Biomimetic ZIF8 Nanosystem With Tumor Hypoxia Relief Ability to Enhance Chemo-Photothermal Synergistic Therapy.

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.

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.

Hybridization chain reaction triggered poly adenine to absorb silver nanoparticles for label-free electrochemical detection of Alzheimer's disease biomarkers amyloid ß-peptide oligomers.

Amyloid ß-peptide oligomer (AßO) has received extensive attention from researchers because of its clinical therapeutic intervention targets and the value of reliable biological macromolecules markers for early diagnosis of Alzheimer's disease. We have developed a novel label-free electrochemical detection sensor for AßO based on hybridization chain reaction (HCR)-triggered poly adenine to absorb silver nanoparticles (AgNPs). In this method, we first use the "capture probe" to immobilize the aptamer 1 on the surface of the gold electrode (GE) via poly adenine-Au. Next, aptamer 2 and AßO were deposited on the electrode surface. The HCR process was initiated by the aptamer 2 fragment as a primer, producing a large number of long DNA sequences, which contained many adenines. Thereafter, the HCR product with long-repeated adenines could absorb many AgNPs on the surface of the electrode, which were used for subsequent electrochemical stripping of the AgNPs. The concentration range of the electrochemical signal of AßO was 1 pM-10 nM, and the detection limit was 430 fM, which indicated that that the detection system has high selectivity for the target protein.

Proximity hybridization induced DNA assembly for label-free surface-enhanced Raman spectroscopic detection of carcinoembryonic antigen.

In our research, label-free and surface-enhanced Raman dyes-free Raman spectroscopy which was used to detect carcinoembryonic antigen (CEA) according to poly adenine (Poly A)-regulated self-assembly methods was developed and studied. CEA induced partial hybridization of Ab-H2 and Ab-H1, and Ab-H1-CEA-Ab-H2 (a sandwich proximity CEA-DNA complex) was formed, which unfolded molecular beacon 1 (MB1) and modified the substrate. Subsequently, MB2-AuNPs were hybridized with MB1, and Ab-H1-CEA-Ab-H2 was released via toehold regulated displacements of DNA strands. Therefore, hybridization processes of MB2 and MB1 were induced and promoted by CEA-DNA complexes which worked as catalysts. The misplaced target then induced a next round of strand exchange, and the signals for determination of CEA were amplified by AuNPs absorbed on the substrate. It was indicated that the spectral characteristics of adenine at 736 cm-1 were consistent with the SERS spectrum of DNA. Adenine acted as an internal marker for label-free SERS detection of CEA. Moreover, satisfactory stability and reproducibility were found. Meanwhile, the antibody could specifically recognize the corresponding antigen. Since adenine was dominant in SERS spectra, which was also proximal to Au surface, the sensitivity of the novel method was high without modifications. The analytical performance of this method in determining serum CEA was satisfactory.

Mimic Lipoproteins Responsive to Intratumoral pH and Allosteric Enzyme for Efficient Tumor Therapy.

Discoid-reconstituted high-density lipoprotein (d-rHDL) is advantageous for tumor-targeted drug delivery due to its small size, long circulation, and efficient internalization into cancer cells. Nevertheless, an allosteric reaction catalyzed by serum lecithin-cholesterol acyltransferase (LCAT) may cause drug leakage from d-rHDL and reduce its targeting efficiency. Conversely, similar "structural weakening" catalyzed by acyl-coenzyme A-cholesterol acyltransferase (ACAT) inside tumor cells can stimulate precise intracellular drug release. Therefore, we synthesized and characterized a pH-sensitive n-butyraldehyde bi-cholesterol (BCC) to substitute for cholesterol in the d-rHDL particle, and bovine serum albumin (BSA) was used as the targeting agent. This dual pH- and ACAT-sensitive d-rHDL (d-d-rHDL) was small with a disk-like appearance. Morphological transformation observation, in vitro release assays, and differences in internalization upon LCAT treatment confirmed that BCC effectively inhibited the remodeling behavior and enhanced the tumor-targeting efficiency. The accumulation of d-d-rHDL in HepG2 cells was significantly higher than that in LO2 cells, and accumulation was inhibited by free BSA. The pH sensitivity was verified, and d-d-rHDL achieved efficient drug release in vitro and inside tumor cells after exposure to acidic conditions and ACAT. Confocal laser scanning microscopy demonstrated that d-d-rHDL escaped from lysosomes and became distributed evenly throughout cells. Moreover, in vivo imaging assays in a tumor-bearing mouse model demonstrated tumor-targeting properties of d-d-rHDL, and paclitaxel-loaded d-d-rHDL showed strong anticancer activity in these mice. This dual-sensitive d-d-rHDL thus combines structural stability in plasma and an intracellular pH/ACAT-triggered drug release to facilitate inhibition of tumor growth.

