26 results about "Endosome" patented technology

The invention discloses a cationic lipid capable of being ionized and application of the cationic lipid. According to the ionizable cationic grease, adsorption is formed by the structural design of the head and biological drugs such as nucleic acid, and the encapsulation efficiency is improved; the tail part adopts a saturated or unsaturated aliphatic chain to form a branch structure, and the head part and the tail part are connected by an ester bond, so that in-vivo degradation is facilitated to reduce toxicity; due to the design of the unsaturated aliphatic chain, the membrane flowability during release of the endosome is improved, and the release efficiency of the biological medicine is effectively improved; moreover, the ionizable cationic grease provided by the invention has good temperature stability, not only can the product quality be improved, but also the accessibility of the product is expanded. In a word, the ionizable cationic lipid disclosed by the invention has the advantages of high encapsulation efficiency, low toxicity, high endosome release efficiency, good temperature stability and the like, the quality and the treatment effect of lipid nanoparticle drugs can be improved, and a new scheme and a new choice are provided for biological drug delivery.

The invention provides an amino acid skeleton ionizable lipid as well as a preparation method and application thereof, the amino acid skeleton ionizable lipid is modified by taking amino acid as a core, has more ester groups and peptide bonds, and can be quickly hydrolyzed by enzyme after RNA is effectively released in vivo; the transfection body is provided with four tail structures, the cross sectional area of the lipid tail can be increased, drugs such as RNA are helped to escape from an endosome, and then the transfection effect is enhanced; the charge capable of ionizing the lipid is electrically neutral under physiological conditions, so that the cytotoxicity caused by excessive positive charges is reduced, the stability of the lipid nanoparticles is further improved, the cycle time of the loaded nucleic acid medicine is prolonged, and the pharmacokinetic characteristics are improved. The LNP prepared from the ionizable lipid, auxiliary phospholipid, cholesterol and PEG lipid provided by the invention has more excellent nucleic acid carrier performance, and can effectively deliver nucleic acid drugs such as siRNA, mRNA, pDNA and the like into cells to play a role.

The invention discloses a protein degradation agent based on an endosome-phagosome connection assembly and application of the protein degradation agent, and belongs to the technical field of protein degradation and nano biological medicine. According to the endosome-phagosome connecting assembly, by inserting an endosome membrane and marking endosome degradation protein, a special degradation technology strategy enables the endosome-phagosome connecting assembly to expand an autophagy degradation target spectrum in traditional cytoplasm to various target proteins outside a cell membrane / cell, and the current development situation of a current targeted protein degradation tool can be thoroughly changed possibly. The preparation method is simple, raw materials are easy to obtain, the method is suitable for research and application transformation, the traditional degradation thought is broken through by utilizing an endosome-phagosome connecting assembly, most target proteins can be degraded through an endosome-autophagy-lysosome approach, the design is novel, the application range is wide, the cost is low, the efficiency is high, a very good degradation effect can be achieved, and the method is suitable for popularization and application. The method can be applied to the field of various complex diseases and has huge potential development and transformation prospects.

The invention provides esterase-responsive ionizable cationic lipid and application thereof in improving the delivery efficiency of nucleic acid drugs. The lipid provided by the invention is electrically neutral under physiological conditions, has excellent biological safety, is positively charged in a meta-acidic endosome / lysosome environment, promotes escape of a carrier and a nucleic acid drug through a proton sponge effect, is hydrolyzed under the action of intracellular esterase and then is converted into an electrically neutral or electronegative compound, and is used for preparing a drug carrier. Dissociation with nucleic acid drugs with negative charges is completed, and the biological functions of the nucleic acid drugs are played to the maximum extent. Therefore, the lipid provided by the invention can be used for efficient delivery of in-vivo and in-vitro nucleic acid drugs, and has a wide application prospect.

The invention belongs to the field of drug delivery, and provides a piperazine ring-containing branched asymmetric cationic lipid, the structure is shown as a general formula (1), and the definition of each symbol is consistent with that described in the specification. A degradable group is introduced to a proper position of the cationic lipid, and the existence of the degradable group enables the LNP-pharmaceutical composition prepared from the cationic lipid to be timely degraded in vivo and small in cytotoxicity, so that the problems that in the prior art, the LNP-pharmaceutical composition prepared from non-degradable lipid can be stored in the vivo, the endosome environment is acidified, and the toxicity of the LNP-pharmaceutical composition is reduced are solved. The endosome escape of the medicine (such as mRNA) is blocked, and the medicine delivered into the cells cannot fully play a role. The cationic lipid provided by the invention adopts the heterofunctionalization piperazine ring-containing small molecules as raw materials, the preparation process is simple and convenient, the cost is lower, the cationic lipid is greener and more environment-friendly, and the LNP-mRNA composition prepared from the cationic lipid has the advantages of low toxicity, high biocompatibility, high cell transfection and the like.

