Oligonucleotide, oligonucleotide conjugate, composition, and use

Abstract

Provided is a single-stranded oligonucleotide which can inhibit AGT mRNA expression via the RNAi mechanism and has a length of 16-30 nucleotides, wherein each nucleotide is independently a modified or unmodified nucleotide, at least one nucleotide is a nucleotide X, and at least one nucleotide is a fluoro-modified nucleotide; furthermore, along the 5'-end-to-3'-end direction, the 13th nucleotide is a nucleotide modified with a substituted alkoxy group, the 14th nucleotide is a nucleotide X, and each of the 15th nucleotide and all the nucleotides thereafter is independently a modified nucleotide. Further provided are a double-stranded oligonucleotide containing the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, and a pharmaceutical composition.

Description

Oligonucleotides, oligonucleotide conjugates and compositions and their uses Technical Field This disclosure relates to a single-stranded oligonucleotide, a double-stranded oligonucleotide, an oligonucleotide conjugate, a pharmaceutically acceptable salt, a pharmaceutical composition, and the uses and preparation methods thereof. Background Technology Angiotensinogen (AGT) is a member of the serpin family and a component of the renin-angiotensin-aldosterone system (RAAS). The RAAS plays a crucial role in blood pressure regulation. AGT is primarily produced in the liver and released into the bloodstream. Renin in the plasma converts AGT to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II exerts most of its effect on the RAAS through its binding to the angiotensin II type 1 receptor (AT1R). Excessive angiotensin II production and / or AT1R-stimulated RAAS dysregulation lead to hypertension, which further increases the burden on the heart. Hypertension is a significant risk factor for cardiovascular morbidity and mortality, accounting for or constituting 62% of all stroke cases and 49% of all heart disease cases. Small interfering RNA (siRNA) can inhibit or block the expression of any gene of interest in a sequence-specific manner based on the mechanism of RNA interference (RNAi), thereby achieving the goal of treating diseases. If the production of AGT can be inhibited at the mRNA level to lower blood pressure, it would undoubtedly be an ideal treatment for hypertension. In siRNA drugs, the antisense strand is the most important part that determines the performance of double-stranded oligonucleotides. Although existing technologies have disclosed a large number of oligonucleotide modification schemes, how to improve the modification of oligonucleotides, especially their antisense strands, to obtain oligonucleotides with higher activity, higher stability and / or longer duration of action remains the direction of research in this field. Summary of the Invention The present invention provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present invention as the antisense strand, and an oligonucleotide conjugate, all of which exhibit good pharmaceutical activity and stability when targeting AGT mRNA. In one aspect, the present invention provides a single-stranded oligonucleotide of 16-30 nucleotides in length, the composition of which enables the single-stranded oligonucleotide to inhibit the expression of AGT mRNA via an RNAi mechanism; each nucleotide in the single-stranded oligonucleotide is independently modified or unmodified, wherein at least one nucleotide in the single-stranded oligonucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide; furthermore, the 13th nucleotide of the single-stranded oligonucleotide is a substituted alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X; and each of the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide is independently modified; each nucleotide X is independently deoxyribonucleotide or unmodified nucleotide. In another aspect, this disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described in this disclosure. In another aspect, this disclosure also provides an oligonucleotide conjugate containing an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being independently formed by removing one or more atoms or groups of atoms from a single-stranded or double-stranded oligonucleotide as described in this disclosure. In another aspect, this disclosure also provides pharmaceutically acceptable salts of the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described herein. In another aspect, this disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and pharmaceutically acceptable salts described in this disclosure, and pharmaceutically acceptable excipients. In another aspect, this disclosure also provides the use of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with AGT mRNA levels. In another aspect, this disclosure also provides a method for treating and / or preventing diseases or symptoms associated with AGT mRNA levels, the method comprising administering to a subject in need an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. In another aspect, this disclosure also provides a method for regulating the expression level of AGT mRNA in cells, the method comprising contacting the cells with an effective amount of one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and pharmaceutical composition of this disclosure. In another aspect, this disclosure also provides one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure for use as pharmaceuticals. In another aspect, this disclosure also provides a cell expressing AGT mRNA, the cell comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. In addition, this disclosure also provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. Beneficial effects One or more of the following, including single-stranded oligonucleotides as antisense strands, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, contain the single-stranded oligonucleotides of this disclosure as antisense strands and have a high modulatory effect on AGT mRNA and a high long-lasting effect. On the one hand, double-stranded oligonucleotides (e.g., siRNA), oligonucleotide conjugates, and / or pharmaceutical compositions containing the single-stranded oligonucleotides of this disclosure as the antisense strand exhibit excellent AGT mRNA inhibitory effects. For example, in in vitro Huh7 cells, the antisense strand modification of the siRNA conjugates of this disclosure differs from that of the reference conjugates, and both the siRNA conjugates and the reference conjugates of this disclosure inhibit the IC50 of human AGT mRNA. 50 The values ​​were 0.021 nM and 0.027 nM, respectively, indicating that the siRNA conjugate disclosed in this invention has a smaller IC50 value. 50 The values ​​indicate that, compared with the reference conjugate, the siRNA conjugate disclosed herein exhibits higher AGT mRNA inhibition efficiency and superior pharmaceutical activity. For example, in in vitro experiments, it demonstrates good inhibitory activity against AGT mRNA in primary mouse liver cells. At a concentration of 0.2 nM, the conjugate provided herein achieves an inhibition rate of over 72% against the target gene AGT mRNA, and at a concentration of 1 nM, it can reach 98.5%, or even 99%, demonstrating excellent in vitro inhibitory activity. On the other hand, the double-stranded oligonucleotides (e.g., siRNA), conjugates, and / or pharmaceutical compositions of this disclosure, containing the single-stranded oligonucleotides as the antisense strand, have shown highly efficient and long-lasting inhibitory effects on AGT mRNA and protein expression in in vivo animal model experiments. For example, in a 43-day experimental period, hAGT transgenic mice administered the same concentration of the conjugate showed a higher AGT protein expression inhibition rate than mice administered the reference conjugate, maintaining a high inhibition rate throughout the experimental period. On day 43, the inhibition rate of AGT protein expression remained close to 80%, significantly higher than one of the most preferred compounds in the art. Furthermore, in multi-dose experiments, different doses of the conjugates of this disclosure showed excellent hAGT protein inhibition effects, with the inhibition rate reaching up to 96.5% at a dose of 9 mg / kg, exhibiting a dose-dependent effect. At a dose of 9 mg / kg, the inhibition rate remained at a high level of up to 90.3% on day 43 after administration. For example, during a 71-day experimental period, mice given the conjugate of this disclosure exhibited a high inhibition rate of hAGT protein expression. For instance, on day 15, the inhibition rate of hAGT protein expression was above 90%, and on day 71, the inhibition rate remained close to or reached 70%. This demonstrates that the conjugate of this disclosure, containing the antisense strand, can effectively inhibit AGT mRNA expression for a prolonged period, thereby reducing serum hAGT protein expression. In other embodiments, mice given the conjugate of this disclosure exhibited a high inhibition rate of hAGT protein expression, maintaining a high inhibition rate throughout the entire 71-day experimental period. On day 71, at a dose of 1 mg / kg, the inhibition rate of hAGT protein expression was 56%; at a dose of 3 mg / kg, the inhibition rate still reached 70%. Therefore, the conjugate of this disclosure, containing the antisense strand, can effectively inhibit AGT mRNA expression for a prolonged period, thereby reducing serum hAGT protein expression. The above results demonstrate that the conjugates disclosed herein can efficiently inhibit the levels of AGT mRNA and target proteins over a prolonged period in in vivo animal models. This indicates that the conjugates disclosed herein can stably and efficiently inhibit AGT mRNA expression over a long period. The conjugates disclosed herein exhibit significant and long-lasting pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to AGT mRNA expression, and possess excellent development prospects. Attached Figure Description Figures 1A and 1B show the IC50 values ​​of the inhibitory activity of the siRNA conjugate and reference conjugate of this disclosure on the AGT gene in Huh-7 cells in vitro, respectively. 