H2O2/NIR-sensitive "two-step" nano theranostic system based hollow mesoporous copper sulfide/hyaluronic acid/JWH133 as an optimally designed delivery system for multidimensional treatment of RA.

Cannabinoid receptors are widely distributed in many cells in Rheumatoid arthritis RA and strengthening factor to boost the development of RA diseases. Here, the hollow mesoporous copper sulfide (CuS) was used as the carrier skeleton and the cannabinoid type 2 (CB2) receptor agonist JWH133 was efficiently loaded inside of CuS through adsorption, then the outer layer was modified with hyaluronic acid (HA) to prevent the leakage of internal drugs. After the CuS-JWH133@HA nano carrier reached the target area, HA responsive cracked under RA microenvironment to realize the first step of accurate drug delivery of JWH133, and the thermally responsive CuS under near-infrared (NIR) promoted the release of internal drugs. Then, JWH133 specifically combined CB2 receptors on the surface of macrophage, synovial cells and osteoblasts to realize the second step of drug delivery. The inflammatory factors secreted by cells are significantly inhibited, and the activity of osteoblasts was significantly enhanced. Therapeutic effect by CuS-JWH133@HA of RA was well verified by decreasing levels of inflammation in vivo and improvement of inflamed and swollen joints of mice. The CuS-JWH133@HA nanocomposite showed satisfactory multidimensional therapeutic effect of RA in vitro and in vivo, which provided a novel idea for RA treatment.

A Smart Nanoreactor Based on an O2-Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive "Doorkeepers" for Enhanced CDT/PTT of Rheumatoid Arthritis.

Activated fibroblast-like synovial (FLS) cells are regarded as an important target for rheumatoid arthritis (RA) treatment via starvation therapy mediated by glucose oxidase (GOx). However, the hypoxic RA-FLS environment greatly reduces the oxidation process of glucose and leads to a poor therapeutic effect of the GOx-based starvation therapy. In this work, we designed a hollow mesoporous copper sulfide nanoparticles (CuS NPs)-based smart GOx/atovaquone (ATO) codelivery system (named as V-HAGC) targeting RA-FLS cells to realize a O2-economized dual energy inhibition strategy to solve the limitation of GOx-based starvation therapy. V-HAGC armed with dual multi-stimuli-responsive "doorkeepers" can guard drugs intelligently. Once under the stimulation of photothermal and acidic conditions at the targeted area, the dual intelligent responsive "doors" would orderly open to realize the controllable release of drugs. Besides, the efficacy of V-HAGC would be much improved by the additional chemodynamic therapy (CDT) and photothermal therapy (PTT) stimulated by CuS NPs. Meanwhile, the upregulated H2O2 and acid levels by starvation therapy would promote the Fenton-like reaction of CuS NPs under O2-economized dual energy inhibition, which could enhance the PTT and CDT efficacy as well. In vitro and in vivo evaluations revealed V-HAGC with much improved efficacy of this combination therapy for RA. In general, the smart V-HAGC based on the O2-economized dual energy inhibition strategy combined with enhanced CDT and PTT has the potential to be an alternative methodology in the treatment of RA.

Octahedral Pt-MOF with Au deposition for plasmonic effect and Schottky junction enhanced hydrogenothermal therapy of rheumatoid arthritis.

Hydrogen (H2) therapy is a novel and rapidly developing strategy utilized to treat inflammatory diseases. However, the therapeutic efficacy of H2 is largely limited with on-target off-synovium toxic effect, nonpolarity and low solubility. Herein, an intelligent H2 nanogenerator based upon the metal-organic framework (MOF) loaded with polydopamine and Perovskite quantum dots is constructed for the actualization of hydrogenothermal therapy. The biodegradable polydopamine with excellent photothermal conversion efficiencies is used for photothermal therapy (PTT) of rheumatoid arthritis (RA) and perovskite quantum dots (QDs) with unique photophysical properties are used as fluorescent signals for positioning Pt-MOF@Au@QDs/PDA nanoparticles. In addition, the Pt-MOF@Au@QDs/PDA catalyzer combines Au's surface plasmon resonance excitation with Pt-MOF Schottky junction, and exhibits extremely efficient photocatalytic H2 production under visible light irradiation. The Pt-MOF@Au@QDs/PDA achieves the aggregation of rheumatoid synovial cells by the extravasation through "ELVIS" effect (extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration) and extremely efficient photocatalytic H2 production. By combining PTT and H2 therapy, the Pt-MOF@Au@QDs/PDA relieves the oxidative stress of RA, and shows significant improvement in joint damage and inhibition of the overall arthritis severity of collagen-induced RA mouse models. Therefore, the Pt-MOF@Au@QDs/PDA shows great potential in the treatment of RA and further clinical transformation.

