Fibrous topology promoted pBMP2-activated matrix on titanium implants boost osseointegration.

Titanium (Ti) implants have been extensively used after surgical operations. Its surface bioactivity is of importance to facilitate integration with surrounding bone tissue, and ultimately ensure stability and long-term functionality of the implant. The plasmid DNA-activated matrix (DAM) coating on the surface could benefit osseointegration but is still trapped by poor transfection for further application, especially on the bone marrow mesenchymal stem cells (BMSCs) in vivo practical conditions. Herein, we constructed a DAM on the surface of fibrous-grained titanium (FG Ti) composed of phase-transition lysozyme (P) as adhesive, cationic arginine-rich lipid (RLS) as the transfection agent and plasmid DNA (pDNA) for bone morphology protein 2 (BMP2) expression. The cationic lipid RLS improved up to 30-fold higher transfection than that of commercial reagents (Lipofectamine 2000 and polyethyleneimine) on MSC. And importantly, Ti surface topology not only promotes the DAM to achieve high transfection efficiency (∼75.7% positive cells) on MSC due to the favorable combination but also reserves its contact induction effect for osteoblasts. Upon further exploration, the fibrous topology on FG Ti could boost pDNA uptake for gene transfection, and cell migration in MSC through cytoskeleton remodeling and induce contact guidance for enhanced osteointegration. At the same time, the cationic RLS together with adhesive P were both antibacterial, showing up to 90% inhibition rate against Escherichia coli and Staphylococcus aureus with reduced adherent microorganisms and disrupted bacteria. Finally, the FG Ti-P/pBMP2 implant achieved accelerated bone healing capacities through highly efficient gene delivery, aligned surface topological structure and increased antimicrobial properties in a rat femoral condylar defect model.

Early detection of cardiac fibrosis in diabetic mice by targeting myocardiopathy and matrix metalloproteinase 2.

Early detection of myocardial fibrosis in diabetic cardiomyopathy (DCM) has significant clinical implications for diabetes management. In this study, we identified matrix metalloproteinase 2 (MMP2) as a potential biomarker for early fibrosis detection. Based on this finding, we designed a dual-targeting nanoparticle CHP-SPIO-ab MMP2 to specifically target myocardiopathy and MMP2, enabling sensitive fibrosis detection using magnetic resonance imaging (MRI). Our results demonstrate that collagen hyperplasia (early fiber formation) begins to develop in diabetic mice at 12 weeks old, with observable fibrosis occurring at 16 weeks old. Additionally, MMP2 expression significantly up-regulates around collagen starting from 12 weeks of age. T2 MRI analysis revealed significant T2% enhancement in the hearts of 12-week-old diabetic mice following administration of the CHP-SPIO-ab MMP2 probe, indicating noninvasive detection of fiber formation. Furthermore, after fibrosis treatment, a reduction in T2% signal was observed in the hearts of 16-week-old diabetic mice. These findings were supported by Sirius red and Prussian blue staining techniques. Overall, our study presents a promising strategy for early identification of myocardial fibrosis. STATEMENT OF SIGNIFICANCE: Myocardial damage typically exhibits irreversibility, underscoring the paramount importance of early fibrosis diagnosis. However, the clinical used T1 mapping for fibrosis detection still exhibits limitations in terms of sensitivity. Therefore, it is imperative to develop highly sensitive strategies for early cardiac fibrosis detection. Here, we investigated the development of myocardial fibrosis in diabetic mice, and designed a highly sensitive probe that specifically targets cardiomyopathy and high expression of MMP2 for the early diagnosis of fibrosis. The probe enables non-invasive detection of abnormalities through MRI imaging as soon as fiber deposition appear, which can be detected earlier than T1 mapping. This advancement holds great potential for clinical diagnosis of myocardial fibrosis using cardiac magnetic resonance.

Hierarchically decorated magnetic nanoparticles amplify the oxidative stress and promote the chemodynamic/magnetic hyperthermia/immune therapy.