50 Fitted curve. Incorporate by reference All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually incorporated herein by reference. Detailed Implementation The following provides a detailed description of specific embodiments of this disclosure. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit this disclosure. In this disclosure, AGT mRNA refers to AGT mRNA expressed in mammalian cells. Specifically, AGT mRNA refers to the mRNA with the sequence shown in GenBank accession number NM_001384479.1. Furthermore, unless otherwise specified, the term "AGT gene" as used in this disclosure refers to the gene that transcribes the aforementioned AGT mRNA. definition In the preceding and following text, "fluorinated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with fluorine, and "non-fluorinated nucleotides" refers to nucleotides or nucleotide analogs formed by replacing the 2'-hydroxyl group of the ribosome with a non-fluorinated group. "Nucleotide analogs" refer to groups that can replace nucleotides in nucleic acids but whose structure differs from adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, or thymine deoxyribonucleotides. Examples include isonucleotides, bridged nucleic acids (BNAs), or acyclic nucleotides. "Methoxylated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with a methoxy group. In the context of this document, the terms "complementary" and "reverse complementary" are used interchangeably and have the meaning known to those skilled in the art: in a double-stranded nucleic acid molecule, each base of one strand forms a hydrogen bond with a base of the other strand in a complementary manner, achieving base pairing and forming a Watson-Crick base pair. A "base pair" refers to the two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or uracil (U) in RNA); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair consists of one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand, and guanine always pairs with cytosine, the two strands are considered complementary, and the sequence of the complementary strand can be inferred from its sequence. When bases are modified, as long as the pairing relationship of purines and pyrimidines (including but not limited to the number and strength of hydrogen bonds between bases) is not affected, the modified bases are considered to be able to form complementary pairs. Correspondingly, in this field, "mismatch" means that in a double-stranded nucleic acid, the bases at corresponding positions are not paired in a complementary manner; when the corresponding position includes a baseless nucleotide, it is also considered to have formed a mismatch with the bases on the other strand. In the preceding and following text, "at least partially anti-complementary," "substantially anti-complementary," "truly anti-complementary," and "completely anti-complementary" refer to the base pairing between two single-stranded nucleotide sequences: between a single-stranded oligonucleotide and AGT mRNA, between a single-stranded oligonucleotide and nucleotide sequence m, between the sense and antisense strands of a double-stranded oligonucleotide (such as siRNA), and between the antisense strand of a double-stranded oligonucleotide and AGT mRNA. Unless otherwise specified, "at least partially anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 50% base mismatches between the two nucleotide sequences capable of forming a double-stranded region; "substantially anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 3 base mismatches between the two nucleotide sequences capable of forming a double-stranded region; "truly anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 1 base mismatch between the two nucleotide sequences capable of forming a double-stranded region; and "completely anti-complementary" means that within a hypothetical or actual double-stranded region, there are no base mismatches between the two nucleotide sequences capable of forming a double-stranded region. When the two nucleotide sequences are “at least partially reverse complementary,” “substantially reverse complementary,” “truly reverse complementary,” or “completely reverse complementary,” they can form a double-stranded hybrid consisting of Watson-Crick base pairs after annealing. Unless otherwise stated, when referring to a shorter nucleotide sequence as "completely anticomplementary" to a longer nucleotide sequence, it means that the two nucleotide sequences are completely anticomplementary along the entire length of the shorter nucleotide sequence. For example, the complete anticomplementary relationship between the single-stranded oligonucleotide and AGT mRNA described in this disclosure means that the single-stranded oligonucleotide is completely anticomplementary along its entire length; in other words, each nucleotide in the single-stranded oligonucleotide forms a Watson-Crick base pair with a corresponding nucleotide on the AGT mRNA to form a double-stranded hybrid. In the context of this disclosure, a "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences comprising all base pairs on each single strand of a hypothetical or actual double-stranded nucleic acid structure. Therefore, a double-stranded region consists of all base pairs in the double-stranded nucleic acid structure and all base mismatches between those base pairs. In some embodiments, the double-stranded nucleic acid structure includes a double-stranded region and one or more overhanging ends, said overhanging ends consisting of all nucleotides outside the double-stranded region in one or both single strands of the double-stranded nucleic acid structure that do not form base pairs. In some embodiments, the double-stranded nucleic acid structure includes only a double-stranded region. The two nucleotide sequences that can form a double-stranded region can be of the same or different lengths. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region, in which case the two nucleotide sequences forming the double-stranded nucleic acid structure are of the same length. "At least partially anticomplementary" means that there is no more than 50% base mismatch between the two nucleotide sequences; "substantially anticomplementary" means that there is no more than 3 base mismatches between the two nucleotide sequences; "substantially anticomplementary" means that there is no more than 1 base mismatch between the two nucleotide sequences; and "completely anticomplementary" means that there is no base mismatch between the two nucleotide sequences. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of the same length, the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of the longer nucleotide sequence. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of different lengths, the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of the longer nucleotide sequence. For example, in some embodiments, the sense and antisense strands of a double-stranded oligonucleotide are of different lengths. For example, the double-stranded oligonucleotide is siRNA, in which case the sense strand is usually shorter and is a shorter nucleotide sequence, while the antisense strand is longer and is the longer nucleotide sequence. The double-stranded nucleic acid structure includes a double-stranded region and a dangling end in the antisense strand. In the preceding and following text, "nucleotide sequence A and nucleotide sequence B are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary across a length of X nucleotides" means that there exists a continuous nucleotide sequence A' of length X in nucleotide sequence A, which is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence B' of length X in nucleotide sequence B. In the foregoing and hereinafter, particularly in the description of methods for preparing single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, or oligonucleotide conjugates of this disclosure, unless otherwise specified, the nucleoside monomer refers to the modified or unmodified RNA phosphoramidites (sometimes also called nucleoside phosphoramidites) used in phosphoramidite solid-phase synthesis, depending on the type and sequence of nucleotides in the desired single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate. Phosphoramidite solid-phase synthesis is a method known to those skilled in the art for RNA synthesis. All nucleoside monomers used in this disclosure are commercially available. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable. As used herein, “alkyl” refers to a saturated straight-chain and / or branched hydrocarbon group having a specified number of carbon atoms, typically from 1 to 20 carbon atoms, such as from 1 to 10 carbon atoms, or from 1 to 8 or 1 to 6 carbon atoms. For example, C1-C6 alkyl comprises straight-chain and branched alkyl groups having 1 to 6 carbon atoms. When referring to an alkyl residue having a specific number of carbons, it is intended to cover all branched and straight-chain forms having that number of carbons; thus, for example, “butyl” means including n-butyl, sec-butyl, isobutyl, and tert-butyl; “propyl” includes n-propyl and isopropyl. Alkylenes are subsets of alkyl, referring to residues that are identical to alkyl but have two connection sites. As used herein, "alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms connected by oxygen bridges. As used in this article, "alkoxy-modified alkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with an alkoxy group, such as methoxymethyl (CH3OCH2-), ethoxymethyl (CH3CH2OCH2-), methoxyethyl (CH3OCH2CH2-), etc. As used herein, "alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond obtained by removing a hydrogen molecule from an adjacent carbon atom of a parent alkyl group. The group can be in either a cis or trans configuration of the double bond. Typical alkenyl groups include, but are not limited to: vinyl; propenyl, such as propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), propyl-2-en-2-yl; butenyl, such as buten-1-en-1-yl, buten-1-en-2-yl, 2-methylpropen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, buten-1,3-dien-2-yl, etc. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, while in other embodiments, it has 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Subalkenyl groups are a subset of alkenyl groups, referring to residues that are identical to alkenyl groups but have two connection points. As used herein, "alkynyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon triple bond obtained by removing two hydrogen molecules from adjacent carbon atoms of a parent alkyl group. Typical alkynyl groups include, but are not limited to: ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. In some embodiments, the alkynyl group has 2 to 20 carbon atoms, while in other embodiments, it has 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Ionynyl is a subset of alkynyl, referring to residues that are identical to alkynyl but have two connection sites. As used herein, "aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. This aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 6 to 18, wherein at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2)π-electron system according to Hückel's theory. Aryl groups include, but are not limited to, phenyl, fluorenyl, and naphthyl groups. Alearyl groups are a subset of aryl groups, referring to residues identical to aryl groups but with two connection points. As used herein, a "heterocyclic group" refers to a group derived from a monocyclic saturated or partially unsaturated, non-aromatic or bicyclic saturated or partially unsaturated heterocyclic hydrocarbon group, wherein the bicyclic ring system is non-aromatic, the monocyclic or bicyclic ring has, for example, 3 to 10 members or 5 to 10 members, wherein at least one member and up to five members, particularly one, two or three ring members, are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms in a stable combination known to those skilled in the art. The heterocyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. As used herein, the heterocycle can form a bicyclic ring with another ring system, i.e., one or two of the atoms constituting the heterocycle are shared with another ring system. The heterocyclic group can be linked to the rest of the molecule via carbon or heteroatoms; and, in the case of a bicyclic group, the above-mentioned linking can be made via a ring containing heteroatoms or a fused ring. Examples of heterocyclic groups include, but are not limited to: aziridine, pyrrolidinyl, piperidinyl, aziridine-heptyl, diaziridine-heptyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dioxacyclopentyl, morpholinyl, oxazolyl, oxazinyl, indololinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, and dihydropyranyl (e.g., 3,4-dihydropyranyl). 3,6-dihydropyranyl), piperazineyl, dioxane, hexahydropyrimidinyl, pyrazolinyl, pyrazolylylene, 4H-quinazinyl, quininecycloyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiopheneyl, thiazolyl, benzopyranyl, tetrahydroquinolinyl, dihydropyrrolopyridinyl, dihydrobenzoxazinyl, pyrrolopyridinyl, dihydronaphthidinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl. Subheterocyclic groups are a subset of heterocyclic groups, referring to residues identical to heterocyclic groups but with two connection sites. As used herein, "heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring radical, comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, wherein at least one ring in the ring system is fully unsaturated, i.e., comprising a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Heteroaryls include fused ring or bridged ring systems. In some embodiments, the heteroatoms in the heteroaryl are oxidized heteroatoms. In some embodiments, the heteroaryl contains one or more nitrogen atoms. In some embodiments, one or more of the nitrogen atoms in the heteroaryl are quaternized nitrogen atoms. The heteroaryl is attached to the remainder of the molecule via any ring atom. Examples of heteroaryl groups include, but are not limited to: aziridine, heptatrienyl, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzene benzo[a]furanyl, benzo[a]oxazolyl, benzo[a]dioxolyl, benzo[a]dioxinyl, benzo[a]pyranyl, benzo[a]pyranoneyl, benzo[a]furanyl, benzo[a]furanoneyl, benzo[a]thiophenyl, benzo[a]thiophene[3,2-d]pyrimidinyl, benzo[a]triazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cinnolinyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentano[4,5] Thiophene[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8 9,10-Hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indole, isoyindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl (5,8-methano-5,6,7,8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridano[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-c]pyridinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl / thienyl. Hypo-heteroaryl groups are a subset of heteroaryl groups, referring to residues that are identical to heteroaryl groups but have two linkage sites. In the foregoing or hereinafter, "substituted," "substituted," or "substituted" groups refer to substituted amino, substituted alkyl, or substituted aryl groups. Unless otherwise specified, a "substituted" or "substituted" group means a group formed by replacing one or more hydrogen atoms in the group with a substituent. For example, "substituted alkyl" means a group formed by replacing one or more hydrogen atoms in an alkyl group with a substituent. Those skilled in the art will understand that compounds usable in this disclosure may contain various substituents, as long as the introduction of such substituents does not affect the function of this disclosure and achieves the purpose of this disclosure. In some embodiments, the substituents are selected from the group consisting of C1-C1 groups. 10 Alkyl, C6-C 10 Aryl, C5-C 10 heteroaryl, C1-C 10 Halogenated alkyl, -OC1-C 10 Alkyl, -OC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-OH, -OC1-C10 Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10 Alkyl) (C1-C 10 alkyl), -NH(C1-C 10 Alkyl), N(C1-C) 10 Alkyl) (C1-C 10 alkylphenyl), NH(C1-C 10 Alkylphenyl), -CN, -NO2, -CO2H, -C(O)O(C1-C 10 Alkyl), -CON (C1-C) 10 Alkyl) (C1-C 10 Alkyl), -CONH (C1-C) 10 Alkyl group), -CONH2, -NHC(O) (C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 Alkyl)C(O)(C1-C 10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), -C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, -C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (Halogenated alkyl). In some embodiments, the substituent is one of -C1-C3 alkyl, -C6-C8 aryl, -O-C1-C3 alkyl, -O-(C1-C3 alkyl)phenyl, halogen, -OH, -NH2, -CN, or -NO2. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable. As used herein, “halogenated” or “halogenated” refers to fluorinated, chlorinated, bromine, and iodinated substances, and the term “halogen” includes fluorine, chlorine, bromine, and iodine. As used herein, “haloalkyl” means an alkyl group as defined above in which a specified number of carbon atoms are replaced by one or more, up to a maximum permissible number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl. Various protecting groups, such as amino or hydroxyl protecting groups, may be used in this disclosure. Generally, protecting groups make a chemical function insensitive to specific reaction conditions and can be added to and removed from that function in a molecule without substantially impairing the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Peter GMWuts, GREENE's Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons, Inc., New Jersey, 2014, all of which are incorporated herein by reference in their entirety. In some embodiments, the protecting group is stable under basic conditions but can be removed under acidic conditions. In some embodiments, non-exclusive examples of hydroxyl protecting groups that may be used herein include dimethoxytriphenylmethyl (DMT), monomethoxytriphenylmethyl, 9-phenyloxanthracene-9-yl (Pixyl), and 9-(p-methoxyphenyl)oxanthracene-9-yl (Mox). In some embodiments, non-exclusive examples of hydroxyl protecting groups that may be used herein include Tr (triphenylmethyl), MMTr (4-methoxytriphenylmethyl), DMTr (4,4'-dimethoxytriphenylmethyl), and TMTr (4,4',4”-trimethoxytriphenylmethyl). The term “subject” as used herein refers to any animal, such as a mammal or marsupial. Subjects in this disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, rabbits, sheep, rats, and any kind of poultry. In some embodiments, “subject” refers to a mammal, such as a rodent or primate. In some embodiments, “subject” refers to a mouse, rat, or non-human primate. In some embodiments, “subject” refers to a human subject. As used herein, “treatment” refers to a method of achieving a beneficial or desired outcome, including but not limited to treatment benefits. A “treatment benefit” means the eradication or improvement of the underlying disorder being treated. Furthermore, a treatment benefit is achieved by eradicating or improving one or more physical symptoms associated with the underlying disorder, thereby observing improvement in the subject, even though the subject may still be suffering from the underlying disorder. As used herein, “prevention” refers to methods for obtaining a beneficial or desired outcome, including but not limited to preventative benefits. To obtain a “preventative benefit,” the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of this disclosure may be given to a subject at risk of developing a disease associated with AGT mRNA, or to a subject reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease may not have been made. In some embodiments, “prevention” includes, before the disease risk associated with AGT mRNA levels progresses to a defined disease course, intervening in the levels of AGT mRNA or AGT protein to reduce or eliminate the disease risk by giving a double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate to a subject at risk of developing a disease associated with AGT mRNA. Unless otherwise specified, in the context of any reference to an oligonucleotide and / or oligonucleotide conjugate described in the application or method provided in this disclosure, including but not limited to any oligonucleotide and / or oligonucleotide conjugate represented by a structural formula described in the application or method provided in this disclosure, the reference also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or oligonucleotide conjugate, depending on the context. The single-stranded oligonucleotides disclosed herein In one aspect, this disclosure provides a single-chain oligonucleotide of 16-30 nucleotides in length, the composition of which enables the single-chain oligonucleotide to inhibit the expression of AGT mRNA via an RNAi mechanism; each nucleotide in the single-chain oligonucleotide is independently modified or unmodified, wherein at least one nucleotide in the single-chain oligonucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide; furthermore, the 13th nucleotide of the single-chain oligonucleotide is a substituted alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; the 14th nucleotide of the single-chain oligonucleotide is nucleotide X; and each of the 15th nucleotide and all subsequent nucleotides of the single-chain oligonucleotide is independently modified nucleotide; each nucleotide X is independently deoxyribonucleotide or unmodified nucleotide. In this disclosure, by regulating the expression level of AGT mRNA and / or altering the protein level, it is possible to treat or prevent diseases related to the expression level and / or protein level of AGT mRNA. The inventors unexpectedly discovered that the single-stranded oligonucleotides described in this disclosure, the double-stranded oligonucleotides containing the single-stranded oligonucleotides described in this disclosure as antisense strands, and the oligonucleotide conjugates have good stability and AGT mRNA inhibitory activity in cells and / or in subjects, and therefore have good application prospects. To achieve RNAi activity, the single-stranded oligonucleotides described in this disclosure are 16-30 nucleotides in length. In some embodiments, the single-stranded oligonucleotides described in this disclosure are 17-28, 19-27, or 20-25 nucleotides in length. In some embodiments, the single-stranded oligonucleotides described in this disclosure are 19, 21, or 23 nucleotides in length. In these cases, the single-stranded oligonucleotides described in this disclosure, the double-stranded oligonucleotides containing the single-stranded oligonucleotide as the antisense strand, and the oligonucleotide conjugates exhibit a better balance between stability and RNAi activity. In the single-stranded oligonucleotides of this disclosure, at least one nucleotide is nucleotide X, at least one nucleotide is a fluorinated nucleotide, and the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X in the direction from the 5' end to the 3' end, the 13th nucleotide of the single-stranded oligonucleotide is a substituted alkoxy-modified nucleotide, and each of the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide is independently modified nucleotide. The inventors have particularly discovered that the single-stranded oligonucleotides of this disclosure, by comprising the aforementioned fluorinated nucleotide, substituted alkoxy-modified nucleotide, and nucleotide X, can effectively maintain the high inhibitory activity of single-stranded oligonucleotides, double-stranded oligonucleotides, and oligonucleotide conjugates against AGT mRNA while maintaining stability. In some embodiments, the number of nucleotides X in the single-stranded oligonucleotide is 1-3, for example, 1, 2, or 3. In some embodiments, the 12th and 14th nucleotides in the single-stranded oligonucleotide are each independently nucleotide X, with the 5' end to the 3' end in the orientation. In some embodiments, only the 14th nucleotide in the single-stranded oligonucleotide is nucleotide X, with the 5' end to the 3' end in the orientation. Each nucleotide X is independently selected from deoxyribonucleotides or unmodified nucleotides. In this context, "unmodified nucleotide" refers to a ribonucleotide (RNA) with both the base and ribose unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the 2' position of the ribose is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide with modified bases, a nucleotide where the hydroxyl group at the 2' position of the ribose is replaced by another atom or group, or a nucleotide analog. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide are deoxyribonucleotides in the 5' to 3' direction, and the other nucleotides X are unmodified nucleotides. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide is a deoxyribonucleotide in the 5' to 3' direction, and each of the other nucleotides is independently modified nucleotide. In some embodiments, the number of modified nucleotides accounts for more than 50%, 70%, or 85% of the total number of nucleotides in the single-stranded oligonucleotide of this disclosure. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide of this disclosure does not exceed 5 or 4. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide of this disclosure does not exceed 3, 2, or 1. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, each of the nucleotides in the single-stranded oligonucleotide is independently modified. As previously described, in addition to nucleotide X and substituted alkoxy-modified nucleotides, the single-chain oligonucleotides of this disclosure also include fluorinated nucleotides. In some embodiments, the number of fluorinated nucleotides is 2-7. In some embodiments, fluorinated nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to 1 or 2 of the 2nd and 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to the 2nd and 6th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to the 2nd, 6th, and 16th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 5th, 7th, 12th, and 16th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 7th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 6th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, in the single-stranded oligonucleotide, except for the 13th and 14th nucleotides and fluorinated nucleotides, each modified nucleotide is independently selected from alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, alkyl-modified nucleotides, substituted alkyl-modified nucleotides, amine-modified nucleotides, heat-labile nucleotides, and BNA, along the 5' to 3' direction. In some embodiments, in the single-stranded oligonucleotide, except for the 13th and 14th nucleotides and fluorinated nucleotides, each modified nucleotide is independently selected from alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, or heat-labile nucleotides, along the 5' to 3' direction. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed three. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed two. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is one. In some embodiments, the single-stranded oligonucleotide does not contain heat-labile nucleotides. In some embodiments, the number of heat-labile nucleotides does not exceed two. In some embodiments, the number of heat-labile nucleotides is one or two. In some embodiments, each modified nucleotide other than the substituted alkoxy-modified nucleotide, nucleotide X, fluorinated nucleotide, and heat-labile nucleotide is independently an alkoxy-modified nucleotide. In this context, "thermally unstable nucleotide" refers to a nucleotide with a thermally unstable modification, wherein the thermally unstable modification is a modification that lowers the thermal dissociation temperature of the oligonucleotide duplex by at least 0.5 °C compared to an oligonucleotide duplex with an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification in PCT Publication WO2018 / 098328A1.

[0236] -

[0251] The thermal instability modification described in the paragraph. In some embodiments, the heat-labile nucleotide is a type of acyclic nucleotide or heteronucleotide. Acyclic nucleotides are a class of nucleotides formed by opening the sugar ring of a nucleotide. In some embodiments, acyclic nucleotides can be unblocking nucleic acids (UNA) or glycerol nucleic acids (GNA), wherein UNA is shown in formula (15) and GNA is shown in formula (16): In formulas (15) and (16) above, R is selected from H, OH or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C or T. Isonucleotides are compounds formed by altering the position of a base on the ribose ring in a nucleotide. In some embodiments, an isonucleotide can be a compound formed by moving a base from the 1'-position to the 2'-position or 3'-position on the ribose ring, as shown in formula (17) or (18). In the compounds of formulas (17)-(18) above, Base represents a nucleic acid base, such as A, U, G, C or T; R is selected from H, OH, F or non-fluorine groups as described above. In some embodiments, the heat-labile nucleotide is selected from one of the following: GNA as shown in formula (27A), 2'-OMe abasic nucleotide as shown in formula (27B), 3'-OMe modified nucleotide as shown in formula (27C), 5'-Me modified nucleotide as shown in formula (27D), SNA as shown in formula (27E), hGNA as shown in formula (27F), hhGNA as shown in formula (27G), mGNA as shown in formula (27H), TNA as shown in formula (27I), h'GNA as shown in formula (27J), UNA as shown in formula (27K), or a hyperspacer as shown in formula (27L). In the compounds of formulas (27A)-(27L) above, Base represents a nucleic acid base, such as A, U, G, C, or T; R 27 Selected from H, OH, F, alkoxy, alkyl, or alkoxy-substituted alkyl groups. * indicates that the carbon atom is chiral, and the compound can be an R configuration, an S configuration, or a racemic mixture of R and S configurations. In some embodiments, each thermally unstable nucleotide is independently a GNA as shown in formula (27A). In this context, BNA refers to a restricted or inaccessible nucleotide. A BNA can contain a bridging structure with a "fixed" C3'-endoglucan condensation, consisting of a five-, six-, or seven-membered ring. This bridge is typically incorporated into the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be an LNA, ENA, cET BNA, etc., where LNA is shown in formula (12), ENA in formula (13), and cET BNA in formula (14). In some embodiments, for ease of synthesis, each alkoxy-modified nucleotide is independently a 2'-methoxy-modified nucleotide (2'-OMe), as shown in formula (8). In some embodiments, the 2'-amino-modified nucleotide (2'-NH2) is shown in formula (9). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in formula (10). In equations (7) to (10) above, Base represents a nucleic acid base, such as A, U, G, C or T. In the preceding and following text, “fluorinated nucleotides,” “2’-fluorinated nucleotides,” “nucleotides in which the 2’-hydroxyl group of the ribose group is replaced by fluorine,” and “nucleotides with a 2’-fluorinated ribose group” have the same meaning, all referring to compounds in which the 2’-hydroxyl group of the nucleotide is replaced by fluorine, resulting in compounds with the structure shown in formula (7); “methoxylated nucleotides,” “2’-methoxylated nucleotides,” “nucleotides in which the 2’-hydroxyl group of the ribose group is replaced by methoxyl,” and “nucleotides with a 2’-methoxy ribose group” have the same meaning, all referring to compounds in which the 2’-hydroxyl group of the ribose group of the nucleotide is replaced by methoxyl, resulting in compounds with the structure shown in formula (8). In some embodiments, the single-stranded oligonucleotides of this disclosure are 19-23 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, one of the 5th-7th nucleotides, and the 2nd and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and when the 5th nucleotide is not a fluorinated nucleotide, it is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide. In some embodiments, each nucleotide X in the single-chain oligonucleotides described herein refers to a deoxynucleotide. In some embodiments, each alkoxy-modified nucleotide in the single-chain oligonucleotides described herein refers to a methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide in the single-chain oligonucleotides described herein refers to a 2'-O-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single-chain oligonucleotides described herein refers to an LNA or cET BNA. In some embodiments, each heat-labile nucleotide in the single-chain oligonucleotides described herein refers to a GNA. In some embodiments, each of at least two linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of one to four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of one to four linking groups between adjacent nucleotides in the 3'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of two linking groups or four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of two linking groups or four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, in the single-stranded oligonucleotides of this disclosure, if unmodified nucleotides are present, each of the two linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate ester group with a modifying group. The modified phosphate ester groups can enhance the resistance of the single-stranded oligonucleotides of this disclosure to exonuclease activity, thereby increasing the stability of the oligonucleotides in the body. In some embodiments, each of 2-6 linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of 3 or 4 linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, if unmodified nucleotides are present in the single-stranded oligonucleotide, each of 1 or all 2 of the 2 linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate group with a modifying group. In some embodiments, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28): In some embodiments, the 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxynucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog-modified nucleotide, wherein the 5'-hydroxynucleotide has the structure shown in formula (29); the 5'-phosphate nucleotide has the structure shown in formula (30); and the 5'-phosphate analog-modified nucleotide has a structure selected from those shown in formulas (31) to (34). R is selected from H, OH, OCH3 and F; Base represents a nucleic acid base, selected from A, U, C, G or T. In some embodiments, the 5'-phosphate nucleotide is a nucleotide containing a 5'-phosphate modification as shown in formula (30), and the 5'-phosphate analog modified nucleotide is a nucleotide containing a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modification as shown in formula (31), or a nucleotide modified with a 5'-thiophosphate as shown in formula (33). In some embodiments, the 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxy nucleotide or a nucleotide containing a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modification. In some embodiments, the 5'-terminal nucleotide being a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modified nucleotide can further increase one or more of the stability, in vivo pharmacodynamic activity, and long-lasting effect of the single-stranded oligonucleotide, double-stranded oligonucleotide containing the single-stranded oligonucleotide, and oligonucleotide conjugates described herein. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a 2'-O-methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, and the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a methoxy modified nucleotide; the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end is a thiophosphate group; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). As previously stated, the single-chain oligonucleotides described in this disclosure have sufficient complementarity with AGT mRNA to produce RNAi effects. In some embodiments, the composition of the single-chain oligonucleotides described in this disclosure enables them to inhibit AGT mRNA expression via an RNAi mechanism. In some embodiments, the single-chain oligonucleotides described in this disclosure are sufficiently complementary to AGT mRNA. In the context of this disclosure, "sufficiently complementary" means that the complementarity between the single-chain oligonucleotides described in this disclosure and AGT mRNA is sufficient to reduce or eliminate the production of the protein encoded by the AGT mRNA through RNAi. In some embodiments, "sufficiently complementary" means that the single-chain oligonucleotides described in this disclosure are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to AGT mRNA across at least 16 nucleotides, for example, across 16-25 nucleotides, across 18-23 nucleotides, or across 19-21 nucleotides. In some embodiments, the single-chain oligonucleotides described in this disclosure are completely anticomplementary to AGT mRNA. In some embodiments, the two "fully complementary" nucleotide sequences may include completely anticomplementary internal regions (e.g., completely anticomplementary across a length of at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotide of this disclosure is completely anticomplementary to AGT mRNA at least within a seed region. The "seed region" refers to the region of nucleotides 2-8 of the single-stranded oligonucleotide of this disclosure, where the single-stranded oligonucleotide of this disclosure can better mediate RNAi action and suppress AGT mRNA levels. In some embodiments, the single-stranded oligonucleotide is substantially anticomplementary or completely anticomplementary to AGT mRNA across at least 16 nucleotides. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide from position 2 to 19 is completely anticomplementary to AGT mRNA in the 5' to 3' direction. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide other than position 1 at the 5' end is completely anticomplementary to AGT mRNA in the 5' to 3' direction. In some embodiments, all nucleotides of the single-stranded oligonucleotide are completely anticomplementary to the AGT mRNA. In some embodiments, the single-stranded oligonucleotide is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence m in the AGT mRNA; the length of the nucleotide sequence m is not greater than the length of the single-stranded oligonucleotide, and the length of the nucleotide sequence m is the same as the length of the single-stranded oligonucleotide, or differs by no more than 8 nucleotides, or differs by 1-5 nucleotides. In some embodiments, the length of the nucleotide sequence m is at least 16 nucleotides, or 16-25 nucleotides, or 18-23 nucleotides, or 19-21 nucleotides; or, the length of the nucleotide sequence m is 19, 21, or 23 nucleotides. In some embodiments, the single-stranded oligonucleotide has the same length as the nucleotide sequence m, and at least the nucleotide sequence other than the terminal nucleotide of the single-stranded oligonucleotide is completely anticomplementary to the nucleotide sequence m. Thus, double-stranded oligonucleotides or oligonucleotide conjugates containing the single-stranded oligonucleotide as the antisense strand of this disclosure can further improve the inhibitory effect on AGT mRNA. In some embodiments, the nucleotide sequence other than the first position of the single-stranded oligonucleotide is completely anticomplementary to the nucleotide sequence m in the 5'-3' direction. In some embodiments, all nucleotides of the single-stranded oligonucleotide are completely anticomplementary to the nucleotide sequence m. In some embodiments, the single-chain oligonucleotides of this disclosure can exert pharmacological activity independently. In some embodiments, the single-chain oligonucleotides of this disclosure are antisense oligonucleotides (ASO). In some embodiments, the single-chain oligonucleotides of this disclosure are single-chain RNAi (ssRNAi) compounds. In some embodiments, the single-chain oligonucleotides of this disclosure exert pharmacological activity as a single strand (e.g., antisense strand) of a double-chain oligonucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:2 and differs from it by no more than 3 bases. 5'-Z2CUUAGACCAAGGAGAAAC-3'(SEQ ID NO:2), Wherein, Z2 is A or U, and the nucleotide sequence II contains a nucleotide Z4 at a position corresponding to Z2, wherein Z4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In the preceding and following text of this disclosure, "positional correspondence" means that the nucleotides are located at the same position in the nucleotide sequence, starting from the same end of the nucleotide sequence. For example, the first nucleotide at the 5' end of nucleotide sequence II is the nucleotide that corresponds to the first nucleotide of SEQ ID NO:2. In some embodiments, the nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one base. This base difference may include a difference at the Z4 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 may include a base difference at the Z4 position and / or a base difference at a nucleotide position adjacent to Z4. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 includes a difference at position Z4, where Z4 is selected from C or G. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 is a difference at position Z4, where Z4 is selected from C or G. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2. In some embodiments, Z4 is A. In some embodiments, Z4 is U. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to AGT mRNA. Each non-fluorinated nucleotide is independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having 1-3 carbon atoms, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a heat-labile nucleotide. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has a base of G; or, the nucleotide sequence IV is 2 nucleotides in length and has a base composition of GG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has a base composition of GGC in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has a base composition of GGCU in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide of this disclosure further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V being an independently non-fluorinated nucleotide, the nucleotide sequence V being 1 to 3 nucleotides in length and attached to the 3' end of a nucleotide sequence IV or a nucleotide sequence II, wherein the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand. In some embodiments, the nucleotide sequence V of this disclosure is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or completely reverse complementary to AGT mRNA. In some embodiments, the nucleotide sequence V of this disclosure is attached to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is GG in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2 and nucleotide sequence V has a base composition of GG. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1–siRNA4 shown in Table 1. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of conjugates 1–5 shown in Table 2. The double-stranded oligonucleotides disclosed herein In another aspect, this disclosure also provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described above in this disclosure. In the double-stranded oligonucleotides of this disclosure, the length of the sense strand and the antisense strand is each 19-26 nucleotides. In some embodiments, the length of the antisense strand is not less than the length of the sense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Thus, the length ratio of the sense strand to the antisense strand of the double-stranded oligonucleotides of this disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, the length of the sense strand is 15-26 or 17-24 nucleotides. In some embodiments, the length of the sense strand is 19-21 nucleotides. In some embodiments, for ease of synthesis, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 19-23 nucleotides. The length difference between the sense and antisense strands is 0-5 nucleotides. In some embodiments, the length of the sense strand is not greater than the length of the antisense strand. In some embodiments, the lengths of the sense and antisense strands are the same, both being 19, 20, or 21 nucleotides. In some embodiments, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 20-24 nucleotides, with the antisense strand being 1-3 nucleotides longer than the sense strand. In some embodiments, the length of the antisense strand is 2 nucleotides longer than the sense strand. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides. In some embodiments, the sense strand is 19 nucleotides long and the antisense strand is 21 nucleotides long. In some embodiments, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long. In some embodiments, in the positive strand of the double-stranded oligonucleotide of this disclosure, 2-3 of the 11th-13th nucleotides of the positive strand, in the direction from the 3' end to the 5' end, are fluorinated nucleotides, and the first and / or last nucleotide of the positive strand is an alkoxylated nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having the structure shown in formula (35)). In some embodiments, in the direction from the 3' end to the 5' end, the first nucleotide of the positive strand is an alkoxylated nucleotide or an inverted abasic deoxyribonucleotide. In some embodiments, apart from the fluorinated and inverted abasic deoxyribonucleotides described above, the nucleotides at the remaining positions in the positive strand are each independently non-fluorinated nucleotides, and each non-fluorinated nucleotide is independently selected from one of alkoxylated nucleotides, alkylated nucleotides, amine-modified nucleotides, and thermally unstable nucleotides. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the penultimate nucleotide of the positive strand. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the 3' terminal nucleotide of the positive strand, and the oxygen atom attached to the ribose ring via a methylene group as shown in formula (35) may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand, and the oxygen atom of formula (35) directly attached to the ribose ring may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, the 11th and 13th nucleotides, or nucleotides 11-13, of the positive strand are fluorinated nucleotides, and the first and / or last nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, with the remaining nucleotides in the positive strand being alkoxylated nucleotides. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or nucleotides 11-13, of the sense strand are fluorinated nucleotides, arranged from the 3' end to the 5' end; the first and / or last nucleotide of the sense strand is an alkoxylated nucleotide or a reverse debased deoxynucleotide; and the remaining nucleotides are each independently alkoxylated nucleotides. In this case, through the positional coordination of the modified nucleotides of the sense and antisense strands, the double-stranded oligonucleotides of this disclosure exhibit better stability and / or RISC complex formation activity, thereby demonstrating stable and efficient AGT mRNA repressive activity. In some embodiments, each alkoxylated nucleotide is independently methoxylated nucleotide. In some embodiments, in the positive strand, at least one of the linking groups connecting two adjacent nucleotides is independently a phosphate group with a modifying group, and the phosphate group with the modifying group is present at least once between two adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand and between two adjacent nucleotides in the first to fifth nucleotides at the 3' end. In this case, the double-stranded oligonucleotide of this disclosure has a good balance between resistance to exonucleases and AGT mRNA, thereby improving stability while also exhibiting highly efficient AGT mRNA inhibitory activity. In some embodiments, each of 1-4 linking groups between any two adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand, and / or each of 1-4 linking groups between any two adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand, is independently a phosphate group with a modifying group. In some embodiments, each of all four linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand is independently a phosphate group with a modifying group. In some embodiments, each of the four linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the sense strand is independently a phosphate group with a modifying group. In some embodiments, the linking group connecting two adjacent nucleotides in the first to third, first to fourth, or first to fifth nucleotides at the 5' end and / or the 3' end of the sense strand is a phosphate group with a modifying group. In some embodiments, the linking group between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the sense strand is a phosphate group with a modifying group. The definition and selection range of the phosphate group with a modifying group are the same as those described above for the antisense strand of this disclosure. In some embodiments, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28). In some embodiments, the positive sense strand is the positive sense strand of any one of siRNA1–siRNA3 shown in Table 1; in some embodiments, the positive sense strand is the positive sense strand of any one of conjugates 1–conjugates 5 shown in Table 2. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides, are fluorinated nucleotides in the direction from the 3' end to the 5' end; the first and / or last nucleotide of the sense strand is an alkoxylated nucleotide or a reverse debased deoxynucleotide; and the nucleotides at the remaining positions are each independently alkoxylated nucleotides; and each of 1-4 linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand, is independently a phosphate ester group with a modifying group. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, from the 3' end to the 5' end, the 11th-13th nucleotides are fluorinated nucleotides, the 1st nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, and the remaining nucleotides are each independently alkoxylated nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand, are each independently phosphate groups with a modifying group; in the antisense strand, from the 5' end... In the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, and the 2nd, 6th and 16th nucleotides are fluorinated nucleotides. Each of the remaining nucleotides in the antisense strand is independently an alkoxy-modified nucleotide. The linking group between any two adjacent nucleotides in the 5' end of the first to third nucleotides and between any two adjacent nucleotides in the 3' end of the first to third nucleotides are independently phosphate groups with modifying groups. The 5' end nucleotide of the antisense strand is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate-modified nucleotide of formula (31). In some embodiments, the linking group between every two adjacent nucleotides in the 1-2, 1-3, 1-4, or 1-5 nucleotides at the 5' and / or 3' ends of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the linking group between every two adjacent nucleotides in the 1-3, 1-4, or 1-5 nucleotides at the 5' end of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the linking group between two adjacent nucleotides in the 1-2, 1-3, 1-4, or 1-5 nucleotides at the 3' end of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the phosphate ester group with the modifying group is a thiophosphate ester group with the structure shown in formula (28), and the alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises 19 nucleotides in the sense strand and 21 nucleotides in the antisense strand; in the sense strand, from the 3' end to the 5' end, the 11th to 13th nucleotides are fluorinated nucleotides, the first nucleotide is a reverse debased deoxynucleotide, and the nucleotides at the remaining positions are each independently methoxylated nucleotides; the linking group between adjacent nucleotides in the 1st to 5th nucleotides at the 5' end of the sense strand is a thiophosphate group. In some