472 results about "Lysosome" patented technology

Aspects of the disclosure relate to complexes comprising an anti-TfR1 antibody covalently linked (e.g., via a linker such as a peptide linker) to a lysosomal enzyme (e.g., an acid alpha glucosidase enzyme), and methods of making and using the fusion complexes to treat a lysosomal storage disease (e.g., Pompe disease).

The invention belongs to the field of biological medicines, and relates to a drug-loaded nano-vesicle as well as a preparation method and application thereof. The drug-loaded nano-vesicle comprises a vesicle core and a drug-loaded nano-vesicle, wherein the vesicle core comprises siRNA (small interfering Ribonucleic Acid) capable of specifically targeting and silencing an NR1D1 gene; the vesicle membrane is formed by fusing an erythrocyte membrane, a macrophage membrane, cardiolipin, cholesterol and lecithin. The drug-loaded nano-vesicle can specifically target macrophages in a sepsis immunosuppression stage, has an intracellular response release function, recovers BMAL1 and IGF2BP2-ATP6V1B2 / ATP6V0c axis functions by inhibiting NR1D1 expression, reconstructs a macrophage phagocytosis function and lysosome-dependent bacterium removal capability, and can be used for preparing a drug-loaded nano-vesicle with a specific targeting function. The survival rate of sepsis immunosuppression model animals is obviously improved; and the bacterial load is reduced. Compared with a traditional electroporation method, the preparation method disclosed by the invention has the advantage that the encapsulation efficiency of siRNA is remarkably improved.

The invention belongs to the technical field of biological medicine, and particularly relates to an LYTAC molecule for targeted degradation of GPC3 and a preparation method and application of the LYTAC molecule. The LYTAC molecule is composed of a target TfR1 nucleic acid aptamer and a target GPC3 nucleic acid aptamer, wherein the nucleotide sequence of the targeted TfR1 nucleic acid aptamer is as shown in SEQ ID NO: 1; the nucleotide sequence of the targeted GPC3 nucleic acid aptamer is as shown in SEQ ID NO: 2. According to the present invention, the research results show that the GPC3 protein content is not affected by the single TfR1 nucleic acid aptamer or the GPC3 nucleic acid aptamer, and the LYTAC molecule can significantly reduce the GPC3 protein content on the surfaces of Hep3B and HepG2 cells. The LYTAC molecule induces GPC3 protein degradation through a lysosome way, then proliferation and migration of liver cancer cells are inhibited, liver cancer treatment is achieved, and the LYTAC molecule has wide application prospects.

The invention relates to the cross technical field of biological medicine and image processing, and discloses a mesenchymal stem cell aging detection method based on image processing. The method comprises the following steps: automatically collecting bright field and multi-channel fluorescence images in an integrated cell culture monitoring device; after background correction and illumination homogenization, segmenting the cells by using a U-Net network and extracting single cell contours; calculating characteristics such as cell area, roundness, cytoplasmic ratio, nuclear form irregularity index, lysosome fluorescence intensity mean value and distribution entropy; and inputting a gradient boosting decision tree model to judge the unicellular aging state, and evaluating population aging with a 20% positive rate threshold. According to the invention, label-free, non-invasive and high-flux accurate detection is realized, and the method is superior to manual interpretation.

Aspects of the disclosure relate to bicistronic AAV nucleic acid constructs comprising a transgene encoding hexosaminidase A (HEXA) and hexosaminidase (HEXB) proteins. In some embodiments, the disclosure provides methods for treating or preventing lysosomal storage disorders, such as Tay-Sachs disease and Sandhoff disease, using bicistronic nucleic acid constructs described by the disclosure.