Gold-Bipyramid-Based Nanothernostics: FRET-Mediated Protein-Specific Sialylation Visualization and Oxygen-Augmenting Phototherapy against Hypoxic Tumor.

Despite several attempts, incorporating biological detection that supplies necessary biological information into therapeutic nanotheranostics for hypoxic tumor treatments is considered to be in its infancy. It is therefore imperative to consolidate biological detection and desirable phototherapy into a single nanosystem for maximizing theranostic advantages. Herein, we develop a versatile nanoprobe through combined fluorescence resonance energy transfer (FRET) and oxygen-augmenting strategy, namely APT, which enables glycosylation detection, O2 self-sufficiency, and collaborative phototherapy. Such APT nanoprobes were constructed by depositing platinum onto gold nano-bipyramids (Au NBPs), linking FITC fluorophore-labeled AS1411 aptamers for introducing FRET donors, and by conjugating G-quadruplex intercalated with TMPyP4 to their surfaces via the SH-DNA chain. By installing FRET acceptors on the glycan of targeted EpCAM glycoprotein using the metabolic glycan labeling and click chemistry, FRET signals appear on the cancerous cell membranes, not normal cells, when donors and acceptors are within an appropriate distance. This actualizes protein-specific glycosylation visualization while revealing glycan-based changes correlated with tumor progression. Interestingly, the deposited platinum scavenges excessive H2O2 as artificial nanoenzymes to transform O2 that alleviates tumor hypoxia and simultaneously elevates singlet oxygen (1O2) for inducing cancer cell apoptosis. Notably, the significant hyperthermia devastation was elicited via APT nanoprobes with phenomenal photothermal therapy (PTT) efficiency (71.8%) for thermally ablating cancer cells, resulting in synergistically enhanced photodynamic-hyperthermia therapy. Consequently, APT nanoprobes nearly actualized thorough tumor ablation while demonstrating highly curative biosafety. This work offers a new paradigm to rationally explore a combined FRET and oxygen-augmenting strategy with a focus on nanotheranostics for hypoxic tumor elimination.

Biomimetic Nanotheranostics Camouflaged with Cancer Cell Membranes Integrating Persistent Oxygen Supply and Homotypic Targeting for Hypoxic Tumor Elimination.

Treatment resistance of the tumors to photodynamic therapy (PDT) owing to O2 deficiency largely compromised the therapeutic efficacy, which could be addressed via modulating oxygen levels by using O2 self-enriched nanosystems. Here, we report on augmenting the O2-evolving strategy based on a biomimetic, catalytic nanovehicle (named as N/P@MCC), constructed by the catalase-immobilized hollow mesoporous nanospheres by enveloping a cancer cell membrane (CCM), which acts as an efficient nanocontainer to accommodate nitrogen-doped graphene quantum dots (N-GQDs) and protoporphyrin IX (PpIX). Inheriting the virtues of biomimetic CCM cloaking, the CCM-derived shell conferred N/P@MCC nanovehicles with highly specific self-recognition and homotypic targeting toward cancerous cells, ensuring tumor-specific accumulation and superior circulation durations. N-GQDs, for the first time, have been evidenced as a new dual-functional nanoagents with PTT and PDT capacities, enabling the generation of 1O2 for PDT and inducing local low-temperature hyperthermia for thermally ablating cancer cells and infrared thermal imaging (IRT). Leveraging the intrinsic catalytic features of catalase, such N/P@MCC nanovehicles effectively scavenged the excessive H2O2 to sustainably evolve oxygen for a synchronous O2 self-supply and hypoxia alleviation, with an additional benefit because the resulting O2 bubbles could function as an echo amplifier, leading to the sufficient echogenic reflectivity for ultrasound imaging. Concurrently, the elevated O2 reacted with N-GQDs and PpIX to elicit a maximally increased 1O2 output for augmented PDT. Significantly, the ultrasound imaging coupled with fluorescence imaging, IRT, performs a tumor-modulated trimodal bioimaging effect. Overall, this offers a paradigm to rationally explore O2 self-supply strategies focused on versatile nanotheranostics for hypoxic tumor elimination.

Target-Induced Core-Satellite Nanostructure Assembly Strategy for Dual-Signal-On Fluorescence Imaging and Raman Quantification of Intracellular MicroRNA Guided Photothermal Therapy.

