Hollow Carbon Nanospheres with Tunable Hierarchical Pores for Drug, Gene, and Photothermal Synergistic Treatment.

Design and synthesis of porous and hollow carbon spheres have attracted considerable interest in the past decade due to their superior physicochemical properties and widespread applications. However, it is still a big challenge to achieve controllable synthesis of hollow carbon nanospheres with center-radial large mesopores in the shells and inner surface roughness. Herein, porous hollow carbon nanospheres (PHCNs) are successfully synthesized with tunable center-radial mesopore channels in the shells and crater-like inner surfaces by employing dendrimer-like mesoporous silica nanospheres (DMSNs) as hard templates. Compared with conventional mesoporous nanospheres, DMSN templates not only result in the formation of center-radial large mesopores in the shells, but also produce a crater-like inner surface. PHCNs can be tuned from open center-radial mesoporous shells to relatively closed microporous shells. After functionalization with polyethyleneimine (PEI) and poly(ethylene glycol) (PEG), PHCNs not only have negligible cytotoxicity, excellent photothermal property, and high coloading capacity of 482 µg of doxorubicin and 44 µg of siRNA per mg, but can also efficiently deliver these substances into cells, thus displaying enhanced cancer cell killing capacity by triple-combination therapy.

Magnetic Core-Shell Silica Nanoparticles with Large Radial Mesopores for siRNA Delivery.

A novel type of magnetic core-shell silica nanoparticles is developed for small interfering RNA (siRNA) delivery. These nanoparticles are fabricated by coating super-paramagnetic magnetite nanocrystal clusters with radial large-pore mesoporous silica. The amine functionalized nanoparticles have small particle sizes around 150 nm, large radial mesopores of 12 nm, large surface area of 411 m(2) g(-1) , high pore volume of 1.13 cm(3) g(-1) and magnetization of 25 emu g(-1) . Thus, these nanoparticles possess both high loading capacity of siRNA (2 wt%) and strong magnetic response under an external magnetic field. An acid-liable coating composed of tannic acid can further protect the siRNA loaded in these nanoparticles. The coating also increases the dispersion stability of the siRNA-loaded carrier and can serve as a pH-responsive releasing switch. Using the magnetic silica nanoparticles with tannic acid coating as carriers, functional siRNA has been successfully delivered into the cytoplasm of human osteosarcoma cancer cells in vitro. The delivery is significantly enhanced with the aid of the external magnetic field.

Proton-functionalized two-dimensional graphitic carbon nitride nanosheet: an excellent metal-/label-free biosensing platform.

Ultrathin graphitic carbon nitride (g-C3N4) nanosheets, due to their interesting two-dimensional graphene-like structure and unique physicochemical properties, have attracted great research attention recently. Here, a new approach is developed to prepare, for the first time, proton-functionalized ultrathin g-C3N4 nanosheets by sonication-exfoliation of bulk g-C3N4 under an acid condition. This method not only reduces the exfoliation time from more than 10 h to 2 h, but also endows the nanosheets with positive charges. Besides retaining the properties of g-C3N4, the obtained nanosheets with the thickness of 2-4 nm (i.e., 6-12 atomic monolayers) also exhibit large specific surface area of 305 m(2) g(-1), enhanced fluorescence intensity, and excellent water dispersion stability due to their surface protonation and ultrathin morphology. The well-dispersed protonated g-C3N4 nanosheets are able to interact with negatively charged heparin, which results in the quenching of g-C3N4 fluorescence. A highly sensitive and highly selective heparin sensing platform based on protonated g-C3N4 nanosheets is established. This metal-free and fluorophore label-free system can reach the lowest heparin detection limit of 18 ng mL(-1).

Intracellular microenvironment responsive polymers: a multiple-stage transport platform for high-performance gene delivery.

A new strategy for promoting endoplasmic gene delivery and nucleus uptake is proposed by developing intracellular microenvironment responsive biocompatible polymers. This delivery system can efficiently load and self-assemble nucleic acids into nano-structured polyplexes at a neutral pH, release smaller imidazole-gene complexes from the polymer backbones at intracellular endosomal pH, transport nucleic acids into nucleus through intracellular environment responsive multiple-stage gene delivery, thus leading to a high cell transfection efficiency.

NIPAM-based Microgel Microenvironment Regulates the Therapeutic Function of Cardiac Stromal Cells.