A cage-like nanocarrier for targeted delivery of siRNA, and a preparation method therefor and the use thereof. The preparation method comprises: (A) mutating a negatively charged or uncharged amino acid on the inner surface of a ferritin into a positively charged amino acid; and any one or more of the following steps: (B) coupling the N-terminus of the ferritin to a functional peptide having nucleic acid affinity; (C) coupling the N-terminus of the ferritin to a functional peptide promoting lysosomal escape; (D) truncating the E-helix at the C-terminus of the ferritin; (E) coupling the C-terminus of the ferritin to a functional peptide having nucleic acid affinity; and (F) coupling the C-terminus of the ferritin to a functional peptide promoting lysosomal escape. A new nucleic-acid-loaded protein nanocage carrier is constructed by means of modifying a negatively charged inner cavity of ferritin to make same positively charged. By means of electrostatic adsorption, a negatively charged siRNA can be efficiently loaded into a ferritin nanocage, thereby significantly improving the in-vivo and in-vitro delivery stability of siRNA, lysosomal escape functions, and efficacy of targeted therapy.

The invention belongs to the field of biological medicines, and discloses an application of a stem cell extract in preparation of a medicine for treating or preventing arthritis by regulating lysosome and / or mitochondrial function, a preparation method of the stem cell extract comprises the following steps: S1) culturing mesenchymal stem cells and producing stress conditions to stimulate the mesenchymal stem cells; s2) separating and purifying the culture supernatant of the mesenchymal stem cells cultured in the step S1) to obtain a stem cell extract; wherein S21) the culture supernatant is filtered to obtain a filtrate; the preparation method comprises the following steps of (S1) extracting a culture supernatant containing stress stem cell secretions through stress culture of stem cells, (S2) carrying out 3KD ultrafiltration concentration on the filtrate to obtain a crude sample, (S23) purifying the crude sample through molecular sieve exclusion chromatography or reversed-phase chromatography to obtain a purified sample, and (S24) taking the purified sample to form the preparation.

Provided herein are compositions and methods of using a bicistronic vector for treating or preventing a lysosomal storage disorder (LSD) in a subject. The disclosed compositions comprise a bicistronic vector comprising a promoter, an Internal Ribosome Entry Site (IRES), a polynucleotide encoding a lysosomal enzyme and a polynucleotide encoding a modified GlcNAc-1 phosphotransferase (GlcNAc-1 PTase). The present methods comprise administering to the subject a pharmaceutical composition comprising the bicistronic vector as disclosed herein.

The invention relates to a response type DNA tetrahedral lysosome targeting chimera as well as a construction method and application thereof, and belongs to the technical field of biology. The response type DNA tetrahedron lysosome targeting chimera is obtained by self-assembling a tetrahedron I and a tetrahedron II; a sticky tail end H1 is arranged on the tetrahedron I, and a sticky tail end H2 is arranged on the tetrahedron II; three tyrosine kinase receptor aptamers are anchored on the first tetrahedron, three lysosome shuttle receptor aptamers are anchored on the second tetrahedron, stimuli-responsive factor aptamers are hybridized on the cohesive end H2, and the binding capacity with cells is obviously enhanced based on a trivalent aptamer modification strategy of a tetrahedral framework. According to the present invention, the VEGF is adopted as the stimulation response factor to construct the responsive DNA tetrahedral lysosome targeting chimera, and the responsive DNA tetrahedral lysosome targeting chimera carries the HER2 protein to the lysosome under the mediation of the lysosome shuttle receptor IGF2R so as to degrade, such that the HER2 protein expression on the cell membrane is reduced, and the degradation specificity and the degradation effect are enhanced.

The present disclosure provides methods of increasing cellular production of Niemann-Pick Disease, Type-C, Protein 1 (NPC1) in a patient in need thereof by administering a therapeutically effective amount of arimoclomol in combination with miglustat. The present disclosure further provides methods of reducing and / or delaying progression of Niemann-Pick Disease, Type-C in said patients.