Nanoparticle compositions including one or more active agents, and strategies for enhanced delivery of the active agents, are provided. In preferred embodiments, the nanoparticles are composed of block copolymers of one or more hydrophobic polymers that form the core, and a hyperbranched polymer that forms a shell or corona. In some embodiments, the particles include an acid-sensitive, poly(amine-co-ester) (PACE) that can increase release of the active agent in acidic environments, for example within endosomes. The compositions can include one or more targeting moieties. Preferred targeting moieties include adenosine agonists and pHLIP which can enhance delivery to tumor cells. Methods of using the compositions to treat diseases and disorders of the central nervous system, for example, brain cancers such as glioma, are also provided.

Guanosine-targeted nanocarriers for encapsulating an active agent and delivering it to extracellular guanosine and DNA are provided. The nanocarriers, for example, polymeric particles, liposomes, and multilamellar vesicles have targeting moiety that targets guanosine attached, linked, or conjugated thereto. The targeting moiety that targets guanosine is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to guanosine. The targeting moiety can be a circulating autoantibody that binds guanosine such as those commonly found in patients with SLE. Cytoplasmic delivery vehicles that do not localize into endosomes or lysosomes are also provided. The delivery agent is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to guanosine. In some embodiments, the targeting moiety or delivery agent is antibody 4H2 or a variant, fragment, or fusion protein derived therefrom. Pharmaceutical compositions, methods of use, and dosage regimens are also provided.

The invention provides a multi-antigen loaded, active lymph node targeting and ultrasonic response senescence nano vaccine based on artificial vesicles as well as a preparation method and application of the senescence nano vaccine, and belongs to the technical field of vaccines. The invention relates to a modular two-component senescence nano vaccine based on click chemistry, which comprises DSPE-PEG-DBCO and azide functionalized senescence cell-derived artificial nano vesicles (N3-SCAVH / R) co-carrying a sound sensitive agent and a TLR7 / 8 receptor agonist, and the N3-SCAVH / R carries abundant SAAs. According to the vaccine, a DBCO target is pre-marked on a lymph node through subcutaneous injection of DSPE-PEG-DBCO, and N3-SCAVH / R which is continuously delivered can be anchored to the lymph node through a click chemical reaction; and then ultrasonically irradiating the lymph node to activate the sound-sensitive agent to assist the antigen in escaping from the endosome and enhance DC cross presentation. The nano vaccine can effectively remove plaque senescence cells and delay disease progression, and is good in safety.

The invention lies in the field of delivery of nucleic acids into a cell. In particular, disclosed herein is a nucleic acid that is polyplexed with a polymeric scaffold, which is provided in combination with an endosomal escape-enhancing saponin that is covalently bound either to the polymeric scaffold or to a cell targeting ligand by a linker configured to release the saponin from the scaffold under conditions present in an endosome. The disclosed herein compositions and methods may be exploited in the treatment of various diseases and / or conditions by systemic delivery.

The invention relates to the technical field of microneedle patches, in particular to a tremella polysaccharide microneedle patch carrying magnetic endosomes and a preparation method and application of the tremella polysaccharide microneedle patch, the microneedle patch comprises a microneedle body and a base backing layer, the needle body takes a high polymer material and tremella polysaccharide as main components and carries the magnetic endosomes, and the magnetic endosomes are arranged on the substrate backing layer. The needle body is attached to the surface of the substrate backing layer and can be completely separated when dissolved. According to the tremella polysaccharide microneedle patch carrying the magnetic endosome, the needle body has enough mechanical strength to pierce a skin cuticle to deliver effective components to a corium layer, and the back lining layer is low in dissolution speed and convenient to disassemble completely. According to the tremella polysaccharide microneedle patch carrying the magnetic endosome, the tremella polysaccharide serves as natural polysaccharide, preparation is easy, components are safe, and the tremella polysaccharide microneedle patch has anti-inflammatory activity for adjuvant therapy. The tremella polysaccharide microneedle patch carrying the magnetic endosome contains the magnetic endosome, has good biocompatibility, and plays a dual role in resisting oxidation and promoting blood vessels.

