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.

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.

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.

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.

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.

A Bioactive and Photoresponsive Platform for Wireless Electrical Stimulation to Promote Neurogenesis.

Delivering electrical signals to neural cells and tissue has attracted increasing attention in the treatment of nerve injuries. Unlike traditional wired electrical stimulation, wireless and remote light stimulation provides less invasive and longer-lasting interfaces, holding great promise in the treatment of nerve injuries and neurodegenerative diseases, as well as human-computer interaction. Additionally, a bioactive matrix that bridges the injured gap and induces nerve regeneration is essential for injured nerve repair. However, it is still challenging to construct a 3D biomimetic cell niche with optoelectrical responsiveness. Herein, a bioactive platform for remote and wireless optoelectrical stimulation is established by incorporating hydrophilic poly(3-hexylthiophene) nanoparticles (P3HT NPs) into a biomimetic hydrogel matrix. Moreover, the hydrogel matrix is modified by varying the composition and/or the crosslinking degree to meet the needs of different application scenarios. When exposed to pulsed green light, P3HT NPs in hydrogels convert light signals into electrical signals, resulting in the generation of tens of picoampere photocurrent, which is proved to promote the growth of cortical neurons that covered by hydrogels and the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) encapsulated in hydrogels. This work is of great significance for the design of next-generation neural electrodes and scaffolds.

A Gd-doped polydopamine (PDA)-based theranostic nanoplatform as a strong MR/PA dual-modal imaging agent for PTT/PDT synergistic therapy.

Based on widely used photoacoustic imaging (PAI) and photothermal properties of polydopamine (PDA), a multifunctional Gd-PDA-Ce6@Gd-MOF (GPCG) nanosystem with a core-shell structure and strong imaging ability was constructed. Benefitting from the metal-organic framework (MOF) structure, GPCG nanoparticles (NPs) showed enhanced magnetic resonance imaging (MRI) ability with high relaxation rates (r1 = 13.72 mM-1 s-1 and r2 = 216.14 mM-1 s-1). The MRI effect of Gd ions combined with the PAI effect of PDA, giving GPCG NPs a dual-modal imaging ability. The core, mainly composed of PDA and photodynamic photosensitizer chlorin e6 (Ce6), achieved photothermal/photodynamic therapy (PTT/PDT) synergistic performance. Besides, to overcome the unexpected release of Ce6, the MOF shell realized pH-sensitive release and a high local concentration. Through in vivo studies, we concluded that GPCG NPs show a good inhibitory effect on tumor growth. In conclusion, we successfully obtained a GPCG theranostic nanoplatform and paved the way for subsequent design of imaging guided therapeutic nanostructures based on metal-doped PDA.