Magnetic nanoparticles (MNPs) are promising in tumor treatments due to their capacity for magnetic hyperthermia therapy (MHT), chemodynamic therapy (CDT), and immuno-related therapies, but still suffer from unsatisfactory tumor inhibition in the clinic. Insufficient hydrogen peroxide supply, glutathione-induced resistance, and high-density extracellular matrix (ECM) are the barriers. Herein, we hierarchically decorated MNPs with disulfide bonds (S-S), dendritic L-arginine (R), and glucose oxidase (GOx) to form a nanosystem (MNPs-SS-R-GOx). Its outer GOx layer not only enhanced the H2O2 supply to produce .OH by Fenton reaction, but also generated stronger oxidants (ONOO-) together with the interfaced R layer. The inner S-S layer consumed glutathione to interdict its reaction with oxidants, thus enhancing CDT effects. Importantly, the generated ONOO- tripled the MMP-9 expression to induce ECM degradation, enabling much deeper penetration of MNPs and benefiting CDT, MHT, and immunotherapy. Finally, the MNPs-SS-R-GOx demonstrated a remarkable 91.7% tumor inhibition in vivo. STATEMENT OF SIGNIFICANCE: Magnetic nanoparticles (MNPs) are a promising tumor therapeutic agent but with limited effectiveness. Our hierarchical MNP design features disulfide bonds (S-S), dendritic L-arginine (R), and glucose oxidase (GOx), which boosts H2O2 supply for ·OH generation in Fenton reactions, produces potent ONOO-, and enhances chemodynamic therapy via glutathione consumption. Moreover, the ONOO- facilitates the upregulation of matrix metalloprotein expression beneficial for extracellular matrix degradation, which in turn enhances the penetration of MNPs and benefits the antitumor CDT/MHT/immuno-related therapy. In vivo experiments have demonstrated an impressive 91.7% inhibition of tumor growth. This hierarchical design offers groundbreaking insights for further advancements in MNP-based tumor therapy. Its implications extend to a broader audience, encompassing those interested in material science, biology, oncology, and beyond.

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity.

Carbohydrates have emerged as promising candidates for immunomodulation, however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles, comparing to mannose and galactose. In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK, and STAT1 signaling pathways. Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy.

A DNA vaccine (EG95-PT1/2/3-IL2) encoding multi-epitope antigen and IL-2 provokes efficient and long-term immunity to echinococcosis.

Echinococcosis is a highly prevalent global zoonosis, and vaccines are required. The commercial vaccine based on a protein-based subunit (EG95), however, is limited by its insufficient cellular immunity, a short protection period, and limited prevention against novel mutant strains. Herein, we applied bioinformatics to develop a DNA vaccine (pEG95-IL2) expressing both multi-epitope-based antigens (EG95-PT1/2/3) and an IL-2 adjuvant to regulate T cell differentiation and memory cell response. EG95-PT1/2/3 was screened with hierarchical structure prediction from the epitope conformation of B cells with high confidence across various species to guarantee immunogenicity. Importantly, cationic arginine-rich lipid nanoparticles (RNP) were utilized as a delivery vehicle to form lipoplexes that had a transfection efficiency of nearly two orders of magnitude greater than that of commercial reagents (Lipofectamine 2000 and polyethyleneimine) with both immune and nonimmune cells (DC2.4 and L929 cells, respectively). RNP/pEG95-IL2 lipoplexes displayed a robust and long-term antigen expression, as well as adjuvant effects during the immunization. Consequently, intramuscular injection of RNP/pEG95-IL2 elicited similar humoral immune responses and significantly greater cellular responses in mice when compared with those of the commercial vaccine. In addition, the inoculation protocol of RNP/pEG95-IL2 with sequential booster further strengthens cellular immunity in comparison with the homologous booster. Those findings provide a promising strategy for improving plasmid vaccine efficacy.

Bifunctional Cascading Nanozymes Based on Carbon Dots Promotes Photodynamic Therapy by Regulating Hypoxia and Glycolysis.