The present invention relates to a lipid complex for the nasal delivery of nucleic acid molecules comprising ionized lipids, structural lipids, cholesterol, and lysoPC as active ingredients. The lipid complex of the present invention can be usefully utilized for the local and intensive delivery of therapeutic nucleic acid molecules specifically to nasal epithelial cells by efficiently being compatible with the microenvironment unique to nasal tissue, easily penetrating the mucus layer barrier, and effectively escaping endosomes. Furthermore, the lipid complex of the present invention can be applied as a combination administration platform that induces a synergistic therapeutic effect by two pharmacological components by loading additional drugs into internal compartments of the lipid complex, as well as improving dispersibility by loading the target nucleic acid molecule externally.

The invention provides a nitrogen-containing heterocyclic ring branched cationic lipid, the structure is shown as a general formula (1), and the definition of each symbol is consistent with that described in the specification. The nitrogen-containing heterocyclic ring branched cationic lipid takes a nitrogen-containing heterocyclic ring as a branched core, amino acid or an amino acid derivative as a connecting arm and saturated or unsaturated alkyl as a tail chain, and has the advantages of low toxicity, low immunogenicity and high biocompatibility. The positive electricity of nitrogen on the nitrogen-containing heterocyclic ring in the novel cationic lipid is delocalized to the whole ring, so that the cationic lipid shows higher transfection efficiency and lower cytotoxicity. One or more biodegradable groups are contained between the nitrogen-containing heterocyclic ring and the hydrophobic tail part of the novel cationic lipid, and due to the existence of the biodegradable groups, the prepared lipid nano-particles LNP can be timely degraded in an endosome, so that the problems that in the prior art, the LNP prepared from non-degradable lipid can be stored in the endosome, the endosome environment is acidified, and the lipid nano-particles LNP cannot be degraded are solved. Endosome escape of drug molecules (such as nucleic acid) is blocked, and the problem that drugs delivered into cells cannot play a role is solved.

The invention discloses a signal peptide, a polypeptide-nucleic acid conjugate and a synthesis method and application thereof, and belongs to the technical field of molecular biology. The signal peptide is one of NPXY, YXXphi, [DE] XXX [LI] and DXXLL; wherein X is any amino acid, phi is any large-volume hydrophobic side chain amino acid, [DE] represents one of D and E, and [LI] represents one of L and I. In addition, the invention also provides application of the signal peptide in preparation of a compound capable of penetrating through a cell membrane or a body tissue barrier by being connected with a nucleic acid fragment. The invention also provides a polypeptide-nucleic acid conjugate which is a conjugate of any one of the signal peptides and siRNA (small interfering Ribonucleic Acid). After several signal peptides provided by the invention are coupled with the siRNA, the siRNA can be promoted to escape into cytoplasm from an endosome, so that the siRNA drug transfection efficiency is improved.

The present invention relates to: an antibody constant region in which an endosome escape motif having activity under the slightly acidic conditions of an endosome is introduced into the constant region of an antibody, thereby imparting the ability of an immunoglobulin G (IgG) antibody to actively translocate from outside a cell to the cytoplasm; an antibody comprising the same; a method of producing the same; and uses thereof. More particularly, the present invention provides a highly efficient cytosol penetrating antibody (cytotransmab) having improved endosome escape ability by introducing an endosome escape motif into a CH3 domain, which is a heavy chain constant region of an IgG antibody, and / or a CL domain, which is a light chain constant region of an IgG antibody, and relates to a pharmaceutical composition for the treatment, prevention, or diagnosis of cancer comprising the same.

The present application relates to pH-sensitive polymersomes. The polymersomes are capable of degradation at endosomes' mild acidic pH into resorbable materials, which also allows avoiding liposome premature degradation of the payload once internalised inside the cells. The polymersomes can thus be used in methods for the treatment or prevention of diseases.