Integrating biological detection and treatment into one system is a smart therapeutic maneuver for efficient cancer treatment. Herein, a target-activated core-satellite nanostructure (CS nanostructure) assembly built on gold nanobipyramids motor (AuNBPs motor)/gold nanoparticle probe (AuNP probe) exhibiting simultaneous dual signal-on imaging, quantification of intracellular microRNA-21 (miR-21), and photothermal therapy (PTT) for cancer is designed. Of note, when the AuNBPs motor/AuNP probe enters into cells, miR-21 triggers the reaction between AuNBPs motor and AuNP probe, resulting in the formation of CS nanostructure assembly. The process of assembling the CS nanostructure is accompanied with strong fluorescent signals from TAMRA and surface-enhanced Raman scattering (SERS) signals from adenine. The fluorescent signal is leveraged to image the intracellular miR-21 level, whereas the SERS signal is utilized for absolute quantification of intracellular miR-21, and the CS nanostructure acts as the photosensitizer for PTT. This strategy can successfully image and quantify miR-21 in a single cell, and also distinguish normal cells from tumor cells. Moreover, under the guidance of fluorescence signal, the assembly kills tumor cells and inhibits tumor growth via PTT. In vitro and in vivo results prove that the proposed strategy possesses enormous potential for application in the diagnosis and treatment of cancer.

DNAzyme-Powered Three-Dimensional DNA Walker Nanoprobe for Detection Amyloid ß-Peptide Oligomer in Living Cells and in Vivo.

Amyloid ß-peptide oligomer (AßO) is widely acknowledged as the promising biomarker for the diagnosis of Alzheimer's disease (AD). In this work, we designed a three-dimensional (3D) DNA walker nanoprobe for AßO detection and real-time imaging in living cells and in vivo. The presence of AßO triggered the DNAzyme walking strand to cleave the fluorophore (TAMRA)-labeled substrate strand modified on the gold nanoparticle (AuNP) surface and release TAMRA-labeled DNA fragment, resulting in the recovery of fluorescent signal. The entire process was autonomous and continuous, without external fuel strands or protease, and finally produced plenty of TAMRA fluorescence, achieving signal amplification effect. The nanoprobe enabled the quantitative detection of AßO in vitro, and the limit of detection was 22.3 pM. Given the good biocompatibility of 3D DNA walker nanoprobe, we extended this enzyme-free signal amplification method to real-time imaging of AßO. Under the microscope, nanoprobe accurately located and visualized the distribution of AßO in living cells. Moreover, in vivo imaging results showed that our nanoprobe could be used to effectively distinguish the AD mice from the wild-type mice. This nanoprobe with the advantages of great sensitivity, high specificity, and convenience, provides an outstanding prospect for AD's early diagnosis development.

Carbon Nitride Hollow Theranostic Nanoregulators Executing Laser-Activatable Water Splitting for Enhanced Ultrasound/Fluorescence Imaging and Cooperative Phototherapy.

The limited efficacy of "smart" nanotheranostic agents in eradicating tumors calls for the development of highly desirable nanoagents with diagnostics and therapeutics. Herein, to surmount these challenges, we constructed an intelligent nanoregulator by coating a mesoporous carbon nitride (C3N4) layer on a core-shell nitrogen-doped graphene quantum dot (N-GQD)@hollow mesoporous silica nanosphere (HMSN) and decorated it with a P-PEG-RGD polymer, to achieve active-targeting delivery (designated as R-NCNP). Upon irradiation, the resultant R-NCNP nanoregulators exhibit significant catalytic breakdown of water molecules, causing a sustainable elevation of oxygen level owing to the C3N4 shell, which facilitates tumor oxygenation and relieves tumor hypoxia. The generated oxygen bubbles serve as an echogenic source, triggering tissue impedance mismatch, thereby enhancing the generation of an echogenicity signal, making them laser-activatable ultrasound imaging agents. In addition, the encapsulated photosensitizers and C3N4-layered photosensitizer are simultaneously activated to maximize the yield of ROS, actualizing a triple-photosensitizer hybrid nanosystem exploited for enhanced PDT. Intriguingly, the N-GQDs endow the R-NCNP nanoregulator with a photothermal effect for hyperthemia, making it exhibit considerable photothermal outcomes and infrared thermal imaging (IRT). Importantly, further analysis reveals that the polymer-modified R-NCNPs actively target specific tumor tissues and display a triple-modal US/IRT/FL imaging-assisted cooperative PTT/PDT for real-time monitoring of tumor ablation and therapeutic evaluation. The rational synergy of triple-model PDT and efficient PTT in the designed nanoregulator confers excellent anticancer effects, as evidenced by in vitro and in vivo assays, which might explore more possibilities in personalized cancer treatment.