To tune the chemical, physical, and mechanical microenvironment for cardiac stromal cells to treat acute myocardial infarction (MI), we prepared a series of thermally responsive microgels with different surface charges (positive, negative, and neutral) and different degrees of hydrophilicity, as well as functional groups (carboxyl, hydroxyl, amino, and methyl). These microgels were used as injectable hydrogels to create an optimized microenvironment for cardiac stromal cells (CSCs). Our results indicated that a hydrophilic and negatively charged microenvironment created from poly( N-isopropylacrylamide- co-itaconic acid) was favorable for maintaining high viability of CSCs, promoting CSC proliferation and facilitating the formation of CSC spheroids. A large number of growth factors, such as vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-1), and stromal-derived factor-1 (SDF-1) were released from the spheroids, promoting neonatal rat cardiomyocyte activation and survival. After injecting the poly( N-isopropylacrylamide- co-itaconic acid) microgel into mice, we examined their acute inflammation and T-cell immune reactions. The microgel itself did not elicit obvious immune response. We then injected the same microgel-encapsulated with CSCs into MI mice. The result revealed the treatment-promoted MI heart repair through angiogenesis and inhibition of apoptosis with an improved cell retention rate. This study will open a door for tailoring poly( N-isopropylacrylamide)-based microgel as a delivery vehicle for CSC therapy.

γ-PGA-coated mesoporous silica nanoparticles with covalently attached prodrugs for enhanced cellular uptake and intracellular GSH-responsive release.

Poor cellular uptake of drug delivery carriers and uncontrolled drug release remain to be the major obstacles in cancer therapy due to their low delivery efficiency. In this study, a multifunctional intracellular GSH (glutathione)-responsive silica-based drug delivery system with enhanced cellular uptake capability is developed. Uniform 50 nm colloidal mesoporous silica nanoparticles (MSNs) with mercaptopropyl-functionalized core and silanol-contained silica surface (MSNs-SHin ) are designed and fabricated as a platform for drug covalent attachment and particle surface modification. Doxorubicin (DOX) with primary amine group as an anticancer model drug is covalently conjugated to the mesopores of MSNs-SHin via disulfide bonds in the presence of a heterobifunctional linker (N-Succinimidyl 3-(2-pyridyldithio) propionate). Poly(γ-glutamic acid) (γ-PGA) can be coated onto the particle surface by sequential electrostatic adsorption of polyethyleneimine (PEI) and γ-PGA. The constructed delivery system exhibits enhanced cellular uptake via a speculated γ-glutamyl transpeptidase (GGT)-mediated endocytosis pathway and controlled drug release capacity via intracellular GSH-responsive disulfide-bond cleavage, and thus significantly inhibits the growth of cancer cells. The multifunctional delivery system paves a new way for developing high-efficient particle-based nanotherapeutic approach for cancer treatment.

Intracellular microenvironment-responsive label-free autofluorescent nanogels for traceable gene delivery.

Gene therapy presents a unique opportunity for the treatment of genetic diseases, but the lack of multifunctional delivery systems has hindered its clinical applications. Here, a new delivery vector, autofluorescent polyethyleneimine (PEI) nanogels, for highly efficient and traceable gene delivery is developed. Different from commercial high-molecular-weight PEI, the cationic nanogels are noncytotoxic and able to be fragmented due to their unique intracellular microenvironment-responsive structures. The biodegradable nanogels can effectively load plasmid DNA (pDNA), and the self-assembled polyplexes can be cleaved after cellular uptake to improve gene transfection efficiency. Most importantly, the nanogels and the nanogel/pDNA polyplexes are autofluorescent. The fluorescence is stable in blood plasma and responsive to the intracellular microenvironment. The breakup of the nanogels or polyplexes leads to the loss of fluorescence, and thus the gene delivery and carrier biodegradation processes can be monitored. The reported multifunctional system demonstrates excellent biocompatibility, high transfection efficiency, responsive biodegradability, controlled gene release, label-free and simultaneous fluorescence tracking, which will provide a new platform for future scientific investigation and practical implications in gene therapy.

Label-free dendrimer-like silica nanohybrids for traceable and controlled gene delivery.

To create advanced functional nanocarriers for achieving excellent gene delivery performance, fluorescence label-free hybridized dendrimer-like silica nanocarriers (HPSNs-AC-PEI) were developed by using the endosomal pH and cytoplasmic glutathione (GSH) responsive autofluorescent acetaldehyde-modified-cystine (AC) to link non-toxic low molecular weight branched polyethyleneimine (PEI) onto amino-functionalized dendrimer-like silica nanoparticles with hierarchical pores (HPSNs-NH2). The specific microstructure of this hybridized nanocarrier makes it not only show low cytotoxicity and high gene loading capability, but also display high gene transfection efficiency. The cleavage of disulfide bonds caused by GSH facilitates plasmid DNA (pDNA) release. Moreover, the pH and GSH controlled gene delivery profile can be real-time tracked using the autofluorescence of HPSNs-AC-PEI.