The application discloses a mucous membrane adhesion auxiliary material and a lipid material with mucous membrane adhesion prepared by using the auxiliary material, the nanoparticle has mucous membrane adhesion and can be adhered to the surface of a mucous membrane and is suitable for mucous membrane administration. The lipid nanoparticle promotes the entry of the lipid nanoparticle into cells by forming a disulfide bond with the sulfydryl on the surface of mucous membrane cells, and the entry of the lipid nanoparticle into cells is a non-endosome-lysosome pathway, so that the encapsulated nucleic acid macromolecule can be avoided from being degraded by enzymes in cells, thereby directly delivering the macromolecular nucleic acid in the cytoplasm to play a role.

The present application relates to a kind of hydrolysis targeting chimera based on artificial antibody and its preparation method and application.The hydrolysis targeting chimera is composed of artificial gold antibody and molecule that can activate cell degradation mechanism, the artificial gold antibody is composed of gold nanoparticle and polypeptide coupled on the surface of gold nanoparticle, the molecule that can activate cell degradation mechanism is coupled on the surface of gold nanoparticle.The hydrolysis targeting chimera can simultaneously bind target protein and activate cell degradation mechanism, with the performance of strong specific recognition target protein, and high stability, orientation controllable.At the same time, the hydrolysis targeting chimera can also play the molecule of activation cell degradation mechanism, such as lysosome sorting signal motif, coupled on the surface, induce clathrin-mediated endocytosis, transport the complex of target protein and chimera to lysosome and degrade.The hydrolysis targeting chimera can play multi-mode cancer treatment effect by synergistic inhibition of tumor cell proliferation, invasion pathway and apoptosis activation.

The application discloses a pinacine alkyl tetrahydrocarbazole fluorescent probe capable of detecting cell lysosome polarity and a preparation method and application thereof. 9-(3-(dimethylamino)propyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-2,4-bridged methylene carbazole-6-formaldehyde is used as raw material, and condensation reaction is carried out with 1,3-indan dione to obtain compound 2-(2-(9-(3-(dimethylamino)propyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-2,4-bridged methylene carbazole-6-yl)vinyl)-1-indene-1,3(2H)-dione (TC-AP-ID), and the probe can specifically detect the polarity of cell lysosomes. In a mixed system of 1,4-dioxane and water, with the increase of the polarity of the system, the fluorescence color of the probe gradually changes from orange to red, and the fluorescence intensity significantly decreases. The probe has the advantages of simple synthesis, good selectivity, high sensitivity, good biocompatibility, low toxicity and the like, can be applied to targeted detection of the polarity of cell lysosomes, and has a good application prospect.

The invention discloses a mitochondrial / lysosome dual-targeting viscosity response AIE probe as well as a preparation method and application thereof. According to the probe, tetraphenylethylene (TPE) is used as an AIE light-emitting framework, and two flexible side chains containing hydrophilic units are introduced by utilizing the excellent structural modifiability of the TPE. The tail end of each side chain is modified with a trimethylamine group, quaternary ammonium salt cations derived from the trimethylamine group have localized positive charges, and combination with water molecules can be enhanced through ion-dipole interaction, so that the water solubility and biocompatibility of the molecules are effectively improved. Based on the design, the invention provides the AIE polymer probe which is constructed by taking TPE as a core and taking an amphiphilic flexible chain as a functional unit. The probe can establish a three-dimensional linear relationship among drug action time-regional viscosity-fluorescence lifetime (t-eta-tau) by capturing fluorescence lifetime signals inside and outside cells, so as to realize visual detection and quantitative analysis of average viscosity change of mitochondria and lysosome in the mitochondrial autophagy process.