Photodynamic therapy (PDT) still faces great challenges with suitable photosensitizers, oxygen supply, and reactive oxygen species (ROS) accumulation, especially in the tumor microenvironment, feathering hypoxia, and high glucose metabolism. Herein, a carbon dots (CDs)-based bifunctional nanosystem (MnZ@Au), acting as photosensitizer and nanozyme with cascading glucose oxidase (GOx)- and catalase (CAT)-like reactivity, was developed for improving hypoxia and regulating glucose metabolism to enhance PDT. The MnZ@Au was constructed using Mn-doped CDs (Mn-CDs) as a core and zeolitic imidazolate framework-8 (ZIF-8) as a shell to form a hybrid (MnZ), followed by anchoring ultrasmall Au nanoparticles (AuNPs) onto the surface of MnZ through the ion exchange and in situ reduction methods. MnZ@Au catalyzed glucose consumption and oxygen generation by cascading GOx- and CAT-like nanozyme reactions, which was further enhanced by its own photothermal properties. In vitro and in vivo studies also confirmed that MnZ@Au greatly improved CDs penetration, promoted ROS accumulation, and enhanced PDT efficacy, leading to efficient tumor growth inhibition in the breast tumor model. Besides, MnZ@Au enabled photoacoustic (PA) imaging to provide a mapping of Mn-CDs distribution and oxygen saturation, showing the real-time catalytic process of MnZ@Au in vivo. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging also validated the decreased glucose uptake in tumors treated by MnZ@Au. Therefore, the integrated design provided a promising strategy to utilize and regulate the tumor microenvironment, promote penetration, enhance PDT, and finally prevent tumor deterioration.

High Strength Titanium with Fibrous Grain for Advanced Bone Regeneration.

Pure titanium is widely used in clinical implants, but its bioinert properties (poor strength and mediocre effect on bone healing) limit its use under load-bearing conditions. Modeling on the structure of collagen fibrils and specific nanocrystal plane arrangement of hydroxyapatite in the natural bone, a new type of titanium (Ti) with a highly aligned fibrous-grained (FG) microstructure is constructed. The improved attributes of FG Ti include high strength (≈950 MPa), outstanding affinity to new bone growth, and tight bone-implant contact. The bone-mimicking fibrous grains induce an aligned surface topological structure conducive to forming close contact with osteoblasts and promotes the expression of osteogenic genes. Concurrently, the predominant Ti(0002) crystal plane of FG Ti induces the formation of hydrophilic anatase titanium oxide layers, which accelerate biomineralization. In conclusion, this bioinspired FG Ti not only proves to show mechanical and bone-regenerative improvements but it also provides a new strategy for the future design of metallic biomaterials.

Controlled intracellular aggregation of magnetic particles improves permeation and retention for magnetic hyperthermia promotion and immune activation.

Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors. Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation. The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA). Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated. In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments. Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues. In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment. As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy. Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment. The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation. This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.

Mucus-penetrating nonviral gene vaccine processed in the epithelium for inducing advanced vaginal mucosal immune responses.

Establishment of vaginal immune defenses at the mucosal interface layer through gene vaccines promise to prevent infectious diseases among females. Mucosal barriers composed of a flowing mucus hydrogel and tightly conjugated epithelial cells (ECs), which represent the main technical difficulties for vaccine development, reside in the harsh, acidic human vaginal environment. Different from frequently employed viral vectors, two types of nonviral nanocarriers were designed to concurrently overcome the barriers and induce immune responses. Differing design concepts include the charge-reversal property (DRLS) to mimic a virus that uses any cells as factories, as well as the addition of a hyaluronic acid coating (HA/RLS) to directly target dendritic cells (DCs). With a suitable size and electrostatic neutrality, these two nanoparticles penetrate a mucus hydrogel with similar diffusivity. The DRLS system expressed a higher level of the carried human papillomavirus type 16 L1 gene compared to HA/RLS in vivo. Therefore it induced more robust mucosal, cellular, and humoral immune responses. Moreover, the DLRS applied to intravaginal immunization induced high IgA levels compared with intramuscularly injected DNA (naked), indicating timely protection against pathogens at the mucus layer. These findings also offer important approaches for the design and fabrication of nonviral gene vaccines in other mucosal systems.

A cationic lipid with advanced membrane fusion performance for pDNA and mRNA delivery.