Freeze-drying of ovalbumin loaded mesoporous silica nanoparticle vaccine formulation increases antigen stability under ambient conditions.

Amino functionalised mesoporous silica nanoparticles (AM-41) have been identified as a promising vaccine delivery material. The capacity of AM-41 to stabilise vaccine components at ambient temperature (23-27°C) was determined by adsorbing the model antigen ovalbumin (OVA) to AM-41 particles (OVA-41). The OVA-41 was successfully freeze-dried using the excipients 5% trehalose and 1% PEG8000. The immunological activity of OVA and the nanoparticle structure were maintained following two months storage at ambient temperature. The results of immunisation studies in mice with reconstituted OVA-41 demonstrated the induction of humoral and cell-meditated immune responses. The capacity of AM-41 particles to facilitate ambient storage of vaccine components without the loss of immunological potency will underpin the further development of this promising vaccine delivery platform.

Developing functionalized dendrimer-like silica nanoparticles with hierarchical pores as advanced delivery nanocarriers.

Functionalized dendrimer-like hybrid silica nanoparticles with hierarchical pores are designed and synthesized. The unique structure, large surface area, and excellent biocompability render such materials attractive nanocarriers for the advanced delivery of various sized drugs and genes simultaneously.

Poly-L-lysine functionalized large pore cubic mesostructured silica nanoparticles as biocompatible carriers for gene delivery.

Large pore mesoporous silica nanoparticles (LP-MSNs) functionalized with poly-L-lysine (PLL) were designed as a new carrier material for gene delivery applications. The synthesized LP-MSNs are 100-200 nm in diameter and are composed of cage-like pores organized in a cubic mesostructure. The size of the cavities is about 28 nm with an entrance size of 13.4 nm. Successful grafting of PLL onto the silica surface through covalent immobilization was confirmed by X-ray photoelectron spectroscopy, solid-state (13)C magic-angle spinning nuclear magnetic resonance, Fourier transformed infrared, and thermogravimetric analysis. As a result of the particle modification with PLL, a significant increase of the nanoparticle binding capacity for oligo-DNAs was observed compared to the native unmodified silica particles. Consequently, PLL-functionalized nanoparticles exhibited a strong ability to deliver oligo DNA-Cy3 (a model for siRNA) to Hela cells. Furthermore, PLL-functionalized nanoparticles were proven to be superior as gene carriers compared to amino-functionalized nanoparticles and the native nanoparticles. The system was tested to deliver functional siRNA against minibrain-related kinase and polo-like kinase 1 in osteosarcoma cancer cells. Here, the functionalized particles demonstrated great potential for efficient gene transfer into cancer cells as a decrease of the cellular viability of the osteosarcoma cancer cells was induced. Moreover, the PLL-modified silica nanoparticles also exhibit a high biocompatibility, with low cytotoxicity observed up to 100 µg/mL.

Formation of large 2D nanosheets via PVP-assisted assembly of anatase TiO2 nanomosaics.

We demonstrate an unusual formation of large 2D nanosheets from nanomosaic building blocks of anatase TiO(2) nanosheets with exposed (001) facets. It is proposed that large PVP molecules adsorbed on the (001) facets serve as the linker that brings building blocks together, at the same time prevents them from stacking along the c-axis.

Mesoporous silica nanoparticles for bioadsorption, enzyme immobilisation, and delivery carriers.

Mesoporous silica nanoparticles (MSNs) provide a non-invasive and biocompatible delivery platform for a broad range of applications in therapeutics, pharmaceuticals and diagnosis. The creation of smart, stimuli-responsive systems that respond to subtle changes in the local cellular environment are likely to yield long term solutions to many of the current drug/gene/DNA/RNA delivery problems. In addition, MSNs have proven to be promising supports for enzyme immobilisation, enabling the enzymes to retain their activity, affording them greater potential for wide applications in biocatalysis and energy. This review provides a comprehensive summary of the advances made in the last decade and a future outlook on possible applications of MSNs as nanocontainers for storage and delivery of biomolecules. We discuss some of the important factors affecting the adsorption and release of biomolecules in MSNs and review of the cytotoxicity aspects of such nanomaterials. The review also highlights some promising work on enzyme immobilisation using mesoporous silica nanoparticles.