The present application belongs to the field of drug delivery. Provided is a new cationic lipid with a nitrogen-containing heterocyclic head group, which has a structure as shown in general formula (1), wherein the definition of each symbol is consistent with that described in the text. The cationic lipid of the present application contains a nitrogen-containing heterocyclic head group, a linker arm, a degradable linkage group, and multiple hydrophobic hydrocarbon tail chains, wherein the multiple hydrophobic hydrocarbon tail chains increase the cross-section area of the lipid tail region, thereby facilitating the formation of a cone-shaped structure. The structure can effectively promote the fusion and disruption of LNPs with an endosome membrane, thereby promoting the escape of drugs such as nucleic acids from an endosome into the cytoplasm to exert the functions. The degradable linkage group enables an LNP-pharmaceutical composition prepared therefrom to be degraded in the endosome in a timely manner, thereby promoting the endosomal escape of LNPs. The cationic lipid of the present application can also have an amino acid or a derivative thereof as a linker arm, wherein the raw materials are simple and readily obtainable. An LNP-mRNA composition prepared therefrom has the advantages of low toxicity, high biocompatibility, a high cell transfection efficiency, etc.

The invention relates to application of endosomal membrane labeled nanoparticles in targeted degradation of extracellular proteins, and belongs to the technical field of nano biological medicines. The endosomal membrane labeled nanoparticle provided by the invention takes a high-molecular organic material as a carrier, the surface of the endosomal membrane labeled nanoparticle is modified with extracellular protein targeting peptide and endosomal anchoring phagosome targeting peptide consisting of endosomal membrane insertion polypeptide and phagosome targeting peptide, and the constructed nanoparticle can specifically recognize extracellular target protein, so that the endosomal membrane labeled nanoparticle has the advantages of high specificity and high specificity. According to the present invention, the target protein enters the endosome through the endocytosis mechanism of the target protein, the membrane insertion polypeptide is inserted into the endosome lipid membrane, the phagosome targeting peptide at the terminal is anchored on the endosome surface, the cytoplasm phagosome is recruited to perform phagocytosis, and finally the target protein is degraded through the endosome-phagosome-lysosome approach; the preparation method of the endosomal membrane labeled nanoparticles is simple and convenient, and the endosomal membrane labeled nanoparticles have good biological safety and efficient delivery capacity and have huge potential in the fields of biomedical research and clinical treatment.

The present application provides a polypeptide variant based on ARC protein and its application as a nucleic acid delivery carrier. The polypeptide variant based on ARC protein is a variant based on spatial conformation, amino acid point mutation and side chain modification of lipid base or lipid base derivative. The spatial conformation is alpha helix, and the target of the point mutation is to raise the isoelectric point to above 10.0. The polypeptide variant has excellent nucleic acid affinity constant, can wrap mRNA or DNA and form a structure similar to a viral capsid, can protect mRNA from degradation by nucleases, and also helps to mediate the release of mRNA or DNA after the complex enters the cell under the action of lysosomes / endosomes, can activate effective humoral and cellular immune responses in vivo, has significant immunoprotection against mousepox challenge and melanoma, and has good biocompatibility, and therefore can be prepared into a new nucleic acid delivery carrier based on biomimetic polypeptide.

This invention discloses a protein degrader based on an endosome-phagosome linker assembly and its applications, belonging to the fields of protein degradation and nanobiomedicine. The endosome-phagosome linker assembly can degrade proteins by inserting into the endosome membrane and labeling endosomes. Its unique degradation strategy expands the target spectrum of traditional intracellular autophagy degradation to include multiple target proteins on the cell membrane / extracellularly, potentially revolutionizing the current development of targeted protein degradation tools. The preparation method of this invention is simple, the raw materials are readily available, and it is suitable for research and application transformation. Utilizing the endosome-phagosome linker assembly breaks with traditional degradation approaches, achieving the degradation of most target proteins through an "endosome-autophagy-lysosome" pathway. The novel design has a wide range of applications, is low-cost, and highly efficient, demonstrating excellent degradation effects and potential for application in various complex disease areas, showing great development and translational prospects.

To provide nucleic acid-immobilized gold nanoparticles that can deliver nucleic acid from an intracellular endosome to a cytoplasm highly efficiently, and a method for manufacturing the nucleic acid-immobilized gold nanoparticles.SOLUTION: A compound expressed by the following formula (1): (HS)n-R1-R2-R3-O-P(=O)O--O-Nuc...(1) (in the formula (1), n denotes 1 or 2 integers, R1 denotes a divalent or trivalent linking group, R2 denotes an acid-cleavable group cleavable by a change from neutral to pH 4 to 5 of acid, R3 denotes a divalent linking group, Nuc denotes a residue in which a group expressed by -O-P(=O)O--OH of 5' terminal is removed from a nucleic acid molecule, or a residue in which hydrogen atoms in a hydroxy group of 3' terminal is removed from a nucleic acid molecule) is allowed to bond to surfaces of gold nanoparticles as a ligand.SELECTED DRAWING: None