The success of mRNA vaccines for COVID-19 prevention raised global awareness of the importance of nucleic acid drugs. The approved systems for nucleic acid delivery were mainly formulations of different lipids, yielding lipid nanoparticles (LNPs) with complex internal structures. Due to the multiple components, the relationship between the structure of each component and the overall biological activity of LNPs is hard to study. However, ionizable lipids have been extensively explored. In contrast to former studies on the optimization of hydrophilic parts in single-component self-assemblies, we report in this study on structural alterations of the hydrophobic segment. We synthesize a library of amphiphilic cationic lipids by varying the lengths (C = 8-18), numbers (N = 2, 4), and unsaturation degrees (Ω = 0, 1) of hydrophobic tails. Notably, all self-assemblies with nucleic acid have significant differences in particle size, stability in serum, membrane fusion, and fluidity. Moreover, the novel mRNA/pDNA formulations are characterized by overall low cytotoxicity, efficient compaction, protection, and release of nucleic acids. We find that the length of hydrophobic tails dominates the formation and stability of the assembly. And at a certain length, the unsaturated hydrophobic tails enhance the membrane fusion and fluidity of assemblies and thus significantly affect the transgene expression, followed by the number of hydrophobic tails.

Manganese porphyrin/ICG nanoparticles as magnetic resonance/fluorescent dual-mode probes for imaging of sentinel lymph node metastasis.

Diagnosis of sentinel lymph node (SLN) metastasis and its status are key parameters for predicting overall disease prognosis. In this work, Pluronic F127 stabilized ICG/tetra(4-carboxyphenyl)porphyrin-Mn(III) (TCPP(Mn)) nanoparticles (F127-ICG/Mn NPs) as fluorescent/magnetic resonance (FL/MR) dual-modality probes were prepared. The application of F127-ICG/Mn NPs in SLN imaging was mainly evaluated from two perspectives: the difference between the normal LN and the metastatic SLN and the difference between micrometastasis and macrometastasis. Normal and metastatic SLNs and micro- and macro-SLN metastasis were successfully distinguished through fluorescence and MR imaging with the help of F127-ICG/Mn NPs. In contrast, for the ICG group, the micro- and macro-SLN metastasis status could not be differentiated by fluorescence imaging. Besides, the lymph nodes can be stained green by the F127-ICG/Mn NPs and clearly visualized by the naked eye. In general, F127-ICG/Mn NPs demonstrated the potential of the preoperative diagnosis of SLN metastasis and its status, as well as intraoperative navigation by green-stained SLN and NIR FL imaging. This work provides a reference for developing multimodal nanoparticles for SLN metastasis diagnosis.

Clinical translational barriers against nanoparticle-based imaging agents.

Nanoparticle based imaging agents (NIAs) have been intensively explored in bench studies. Unfortunately, only a few cases have made their ways to clinical translation. In this review, clinical trials of NIAs were investigated for understanding possible barriers behind that. First, the complexity of multifunctional NIAs is considered a main barrier because it brings uncertainty to batch-to-batch fabrication, and results in sophisticated in vivo behaviors. Second, inadequate biosafety studies slow down the translational work. Third, NIA uptake at disease sites is highly heterogeneous, and often exhibits poor targeting efficiency. Focusing on the aforementioned problems, key design parameters were analyzed including NIAs' size, composition, surface characteristics, dosage, administration route, toxicity, whole-body distribution and clearance in clinical trials. Possible strategies were suggested to overcome these barriers. Besides, regulatory guidelines as well as scale-up and reproducibility during manufacturing process were covered as they are also key factors to consider during clinical translation of NIAs.

Surface carboxylation of iron oxide nanoparticles brings reduced macrophage inflammatory response through inhibiting macrophage autophagy.

