Dual siRNA-Loaded Cell Membrane Functionalized Matrix Facilitates Bone Regeneration with Angiogenesis and Neurogenesis.

Vascularization and innervation play irreplaceable roles in bone regeneration and bone defect repair. However, the reconstruction of blood vessels and neural networks is often neglected in material design. This study aims to design a genetically functionalized matrix (GFM) and enable it to regulate angiogenesis and neurogenesis to accelerate the process of bone defect repair. The dual small interfering RNA (siRNA)-polyvinylimide (PEI) (siRP) complexes that locally knocked down soluble vascular endothelial growth factor receptor 1 (sFlt-1) and p75 neurotrophic factor receptor (p75NTR ) are prepared. The hybrid cell membrane (MM) loaded siRP is synthesized as siRNA@MMs to coat on polylactone (PCL) electrospun fibers for mimicking the natural bone matrix. The results indicates that siRNA@MMs could regulate the expression of vascular-related and neuro-related cytokines secreted by mesenchymal stem cells (MSCs). GFMs promote the expression of osteogenic differentiation through paracrine function in vitro. GFMs attenuates inflammation and promotes osseointegration by regulating the coupling of vascularization and innervation in vivo. This study uses the natural hybrid cell membrane to carry genetic material and assist in the vascularization and innervation function of two siRNA. The results present the significance of neuro-vascularized organoid bone and may provide a promising choice for the design of bone tissue engineering scaffold.

Hierarchically Released Liquid Metal Nanoparticles for Mild Photothermal Therapy/Chemotherapy of Breast Cancer Bone Metastases via Remodeling Tumor Stromal Microenvironment.

Currently, the treatment strategy for bone metastasis is mainly to inhibit the growth of tumor cells and the activity of osteoclasts, while ignoring the influence of the tumor stromal microenvironment (TSM) on the progression of bone metastasis. Herein, a dual-target liquid metal (LM)-based drug delivery system (DDS) with favorable photothermal performance is designed to spatially program the delivery of multiple therapeutic agents to enhance the treatment of bone metastasis through TSM remodeling. Briefly, mesoporous silicon-coated LM is integrated into zeolitic imidazolate framework-8 (ZIF-8) with both bone-seeking and tumor-targeting capacities. Curcumin (Cur), a tumor microenvironment modulator, is encapsulated into ZIF-8, and doxorubicin (DOX) is enclosed inside mesoporous silicon. Specific accumulation of the LM-based DDS in bone metastases first relieves the tumor stroma by releasing Cur in response to the acidic tumor microenvironment and then releases DOX deep into the tumor under near-infrared light irradiation. The combined strategy of the LM-based DDS and mild photothermal therapy has been shown to effectively restrain cross-talk between osteoclasts and tumor cells by inhibiting the secretion of transforming growth factor-ß, degrading extracellular matrix components, and increasing infiltration of CD4+ and CD8+ T cells, which provides a promising strategy for the treatment of bone metastases.

Combining dual-targeted liquid metal nanoparticles with autophagy activation and mild photothermal therapy to treat metastatic breast cancer and inhibit bone destruction.

Although mild photothermal therapy (mild-PTT) avoids treatment bottleneck of the traditional PTT, the application of mild-PTT in deep and internal tumors is severely restricted due to thermal resistance, limited irradiation area and penetration depth. In addition, bone resorption caused by tumor colonization in distal bone tissue exacerbates tumor progression. Here, a strategy was developed for the treatment of bone metastasis and alleviation of bone resorption, which was based on liquid metal (LM) nanoparticle to resist thermal resistance induced by mild-PTT via autophagy activation. Briefly, LM and autophagy activator (Curcumin, Cur) were loaded into zeolitic imidazolate framework-8 (ZIF-8), which was then functionalized with hyaluronic acid/alendronate (CLALN). CLALN exhibited good photothermal performance, drug release ability under acidic environment, specifical recognition and aggregation at bone metastasis sites. CLALN combined with mild-PPT dramatically inhibited tumor progress by inducing the impaired autophagy and reduced the expression of programmed cell death ligand 1 (PD-L1) protein triggered by mild-PTT, resisting thermal resistance and alleviating the immunosuppression. Besides, CLALN combined with mild-PPT effectively alleviated osteolysis compared with only CLALN or mild-PPT. Our experiments demonstrated that this multi-functional LM-based nanoparticle combined with autophagy activation provided a promising therapeutic strategy for bone metastasis treatment. STATEMENT OF SIGNIFICANCE: Due to the limited light penetration, photothermal therapy (PTT) has limited inhibitory effect on tumor cells colonized in the bone. In addition, nonspecific heat diffusion of PTT may accidentally burn normal tissues and damage peripheral blood vessels, which can block the accumulation of drugs in deep tumors. Here, a multifunctional liquid metal based mild-PTT delivery system is designed to inhibit tumor growth and bone resorption by modulating the bone microenvironment and activating autophagy "on demand". It can overcome the treatment bottleneck of traditional PTT and improve the treatment effect of mild-PTT by resisting photothermal resistance and immune suppression. In addition, it also exhibits favorable heat/acid-responsive drug release performance and can specifically target tumor cells at the site of bone metastases.