The invention discloses a magnetic-aptamer targeting tumor tissue nano-drug delivery system as well as a preparation method and application thereof, and belongs to the field of medicines. The system comprises a mesoporous ferroferric oxide magnetic core, a polyethyleneimine (PEI) layer coated outside the mesoporous ferroferric oxide magnetic core and an aptamer adsorbed outside the PEI layer, and an autophagy activator can be selectively loaded in the mesoporous core. The preparation method comprises the following steps: sequentially carrying out drug loading, PEI coating and aptamer modification on the mesoporous Fe3O4 nanoparticles. According to the invention, efficient enrichment and endocytosis of tumor tissues are realized through dual effects of magnetic targeting and active targeting of the aptamer; lysosome escape is promoted by using the proton sponge effect of PEI; finally, by virtue of the synergistic effect of iron ions released by degradation of the Fe3O4 nanoparticles and endogenous iron ions released by ferritin autophagy induced by an autophagy activator, ferroptosis of tumor cells is induced through enhanced Fenton-like reaction, so that high-efficiency and low-toxicity targeted therapy is realized.

The invention discloses an application of rapamycin in preparation of a composition for treating a hereditary spastic paraplegia SPG subtype. The rapamycin can obviously improve the motion disorder and pathological injury phenotype of an SPG80 subtype mammal model, improve the lysosome function and promote the autophagy process through mTOR inhibition, provides specific intervention for nerve cell apoptosis and a glial cell abnormal activation mechanism caused by UBAP1 deletion, fills the blank that no effective treatment means exists for the SPG subtype, and has a good application prospect. A theoretical basis is provided for clinical treatment of patients, and a reference is provided for other SPG variations (such as SPG3A).

The application discloses a stapled peptide compound for selectively degrading MYC protein, a preparation method and application thereof; the compound is sequentially connected in the N-terminal to C-terminal direction by a peptide recognition segment, a flexible linker and a chaperone-mediated autophagy recognition motif KFERQ or a similar motif; the peptide recognition segment is introduced by an (i, i+7) site alkenyl amino acid and a Grubbs catalytic RCM reaction to form a full carbon hydrogen stapling bridge to stabilize the alpha-helix conformation; stapled modification of a typical compound MAX-7 significantly improves the alpha-helix content, the protease stability and the cell penetration, so that the compound can efficiently enter cells and be located in lysosomes, and MYC protein is selectively degraded through the CMA pathway; in-vitro experiments show that MAX-7 can inhibit the proliferation, migration and invasion of various MYC-driven tumor cells, and induce apoptosis; the application provides a brand-new lysosome-directed degradation strategy for the "undruggable" target MYC, and establishes a universal technical platform which can be popularized to other difficult drug proteins.

The invention discloses a high-activity BODIPY type photosensitizer targeting double organelles as well as a preparation method and application of the high-activity BODIPY type photosensitizer, and relates to the technical field of medical photosensitizers. The high-activity BODIPY type photosensitizer is prepared by the following steps: reacting 2, 4-dimethyl pyrrole with 4-bromobutyryl chloride to obtain a compound Br-BY containing carboxyl, then reacting with morpholine to obtain a morpholine substituted compound Mor-BY, and finally reacting with N-iodosuccinimide (NIS) to obtain a single atom I substituted BODIPY compound Mor-IBY, namely the target photosensitizer. The photosensitizer prepared by the invention can target mitochondria and lysosome in cancer cells at the same time, and can be excited by visible light; the compound has good water solubility, can generate a large amount of reactive oxygen species (ROS) under irradiation of green light (520 nm), shows excellent photodynamic activity to tumor cells, and has low toxicity to normal cells.

The invention belongs to the technical field of biological medicine, and particularly relates to a nano vaccine based on GD2 mimetic peptide as well as a preparation method and application of the nano vaccine. The nano vaccine provided by the invention comprises a GD2 mimetic peptide, an STING agonist and a polymer carrier, wherein the STING agonist is used as an immunologic adjuvant. The antigen peptide (GD2 mimic peptide 47-LDA) and the adjuvant (STING agonist) are wrapped in the micelle to prepare the nano vaccine GD2-NV, so that the druggability of the antigen peptide and the STING agonist is improved, and the accumulation of drug tumors and drainage lymph node parts is improved. Besides, the nano vaccine can respond to a lysosome acid environment, realize lysosome escape, enhance antigen cross presentation of DC, activate an STING pathway, improve infiltration and activation degrees of CD8 + T cells, induce lasting humoral immune response and inhibit growth and recurrence of tumors, and is good in biological safety.