Macrophage autophagy is a common biological response triggered by nanomaterials, which is closely related to the regulation of inflammation. Superparamagnetic iron oxide (SPIO) nanoparticles have been used for study of autophagy response due to their broad biomedical applications. However, few reports have focused on how to regulate the macrophage autophagy response induced by SPIO nanoparticles. In this study, SPIO nanoparticles grafted with carboxyl groups were synthesized and for the comparison of macrophage autophagy with unmodified nanoparticles. The study on the correlation between autophagy and inflammation induced by the two kinds of SPIO nanoparticles was also included, and the one that grafted with carboxyl groups shows a reduction of autophagy and thereby caused a milder inflammatory response. We proposed that the increased amount of albumin adsorption on the surface of carboxylated SPIO nanoparticles, a protein previously proven to attenuate autophagy, can be considered an important reason for reducing autophagy and inflammation. In general, the carboxyl modification of SPIO nanoparticles has been demonstrated to reduce inflammation by inhibiting macrophage autophagy, which may provide some insights for the design of nanomaterials in the future.

Recent progress in therapeutic strategies and biomimetic nanomedicines for rheumatoid arthritis treatment.

INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune systemic disease in which inflammatory and immune cells accumulate in inflamed joints. Researchers aimed at the characteristics of RA to achieve the effect of treating RA through different therapeutic strategies, and have used various endogenous materials to design drug-loaded nanoparticles that can target RA by binding to cell adhesion molecules or chemokines. In some cases, the nanoparticles can respond to the characteristics of the microenvironment. AREAS COVERED: This article reviews the recent advances in the treatment of RA from two aspects of therapeutic strategies and delivery strategies. Therapeutic strategies mainly include neutralization of inflammatory factors, promotion of inflammatory cell apoptosis, ROS scavenger, immunosuppression, and bone tissue repair. The drug delivery strategy is mainly described from two aspects: chemically functionalized biomimetic nanoparticles and endogenous nanoparticles. EXPERT OPINION: Biomimetic NPs may be effective drug carriers for targeted RA treatment. NPs can reduce the clearance of mononuclear phagocytes, prolong the blood circulation time, and improve the targeting ability. With the deepening of research, more and more biomimetic NPs have entered the clinical trial stage. However, safe and scalable preparation methods are needed to improve their clinical applicability.

Targeted trapping of endogenous endothelial progenitor cells for myocardial ischemic injury repair through neutrophil-mediated SPIO nanoparticle-conjugated CD34 antibody delivery and imaging.

Endothelia progenitor cell (EPC)-based revascularization therapies have shown promise for the treatment of myocardial ischemic injury. However, applications and efficacy are limited by the relatively inefficient recruitment of endogenous EPCs to the ischemic area, while implantation of exogenous EPCs carries the risk of tumorigenicity. In this study, we developed a therapeutic protocol that relies on the capacity of neutrophils (NEs) to target lesions and release preloaded EPC-binding molecules for high efficiency capture. Neutrophils were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface marker CD34 (SPIO-antiCD34/NEs), and the therapeutic efficacy in ischemic mouse heart following SPIO-antiCD34/NEs injection was monitored by SPIO-enhanced magnetic resonance imaging (MRI). These SPIO-antiCD34/NEs exhibited unimpaired cell viability, superoxide generation, and chemotaxis in vitro as well as satisfactory biocompatibility in vivo. In a mouse model of acute myocardial infarction (MI), SPIO-antiCD34 accumulation could be observed 0.5 h after intravenous injection of SPIO-antiCD34/NEs. Moreover, the degree of CD133+ EPC accumulation at MI sites was three-fold higher than in control MI model mice, while ensuing microvessel density was roughly two-fold higher than controls and left ventricular ejection fraction was > 50%. Therapeutic cell biodistribution, MI site targeting, and treatment effects were confirmed by SPIO-enhanced MRI. This study offers a new strategy to improve the endogenous EPC-based myocardial ischemic injury repair through NEs mediated SPIO nanoparticle conjugated CD34 antibody delivery and imaging. STATEMENT OF SIGNIFICANCE: The efficacy of endogenous endothelial progenitor cell (EPC)-based cardiovascular repair therapy for ischemic heart damage is limited by relatively low EPC accumulation at the target site. We have developed a method to improve EPC capture by exploiting the strong targeting ability of neutrophils (NEs) to ischemic inflammatory foci and the capacity of these treated cells to release of preloaded cargo with EPC-binding affinity. Briefly, NEs were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface protein CD34 (SPIO-antiCD34). Thus, we explored sites targeting with nanocomposites cargo for non-invasive EPCs interception and therapy tracking. We demonstrate that SPIO-antiCD34 released from NEs can effectively capture endogenous EPCs and thereby promote heart revascularization and functional recovery in mice. Moreover, the entire process can be monitored by SPIO-enhanced magnetic resonance imaging including therapeutic cell biodistribution, myocardial infarction site targeting, and tissue repair.