PRP-chitosan thermoresponsive hydrogel combined with black phosphorus nanosheets as injectable biomaterial for biotherapy and phototherapy treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease causing destruction of bone and cartilago articularis. Traditional treatment methods have many side effects, or too concerne about the anti-inflammatory mechanisms but ignore osteanagenesis. In this work, a novel therapeutic platform combined black phosphorus nanosheets (BPNs) into platelet-rich plasma (PRP)-chitosan thermoresponsive hydrogel has been prepared for management of RA. The BPNs generate local heat upon near-infrared irradiation, and delivering reactive oxygen species (ROS) to the inflamed joints simultaneously for removing hyperplastic synovial tissue. The injectable chitosan thermoresponsive hydrogel can take control of the releasing of BPNs degradation products, which provide ample raw materials for osteanagenesis. In addition, the PRP can effectively improve the adhesion and increase capacity of mesenchymal stem cells on chitosan thermosensitive hydrogels. And this thermoresponsive hydrogel can protect articular cartilage by reducing the friction on the surrounding tissue. Drug delayed release property was indicated by the release and uptake of methotrexate. The edema degree of the arthritic mouse was reduced obviously by the BPNs/Chitosan/PRP thermoresponsive hydrogel. Both in vitro and in vivo studies suggest that the thermoresponsive hydrogel can provide a potential possibility for the management of RA.

Three-Dimensional High-Porosity Chitosan/Honeycomb Porous Carbon/Hydroxyapatite Scaffold with Enhanced Osteoinductivity for Bone Regeneration.

Three-dimensional honeycomb porous carbon (HPC) has attracted increasing attention in bioengineering due to excellent mechanical properties and a high surface-to-volume ratio. In this paper, a three-dimensional chitosan (CS)/honeycomb porous carbon/hydroxyapatite composite was prepared by nano-sized hydroxyapatite (nHA) on the HPC surface in situ deposition, dissolved in chitosan solution, and vacuum freeze-dried. The structure and composition of CS/HPC/nHA were characterized by scanning electron microscopy, transmission electron miscroscopy, Fourier transform infrared, and X-ray photoelectron spectroscopy, and the porosity, swelling ratio, and mechanical properties of the scaffold were also tested. The as-prepared scaffolds possess hierarchical pores and organic-inorganic components, which are similar in composition and structure to bone tissues. The synthesized composite scaffold has high porosity and a certain mechanical strength. By culturing mouse bone marrow mesenchymal stem cells on the surface of the scaffold, it was confirmed that the scaffold facilitated its growth and promoted its differentiation into the osteogenesis direction. In vivo experiments further demonstrate that the CS/HPC/nHA composite scaffold has a significant advantage in promoting bone formation in the bone defect area. All the results suggested that the CS/HPC/nHA scaffolds have great application prospect in bone tissue engineering.

Bioactive Three-Dimensional Graphene Oxide Foam/Polydimethylsiloxane/Zinc Silicate Scaffolds with Enhanced Osteoinductivity for Bone Regeneration.

Nanocomposite scaffold materials have shown great prospect in promoting bone integration and bone regeneration. A three-dimensional graphene oxide foam/polydimethylsiloxane/zinc silicate (GF/PDMS/ZS) scaffold for bone tissue engineering was synthesized via dip coating and hydrothermal synthesis processes, resulting in the interconnected macroporous structure. The scaffold was characterized with scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and thermogravimetric (TG) analysis. The result showed that scaffolds exhibiting a porous characteristic had organic-inorganic components similar to natural bone tissue. Moreover, the scaffolds possessed suitable pore size, high porosity, and good mechanical properties. In vitro experiments with mouse bone marrow mesenchymal stem cells (mBMSCs) revealed that the composite scaffold not only has great biocompatibility but also has the ability to induce mBMSC proliferation and preferential osteogentic differentiation. Thereafter, the expression of critical genes, ALP, RUNX2, VEGFA, and OPN, was activated. In vivo analysis of critical bone defect in rabbits demonstrated superior bone formation in defect sites in the GF/PDMS/ZS scaffold group at 12 weeks of post implantation without no significant inflammatory response. All the results validated that the GF/PDMS/ZS scaffold is a promising alternative for applications in bone regeneration.