Hyperpolarized Xe NMR signal advancement by metal-organic framework entrapment in aqueous solution.

We report hyperpolarized Xe signal advancement by metal-organic framework (MOF) entrapment (Hyper-SAME) in aqueous solution. The 129Xe NMR signal is drastically promoted by entrapping the Xe into the pores of MOFs. The chemical shift of entrapped 129Xe is clearly distinguishable from that of free 129Xe in water, due to the surface and pore environment of MOFs. The influences from the crystal size of MOFs and their concentration in water are studied. A zinc imidazole MOF, zeolitic imidazole framework-8 (ZIF-8), with particle size of 110 nm at a concentration of 100 mg/mL, was used to give an NMR signal with intensity four times that of free 129Xe in water. Additionally, Hyper-SAME is compatible with hyperpolarized 129Xe chemical exchange saturation transfer. The 129Xe NMR signal can be amplified further by combining the two techniques. More importantly, Hyper-SAME provides a way to make detection of hyperpolarized 129Xe in aqueous solution convenient and broadens the application area of MOFs.

Efficient Separation of Nucleic Acids with Different Secondary Structures by Metal-Organic Frameworks.

We report the use of metal-organic frameworks (MOFs) for the selective separation of nucleic acids (DNA and RNA) with different secondary structures through size, shape, length, and capability of conformational transition. Three MOFs with precisely controlled pore environments, Co-IRMOF-74-II, -III, and -IV, composed of Co2+ and organic linkers (II, III, and IV), respectively, were used for the inclusion of nucleic acid into their pores from the solution. This was proven to be a spontaneous process from disordered free state to restricted ordered state via circular dichroism (CD) spectroscopy. Three critical factors were identified for their inclusion: (1) size selection induced by steric hindrance, (2) conformation transition energy selection induced by stability, and (3) molecular weight selection. These selection rules were used to extract nucleic acids with flexible and unstable secondary structures from complex mixtures of multiple nucleic acids, leaving those with rigid and stable secondary structures in the mother liquor. This provides the possibility to separate and enrich nucleic acids in bulk through their different structure feature, which is highly desirable in genome-wide structural measurement of nucleic acids. Unlike methods that rely on specific binding antibodies or ligand, this MOF method is capable of selecting all kinds of nucleic acids with similar secondary structure features; therefore, it is suitable for the handling of a large variety and quantity of nucleic acids at the same time. This method also has the potential to gather information about the folding stability of biomolecules with secondary structures.

Multiplexed microRNA Detection Using Metal-Organic Framework for Signal Output.

A specificity fluorescence platform for probing of sequence-specific miRNA using fluorophore labeled DNA and metal-organic frameworks (MOFs) is developed. Ni-IRMOF-74-II can quench the fluorescence of four fluorescent dyes labeled in the single strand oligodeoxynucleotides (ssODNs), and fluorescence recovers in the presence of their target miRNA and can be detected in their corresponding channels. Furthermore, recovered fluorescence intensity has a linear relationship with the concentration of the target miRNA in the range from 1.25 to 100 nM at the four corresponding channels. This fluorescence sensor platform can detect several kinds of miRNA in the same system and at same time with the high specificity and negligible cross-reactivity.

Design Rules for Metal-Organic Framework Stability in High-Pressure Hydrogen Environments.

Stability of metal-organic frameworks (MOFs) under hydrogen is of particular importance for a diverse range of applications, including catalysis, gas separations, and hydrogen storage. Hydrogen in gaseous form is known to be a strong reducing agent and can potentially react with the secondary building units of a MOF and decompose the porous framework structure. Moreover, rapid pressure swings expected in vehicular hydrogen storage could create significant mechanical stresses within MOF crystals that cause partial or complete pore collapse. In this work, we examined the stability of a structurally representative suite of MOFs by testing them under both static (70 MPa) and dynamic hydrogen exposure (0.5 to 10 MPa, 1000 pressure cycles) at room temperature. We aim to provide stability information for development of near room-temperature hydrogen storage media based on MOFs and suggest framework design rules to avoid materials unstable for hydrogen storage under relevant technical conditions.

Metal-organic frameworks for precise inclusion of single-stranded DNA and transfection in immune cells.

Effective transfection of genetic molecules such as DNA usually relies on vectors that can reversibly uptake and release these molecules, and protect them from digestion by nuclease. Non-viral vectors meeting these requirements are rare due to the lack of specific interactions with DNA. Here, we design a series of four isoreticular metal-organic frameworks (Ni-IRMOF-74-II to -V) with progressively tuned pore size from 2.2 to 4.2 nm to precisely include single-stranded DNA (ssDNA, 11-53 nt), and to achieve reversible interaction between MOFs and ssDNA. The entire nucleic acid chain is completely confined inside the pores providing excellent protection, and the geometric distribution of the confined ssDNA is visualized by X-ray diffraction. Two MOFs in this series exhibit excellent transfection efficiency in mammalian immune cells, 92% in the primary mouse immune cells (CD4+ T cell) and 30% in human immune cells (THP-1 cell), unrivaled by the commercialized agents (Lipo and Neofect).