MOF-Derived Mesoporous and Hierarchical Hollow-Structured In2O3-NiO Composites for Enhanced Triethylamine Sensing.

It remains a challenge to design and fabricate high-performance gas sensors using metal-organic framework (MOF)-derived metal oxide semiconductors (MOS) as sensing materials due to the structural damage during the annealing process. In this study, the mesoporous In2O3-NiO hollow spheres consisting of nanosheets were prepared via a solvothermal reaction and subsequent cation exchange. More importantly, the transformation of Ni-MOF into In/Ni-MOF through exchanging the Ni2+ ion with In3+ ion can prevent the destruction of the porous reticular skeleton and hierarchical structure of Ni-MOF during calcination. Thus, the mesoporous In2O3-NiO hollow composites possess high porosity and large specific surface area (55.5 m2 g-1), which can produce sufficient permeability pathways for volatile organic compound (VOCs) molecules, maximize the active sites, and enhance the capacity of VOC capture. The mesoporous In2O3-NiO-based sensors exhibit enhanced triethylamine (TEA) sensing performance (S = 33.9-100 ppm) with distinct selectivity, good long-term stability, and lower detection limit (500 ppb) at 200 °C. These results can be attributed to the mesoporous hollow hierarchical structure and p-n junction of In2O3-NiO. The preparation concept mentioned in this work may provide a versatile platform applicable to various mesoporous composite sensing material-based hollow structures.

Dual regulation of osteoclastogenesis and osteogenesis for osteoporosis therapy by iron oxide hydroxyapatite core/shell nanocomposites.

Osteoporosis is a skeletal disorder resulted in significant structural and functional changes, arousing a wide concern for the high prevalence and cost. Imbalance between osteoclastogenesis and osteogenesis have been verified as a main pathology etiology and considered an efficient therapy target in both clinical and pre-clinical studies. In recent years, inorganic nanomaterials have shown provable activities on osteoclastogenesis inhibition and osteogenesis promotion, respectively. Hence, in this study, a class of hydroxyapatite coated superparamagnetic iron oxide nanoparticles (SPIO@HA) were developed with a core-shell structure for targeting both osteoclastogenesis and osteogenesis. The optimal ratio of SPIO@15HA (Fe/Ca = 1:15, mol/mol) was screened to obtain dual function for inducing both bone formation and preventing bone resorption. The obtained nanocomposites significantly prevented the bone loss of ovariectomized (OVX) mice and increased bone mineral density (BMD) by 9.4%, exhibiting high bone accumulation in magnetic resonance imaging evaluation and reasonable biosafety profile. The mechanism study revealed that SPIO@15HA can suppress bone marrow monocyte derived osteoclast differentiation through TRAF6-p62-CYLD signaling complex regulation. Meanwhile, it could activate MSC osteogenic differentiation by TGF-ß, PI3K-AKT and calcium signaling pathway regulation. Moreover, incubation of SPIO@15HA with MSC resulted in several cytokines overexpression such as osteoprotegerin (OPG), CSF2, CCL2 etc., which are responsible for maintaining the bone remodeling balance. The dual function of as-prepared SPIO@15HA may find a new way for designing of inorganic components containing core/shell nanomaterials for osteoporosis treatment.

The prevalence and genotype distribution of human papilloma virus in cervical squamous intraepithelial lesion and squamous cell carcinoma in Taizhou, China.

