porous NiMoO4@CoMoO4 on Co3O4 hollow bones were successfully designed and synthesized by a hydrothermal route from the Co-precursor, followed by a KOH (potassium hydroxide) activation process. The hydrothermally synthesized Co3O4 nanowires act as the scaffold for anchoring the NiMoO4@CoMoO4 units but also show more compatibility with NiMoO4, leading to high conductivity in the heterojunction. The intriguing morphological features endow the hierarchical Co3O4@NiMoO4@CoMoO4 better electrochemical performance where the capacity of the Co3O4@NiMoO4@CoMoO4 heterojunction being 272 mA·h·g-1 at 1 A·g-1 can be achieved with a superior retention of 84.5% over 1000 cycles. The enhanced utilization of single/few NiMoO4@CoMoO4 shell layers on the Co3O4 core make it easy to accept extra electrons, enhancing the adsorption of OH- at the shell surface, which contribute to the high capacity. In our work, an asymmetric supercapacitor utilizing the optimized Co3O4@NiMoO4@CoMoO4 activated carbon (AC) as electrode materials was assembled, namely, Co3O4@NiMoO4@CoMoO4//AC device, yielding a maximum high energy density of 53.9 W·h·kg-1 at 1000 W·kg-1. It can retain 25.92 W·h·kg-1 even at 8100 W·kg-1, revealing its potential and viability for applications. The good power densities are ascribed to the porous feature from the robust architecture with recreated abundant mesopores on the composite, which assure improved conductivity and enhanced diffusion of OH- and also the electron transport. The work demonstrated here holds great promise for synthesizing other heterojunction materials M3O4@MMoO4@MMoO4 (M = Fe, Ni, Sn, etc).

Near infrared II laser controlled free radical releasing nanogenerator for synergistic nitric oxide and alkyl radical therapy of breast cancer.

Recently, alkyl radicals have attracted much attention in cancer therapy due to their oxygen-independent generation property. For the first time, alkyl radical and nitric oxide (NO) combined therapy is demonstrated as an effective strategy for tumor inhibition. As a proof of concept, a biocompatible free radical nanogenerator with near-infrared (NIR) II laser-induced simultaneous NO and alkyl radical release property was elaborately fabricated. In particular, an NIR II molecule (IR 1061), NO donor (BNN6) and alkyl radical initiator (AIPH) were firstly encapsulated in a natural lecithin stabilized phase change material, and then further functionalized by an amphiphile of DSPE-PEG-RGD with specific tumor targeting ability, finally obtaining biocompatible P(IR/BNN6/AIPH)@Lip-RGD. Upon NIR II laser irradiation, the photothermal effect generated from IR 1061 could trigger the phase change of the nanogenerator by releasing the encapsulated BNN6 and AIPH, and subsequently decompose them to generate highly active NO and alkyl radicals. Remarkably, NO and alkyl radical release profiles of P(IR/BNN6/AIPH)@Lip-RGD could be precisely controlled using intermittent NIR II laser irradiation. Moreover, P(IR/BNN6/AIPH)@Lip-RGD displayed a synergistic NO and alkyl radicals' anticancer effect by significantly inhibiting the growth of breast tumors, upon NIR II laser exposure. Furthermore, an in depth mechanistic study revealed that synergistic NO and alkyl radical effect induced cancer cell apoptosis through a mitochondria-mediated apoptotic pathway. The synergistic effect jointly caused a burst generation of mitochondrial ROS, which significantly down-regulated Bcl-2 protein expression, accelerated cytochrome c release and triggered a cascade of apoptosis-related proteins of Caspase-3 and Caspase-9.

Biodegradable Hollow Polydopamine@manganese Dioxide as an Oxygen Self-Supplied Nanoplatform for Boosting Chemo-photodynamic Cancer Therapy.

Photodynamic therapy (PDT) has attracted extensive attention in the clinical treatment of malignant tumor. However, the acidic and hypoxic conditions of the tumor microenvironment (TME) limit the further application of PDT in the clinic. Herein, we fabricate a new nanoplatform─HPDA@MnO2@Ce6/DOX@PEG-RGD (HPMRCD)─by means of coating hollow polydopamine nanoparticles (HPDA) with manganese dioxide (MnO2), which is modified by cyclic RGD functionalized poly(ethylene glycol) (PEG) and further co-loaded with a photosensitizer, Chlorin e6 (Ce6), and a chemotherapy drug, doxorubicin (DOX). This nanoplatform could be enriched in tumor tissues, then instantly dissociated under an acidic and H2O2-rich TME. The dual-responsive release of Mn2+ ions and oxygen (O2) can relieve tumor hypoxia, which can be used as a magnetic resonance contrast agent and the latter can enhance the PDT effect. Furthermore, the degradation of HPMRCD leads to an efficient loaded therapeutic molecule release, thus yielding a potential therapy to enhance tumor suppression by adopting the combined chemo-photodynamic therapy.

A uPAR targeted nanoplatform with an NIR laser-responsive drug release property for tri-modal imaging and synergistic photothermal-chemotherapy of triple-negative breast cancer.

In the present work, an iridium (Ir) complex loaded theranostic nanoplatform was designed for high-efficiency triple-negative breast cancer (TNBC) therapy. For this purpose, the Ir complex was firstly loaded on a photothermal agent of gold nanostars (GNS) by simply mixing followed by functionalization using a urokinase-type plasminogen activator receptor (uPAR) targeted polyetherimide-AE105 peptide conjugate (P-AE105) with the formation of GNS@Ir@P-AE105. It was demonstrated that the resultant GNS@Ir@P-AE105 was a multifunctional nanoplatform with advantages of (1) NIR laser controlled release of the Ir complex; (2) precise delivery of the Ir complex to TNBC cells; (3) excellent photothermal (PT)/photoacoustic (PA)/X-ray computed tomography (CT) tri-modal imaging ability; and (4) a synergistic photothermal-chemotherapeutic effect. An in-depth investigation of the mechanism revealed that binding forces of the Ir complex-GNS and P-AE105-GNS were significantly diminished upon NIR laser irradiation, which conferred an NIR laser-responsive Ir complex release property to the nanoplatform. Moreover, the nanoplatform exerted high efficiency anti-TNBC effects via a ROS-induced p53 apoptotic pathway. Specifically, combinational photothermal-chemotherapeutic treatments stimulated intracellular ROS generation, which significantly up-regulated apoptotic-relative p53 gene expression either by causing severe DNA damage or inducing an arrest effect on the sub-G1 phase of the cell cycle. Taken together, our work provides a novel theranostic nanoplatform for efficient and simultaneous diagnosis and therapy of TNBC.