The application discloses a kind of elastin-like polypeptide V 20 K 40 L, mRNA vaccine and preparation method and application in preparation tumor prevention, mitigation or treating drug.The elastin-like polypeptide carrier V 20 K 40 L provided by the application has good biocompatibility, and has no adverse reaction in vivo.The elastin-like polypeptide V 20 K 40 L provided by the application has amphiphilic structure, can be loaded Melan-A mRNA by hydrophobic self-assembly and electrostatic adsorption, and is in the state of shrinkage when higher than Tt temperature, which can prevent the uncontrollable leakage of mRNA.Furthermore, V 20 K 40 L contains lysosome escape peptide, which can further improve the transfection efficiency of mRNA by promoting lysosome escape.The elastin-like polypeptide V 20 K 40 L in the application can deliver Melan-A mRNA efficiently and safely, and realize the prevention and treatment of melanoma.

Aspects of the disclosure relate to compositions and methods for the treatment of lysosomal storage disorders, such as GM1 gangliosidosis, Tay Sachs disease, and Sandhoff disease. In some embodiments, the compositions comprise viral vectors encoding beta-galactosidase. In some embodiments, the compositions comprise viral vectors encoding beta-hexosaminidase subunits (e.g. HEXA, HEXB, or combinations thereof).

The invention discloses an auxiliary protein composition, iron oxide nanoparticles, a preparation method and application, the composition comprises an SC protein with an amino acid sequence as shown in SEQ ID NO: 1 and an ST protein with an amino acid sequence as shown in SEQ ID NO: 2, and the composition can be used for modifying the iron oxide nanoparticles. The auxiliary protein composition can effectively promote endocytosis of the iron oxide nanoparticles, and assists the iron oxide nanoparticles to realize lysosome escape; moreover, the iron oxide nanoparticles modified by the auxiliary protein composition are good in biocompatibility and long in retention and storage time in cells, can be used for long-time labeling of the cells, and have wide clinical transformation and application prospects as a cell tracer agent.

The invention discloses a virus-like particle coated with an aluminum-containing metal organic framework mineralization layer and application of the virus-like particle. In order to improve the VLPs vaccine stability and immune effect, the invention synthesizes a novel aluminum-containing metal organic framework (ZAM). The ZAM can mineralize the VLPs at a high level under a mild condition to form the VLPs-ZAM nano vaccine. Taking a foot and mouth disease virus (FMDV) virus-like particle (VLPs) vaccine as an example, a heat treatment test shows that ZAM mineralization significantly improves the heat stability of FMDVVLPs, and the effect is superior to that of Al (OH) 3 and ZIF-8. The FMDV VLPs-ZAM not only has the effect of promoting APCs to take in FMDVVLPs, but also can promote antigens to escape from lysosome to cytoplasm due to the pH responsiveness of the FMDV VLPs-ZAM. A mouse immune test shows that ZAM mineralization improves the specific immune response level and stability induced by FMDV VLPs. The invention provides a new technical means for improving the stability of the VLPs vaccine and the immune effect of the VLPs vaccine.

This invention discloses an enhanced CAR-T cell (CARTAC) capable of secreting a targeted membrane protein degrader and its applications. While retaining specific killing function, this cell can expand locally in tumors and continuously secrete the bispecific adaptor molecule scTAC. scTAC can recruit E3 ubiquitin ligases, mediate ubiquitination of tumor cell surface membrane proteins (such as PD-L1), and achieve targeted degradation via the lysosomal pathway, effectively reversing the immunosuppressive microenvironment, overcoming antigen heterogeneity, and eliminating antigen-negative tumor cells through the bystander effect. This invention also utilizes the efficient endocytosis properties of EGFR to design scTAC-dual, which can further enhance degradation efficiency. In various lung cancer mouse models, CARTAC-dual exhibited excellent tumor infiltration capacity, low exhaustion levels, and sustained antitumor activity, without systemic toxicity. This invention integrates the targeted killing and protein degradation delivery functions of CAR-T cells, not only enhancing the control effect on solid tumors but also possessing target scalability, making it suitable for the universal upgrading of various CAR-T products.