ABSTRACT: Human papillomavirus (HPV) infection is a common sexually transmitted disease worldwide and the leading cause of cervical cancer. Current vaccines do not cover all HPV genotypes whereas the distribution of HPV genotypes varies in different geographic regions. The study aimed to investigate the distribution of HPV genotypes in patients with cervical squamous intraepithelial lesion (SIL) and cervical squamous cell carcinoma (SCC) in Taizhou City of Jiangsu Province, China. A total of 940 patients including 489 cases with cervical low-grade squamous intraepithelial lesions (LSIL), 356 cases with cervical high-grade squamous intraepithelial lesions (HSIL), and 95 cases with cervical SCC, underwent a biopsy or surgery in Taizhou People's Hospital between January 2019 and December 2019. The HPV testing results were retrospectively analyzed. The overall prevalence of any, high-risk, and low-risk HPV was 83.83%, 81.91%, and 12.13%, respectively. The 5 most common HPV genotypes were HPV16 (35.64%), HPV52 (16.91%), HPV58 (13.94%), HPV33 (8.94%), and HPV18 (7.98%). The prevalence of any and HR-HPV in SCC was significantly higher than those in LSIL and HSIL, while the prevalence of LR-HPV in SCC was significantly lower than those in LSIL and HSIL (P < .01). Single and dual HPV infections were prevalent in SCC, LSIL, and HSIL. Furthermore, the prevalence of dual HPV infection in SCC was significantly higher than those in LSIL and HSIL (P = .002). The HPV prevalence varied by age, being highest among women with SCC, LSIL, and HSIL aged 40 to 49 years, 40 to 49 years, and 50 to 59 years, respectively. In conclusion, the findings revealed a very high prevalence of HPV in women with cervical lesions in Taizhou. Routine HPV tests must cover all common HPV genotypes in clinical practice.

Foldable Glistening-Free Acrylic Intraocular Lens Biomaterials with Dual-Side Heterogeneous Surface Modification for Postoperative Endophthalmitis and Posterior Capsule Opacification Prophylaxis.

Hydrophobic acrylic intraocular lenses (IOLs) are widely used in cataract treatment for posterior capsule opacification (PCO) prophylaxis. However, undesired glistening and postoperative endophthalmitis are two major potential risks. Hence, a series of poly(2-phenoxyethyl methacrylate-co-2-phenoxyethyl acrylate-co-2-ethylhexyl methacrylate) (PPPE) acrylic IOL materials were synthesized for "glistening-free" optimization. The selected PPPE with 2% 2-ethylhexyl methacrylate showed excellent optical, foldable, and thermomechanical properties. The anterior surface of PPPE was coated with polydopamine followed by gentamycin conjugation (PDA/GS). It inhibited bacterial adhesion by 74% and decreased the biofilm thickness by 87%. In inflammatory mimicking conditions, bacterial proliferation was restrained, with acidic-dependent GS release behavior. The surface of PPPE toward the posterior capsule remained hydrophobic. It was conducive to human lens epithelial cell adhesion, collagen IV and fibronectin adsorption, and the following "sealed sandwich structure" formation. In summary, the PPPE with a dual-side heterogeneous surface displayed good application prospects in postoperative endophthalmitis and PCO prevention.

Pollen-like silica nanoparticles as a nanocarrier for tumor targeted and pH-responsive drug delivery.

Aptamer modified hollow silica nanoparticles with pollen structure (plSP@aptamer) were synthesized and used as a nanocarrier for tumor targeted and pH-responsive drug delivery. The 292 ± 14 nm interior void in diameter together with 11.8 nm surface pore size of plSP@aptamer nanoparticles contributed to a high drug loading efficiency of 0.509 g g-1. Furthermore, the drug delivery system was pH-responsive, and the releasing efficiency was up to 87.5% at pH of 5. The special spikes of this plSP@aptamer nanoparticles acted as "entry claws" to enhanced the interaction between cell and drug nanocarriers and then increased the internalization rate of drug vehicles. The cell uptake assay suggested that most of doxorubicin (DOX)@plSP@aptamer nanoparticles can escape form lysosome and located in nuclei of MCF-7 cells. The targeted performance testing showed that almost no DOX@plSP@aptamer were internalized by normal cells, indicating a high specificity of our drug vehicles. The cytotoxicity of nanoparticles was also investigated, the plSP@aptamer particles had excellent biocompatibility and the cell viability was nearly 100%. After loaded with DOX, DOX@plSP@aptamer showed great potential in targeted therapy of tumors, and only 4.2% MCF-7 cells were viable.