The invention relates to the field of nucleic acid medicines, in particular to an RNA (Ribonucleic Acid) interference triggering molecular structure and clinical application thereof. The RNA interference triggering molecule provided by the invention is a partial double-stranded molecule consisting of an antisense strand and a heterozygous strand, and the heterozygous strand comprises three modules: (1) a shortened sense strand, (2) a DNA strand, and (3) other coupled chemical molecules (including lipids, small molecules, polypeptides, sugar molecules and the like). The length of the sequence of the positive-sense strand is remarkably shortened, the opportunity that the positive-sense strand is competitively combined with RISC can be eliminated, the miss-target effect possibly existing in the positive-sense strand is reduced, meanwhile, due to the fact that the positive-sense strand is shortened and the number of phosphate groups is reduced, the hydrophilicity of small nucleic acid molecules is reduced, and the electronegativity and hydrophilicity of the molecules are reduced; the antisense strand and the positive-sense strand-conjugate are separated from each other when passing through a cell membrane, and the antisense strand independently enters cytoplasm to avoid the ring resistance of endosome / lysosome.

The application discloses a lipid compound with a specific structure (formula (1)), and vesicles or liposomes prepared from the lipid compound have high endosome escape performance and wide application prospects in the biological medicine field. Specifically, the definitions of various groups are described in detail in the specification. The vesicles or liposomes prepared from the lipid compound of the application exhibit excellent cell compatibility in a physiological environment (pH 7.4). In an acidic environment of a cell endosome, the vesicles or liposomes exhibit excellent endosome escape efficiency. The characteristics significantly improve the bioavailability of drugs, promote the more efficient release of drugs into the cytoplasm, and thus enhance the treatment effect. In view of the excellent endosome escape characteristics, the lipid compound and the vesicles or liposomes thereof have wide application potential in the biological medicine field, especially in drug delivery and targeted treatment, and have high industrialization value.

Provided is an agent for increasing the amount of Nrf2 in the nucleus of peripheral blood mononuclear cells, containing papaya fermented food as an active ingredient.

Provided in the present invention is a peptide-type nucleic acid carrier, a gene therapeutic composition including it and a use thereof, wherein the peptide-type nucleic acid carrier comprises one or multiple copolypeptide chains comprising: a hydrophilic peptide segment and a hydrophobic peptide segment disposed at C-terminus of the hydrophilic peptide segment. The hydrophilic peptide segment is consisted of a plurality of positively charged amino acids. With the positively charge, the hydrophilic peptide segment attracts nuclear fragments and form a copolypeptide-nucleic acid complex, enabling nuclear fragments' delivery to target cells. On the other hand, the hydrophobic peptide segment protects the nuclear fragments from degradation by circulatory enzymes or intracellular endosome, thereby enhancing transfection efficiency. In light of this, the present invention provides an innovative means of gene therapy.

The invention belongs to the technical field of biology, and discloses liposome nanoparticles as well as a preparation method and application thereof. According to the preparation method of the lipidosome nano-particles, firstly, co-incubation is conducted on metal nano-particles with the specific particle size and RNA, then a water-phase solution is taken and mixed with an organic-phase solution containing a lipidosome composition, and the lipidosome nano-particles of the core-shell structure with an NPs-RNA composite inner core and a lipidosome shell are formed. The liposome nanoparticle has an excellent destructive effect on a membrane structure of an endosome under physiological conditions of the endosome, can efficiently mediate endosome escape of RNA, and has good endosome escape efficiency, so that efficient delivery of RNA to cytoplasm is realized, a better treatment or immune effect is realized, and the liposome nanoparticle has good application prospects. The method has huge application potential in preparation of RNA drugs and / or RNA vaccines.

The disclosure relates to use of double stranded ribonucleic acid (dsRNAi) agents and compositions targeting an amyloid precursor protein (APP) gene, including methods of inhibiting expression of an APP gene and methods of treating subjects having a disease or disorder characterized by enlarged endosomes, e.g., Alzheimer's disease (AD) and Down syndrome (DS), particularly occurrences of such neurodegenerative diseases associated with one or more mutations in presenilin 1 (PSEN1), using such dsRNAi agents and compositions.