Multitarget Reaction Programmable Automatic Diagnosis and Treatment Logic Device.

Accurate diagnosis and precise and effective treatment are currently the two magic weapons for dealing with cancer. However, a single marker is often associated with multiple cellular events, which is not conducive to accurate diagnosis, and overly mild treatment methods often make the treatment effect unsatisfactory. In this paper, we construct a Au/Pd octopus nanoparticle-DNA nanomachine (Au/Pd ONP-DNA nanomachine) as a fully automatic diagnosis and treatment logic system. In this system, multiple DNA components are targeting detection units, Au/Pd ONPs act as carriers, and Au/Pd ONPs with an 808 nm laser is the treatment unit. In order to achieve the purpose of precise treatment, we will detect two secondary markers under the premise of detecting one major tumor marker. When all of the designated targets are detected (the logic system input is (1, 1, 1), and the output is (1, 1)), the 808 nm laser can be programmed to automatically radiate tumors and perform photothermal therapy and photodynamic therapy. In vivo and in vitro experiments show that this logic system not only can accurately identify tumor cells but also has considerable therapeutic effects.

Tumor microenvironment targeting with dual stimuli-responsive nanoparticles based on small heat shock proteins for antitumor drug delivery.

Tumour microenvironment (TME)-targeting nanoparticles (NPs) were developed based on Methanococcus jannaschii small heat shock proteins (Mj-sHSPs). Transactivator of transcription (TAT) were modified on the surface of Mj-sHSPs (T-HSPs) to enhance their cellular internalization ability (CIA), and a pH/enzyme dual sensitive PEG/N-(2-aminoethyl)piperidine-hyaluronic acid (PAHA) coat was combined with T-HSPs (PT-HSPs). PT-HSP NPs exhibited multi-layered morphologies and good stability against plasma protein adsorption. The release of paclitaxel (PTX) from PT-HSP NPs was negligible at physiological pH. Under conditions similar to the TME (acidic pH and overexpressed hyaluronidase (HAase)), the PAHA coat deshielded from PT-HSP NPs because of two factors: charge reversal and HAase degradation. Once the PAHA coat was shed, the size of the NPs decreased; its surface charge became positive; and remarkable drug release was triggered. Cellular experiments indicated that the CIA of PT-HSPs was shielded in the microenvironment of normal cells and recovered in that of tumour cells. In vivo imaging exhibited that the PT-HSP NPs had an impressive tumour targeting ability compared with the uncoated controls. The antitumor efficacy in vivo demonstrated that tumour-bearing mice treated with PTX-loaded PT-HSP NPs achieved better anti-tumour effects and safety than the Taxol formulation. In summary, this study provided Mj-sHSP NPs with coats that could be shed in response to the particular pH and enzymes in the TME, which improved the efficacy of tumour therapy. STATEMENT OF SIGNIFICANCE: This study reports on tumor microenvironment-targeting protein-based nanoparticles (PT-HSP NPs) for targeted tumor therapy. The NPs had a multilayered structure: a protein cage, a TAT cationic layer, and a dual-sensitive coat. PT-HSP NPs exhibited multilayered morphology, with good stability against plasma protein adsorption, and PTX release negligible at physiological pH. Under the tumor microenvironment (acidic pH and overexpressed HAase), PAHA coat deshielded from PT-HSP NPs due to two factors: the charge reversal induced by protonation of piperidines in PAHA and HAase degradation. The results of cellular uptake, cytotoxicity, in vivo imaging, and tumor inhibition experiments confirmed that PT-HSP NPs exhibited promising tumor targeting efficacy in vitro and in vivo.