The invention discloses an application of abscisic acid in preparation of a medicine for improving secondary brain injury after cerebral hemorrhage, the abscisic acid can relieve neuroinflammation and improve neurological function recovery by repairing microglial cell lysosome functions, enhancing phagocytic ability and promoting hematoma removal, and a new medicine strategy is provided for cerebral hemorrhage treatment.

The application belongs to the technical field of functional polypeptides, and particularly relates to an active peptide for senescent cells and a preparation method thereof, wherein the active peptide is obtained by molecular docking simulation screening and optimization with a helical structure segment in an IL-6R protein combined with a gp130 protein as a polypeptide template; the active peptide after functional optimization contains an FF unit driving nano self-assembly, a GFLG unit capable of being specifically cut by a lysosome protease highly expressed in a microenvironment of senescent cells, and an RYFQKWEKLRNQ unit generating high affinity with an IL-6 / IL-6R / gp130 complex; the designed active peptide itself has anti-aging activity and can also be used for synergistic delivery of drugs, and has a broad application prospect.

To provide an improved antibody-drug conjugate and a pharmaceutical composition containing the antibody-drug conjugate.SOLUTION: The invention is based on the concept that it is possible to generate antibodies that exhibit improved potency (e.g., one or more of increased (e.g., detectable increase) toxin release in target mammalian cells, increased (e.g., detectable increase) killing of target mammalian cells, and increased (e.g., detectable increase) endolysosomal delivery). In some embodiments of any of the antibodies described herein, the heavy chain CH1 - CH2 - CH3 sequence consisting of the specific sequence comprises a substitution of lysine to cysteine at amino acid position 105 and a deletion of threonine at amino acid positions 106 and 108.SELECTED DRAWING: None

The invention relates to means and methods for gene therapy of lysosomal storage disorders (LSDs), preferably a LSD with skeletal involvement, based on an ex vivo gene therapy approach comprising transduction of autologous hematopoietic stem and progenitor cells (HSPCs) with viral vectors for expressing enzymes that are deficient in the disorders. The final formulation is a suspension of transduced cells in culture medium for the administration to patients affected by the LSDs, preferably preceded by a conditioning regimen.

The present disclosure provides oligonucleotides, methods, and compositions for degrading RNA via the lysosomal pathway. Also encompassed are oligonucleotides, methods, and compositions for treating, preventing, or ameliorating diseases, disorders, and conditions associated with EXOC2 , Ku80 and Task1 in a subject in need thereof.

The invention discloses a multifunctional double-drug delivery system based on metal collaborative treatment and application of the multifunctional double-drug delivery system, and belongs to the technical field of biological medicine. The double-drug delivery system is double-drug delivery lipidosome and comprises metal ions, a lipidosome membrane and active ingredients, the metal ions are adsorbed on the surface of the lipidosome membrane, and the active ingredients are wrapped in the lipidosome membrane; the metal ions are divalent metal ions; the active component consists of an STING agonist and a traditional Chinese medicine active monomer component. According to the double-drug delivery system, the STING agonist and the traditional Chinese medicine anti-inflammatory components are co-loaded through lipidosome, and multi-dimensional remodeling of a tumor microenvironment is achieved through the double effects of exciting tumor immunity and inhibiting inflammatory reaction; and meanwhile, by introducing metal ions, the lysosome escape efficiency of a liposome drug delivery system is effectively enhanced, so that the intracellular delivery efficiency of the drug is improved.