embodiments, in the double-stranded oligonucleotide of this disclosure, the sense strand comprises 19 nucleotides and the antisense strand comprises 21 nucleotides; in the sense strand, nucleotides 11-13 are fluorinated nucleotides in the direction from the 3' end to the 5' end, the first nucleotide is a reverse debased deoxynucleotide, and the remaining nucleotides are each independently methoxylated nucleotides; in the sense strand, each of the 1-4 linking groups between adjacent nucleotides in the 5' end of the first-5 nucleotides is independently a phosphate thioate group; in the antisense strand, nucleotide 13 is a 2'-O The antisense chain is a methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, and the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides. Each of the remaining nucleotides in the antisense chain is independently a methoxy modified nucleotide. In the antisense chain, the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end are thiophosphate groups. The 5' terminal nucleotide of the antisense chain is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). The double-stranded oligonucleotides disclosed herein, through the aforementioned modification scheme, achieve a favorable balance between AGT mRNA regulatory activity and in vivo stability. In the context of this disclosure, "modification scheme" refers to a combination of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications of different numbers, positions, and types that are unrelated to or weakly related to a specific sequence. In some embodiments, the double-stranded oligonucleotides of this disclosure, through the aforementioned modification scheme, can maintain excellent stability without significantly reducing the original pharmacological activity of the double-stranded oligonucleotides, thereby achieving a favorable balance between AGT mRNA regulatory activity and in vivo stability. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises a substantially anticomplementary or completely anticomplementary double-stranded region, and one or two dangling ends of the sense strand and / or one or two dangling ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises a substantially anticomplementary or completely anticomplementary double-stranded region and one dangling end of the antisense strand. In some embodiments, the double-stranded region formed by the sense and antisense strands contains at least 16 base pairs. In some embodiments, the double-stranded region formed by the sense and antisense strands contains 16-23 base pairs. In some embodiments, the double-stranded region formed by the sense and antisense strands contains 18, 19, 20, or 21 base pairs. In the context of this disclosure, a "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences comprising all base pairs on each of the single strands of a double-stranded nucleic acid structure. Therefore, a double-stranded region consists of all base pairs in the double-stranded nucleic acid structure and all base mismatches between those base pairs. In some embodiments, the number of base mismatches does not exceed 20%, 15%, 10%, or 5% of the total number of base pairs forming the double-stranded region. In some embodiments, the number of base mismatches in the double-stranded region does not exceed 3, 2, or 1. In some embodiments, the double-stranded nucleic acid structure includes a double-stranded region and one or more overhanging ends consisting of nucleotides that have not formed base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only a double-stranded region. In some embodiments, the sense and antisense strands form a double-stranded region spanning at least 16 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains at least 16 base pairs. In the context of this disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense and antisense strands form a double-stranded region spanning 16-23 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains 16-23 base pairs. In some embodiments, the sense and antisense strands form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains 18, 19, 20, or 21 base pairs. In some embodiments, the sense and antisense strands are substantially anticomplementary or completely anticomplementary within the double-stranded region. In some embodiments, the sense and antisense strands of the double-stranded oligonucleotides of this disclosure are substantially anticomplementary or completely anticomplementary over their entire nucleotide length. In some embodiments, the sense strand and the antisense strand are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary. In some embodiments, the sense strand and the antisense strand are substantially anticomplementary or completely anticomplementary within the double-stranded region. In some embodiments, along the 5'-3' direction, at least the nucleotide sequence of the sense strand other than the first and last positions is substantially anticomplementary or completely anticomplementary to the antisense strand. In some embodiments, along the 5'-3' direction, the nucleotide sequence of the sense strand other than the last position is completely anticomplementary to the antisense strand; or all nucleotides of the sense strand are completely anticomplementary to the antisense strand. In some embodiments, the double-stranded oligonucleotides described in this disclosure include an unmodified equivalent sequence of the positive strand comprising a nucleotide sequence of the same length as nucleotide sequence m, and having a difference of no more than 3 bases, no more than 1 base, or no base difference, wherein the definition and selection of nucleotide sequence m are as described above. In the preceding and following text, "unmodified equivalent sequence" refers to an oligonucleotide sequence that does not contain any ribose ring modifications, base modifications, or phosphate backbone modifications compared to the original sequence used as the basis for alignment. For example, the unmodified equivalent sequence of VPAmsCfsdTGmsUmia is ACUGUN, where N is A, C, G, or U. In the preceding and following text, a "base difference" between two nucleotide sequences refers to a change in the type of bases at the same position of the nucleotides compared to the latter. For example, if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, then a base difference exists between the two nucleotide sequences at that position. When bases are modified, as long as the purine-pyrimidine pairing relationship for forming the aforementioned double-stranded nucleic acid structure is not affected, it is also considered that there is no base difference between the modified base and the original base. In some embodiments, it is considered that there is no base difference between U and T. In some embodiments, it is considered that there is no base difference between C and 5-methylcytosine (5mC). In some embodiments, it is also considered that a base difference has occurred at that position when a baseless nucleotide or its equivalent is replaced with a nucleotide at the original position. When comparing two nucleotide sequences to determine the number of base differences, alignment is performed in the manner with the fewest base differences among all alignment methods, and the base differences are determined based on this alignment method. In this context, "identical positions" refers to the corresponding positions between two nucleotide sequences in that alignment. For example, when nucleotide sequences A (positions 1-5) are aligned with nucleotide sequences B (positions 2-6) in the same direction, the number of base differences is minimized compared to other alignment methods. In this case, "identical positions" means that position 1 of nucleotide sequence A is aligned with position 2 of nucleotide sequence B, position 2 of nucleotide sequence A is aligned with position 3 of nucleotide sequence B, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths refers to the number of base differences calculated from the first nucleotide without a base difference to the last nucleotide without a base difference in the alignment with the minimum number of base differences. In some embodiments, the number of base differences between two nucleotide sequences of the same length refers to the total number of base differences between the first to last nucleotides of one nucleotide sequence and the first to last nucleotides of the other nucleotide sequence, in the same direction. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths means that, in the same direction, there are no base differences between the first to last nucleotides of the shorter nucleotide sequence and each nucleotide at the same position in the other nucleotide sequence. In some embodiments, the absence of base differences between two nucleotide sequences of the same length means that, in the same direction, there are no base differences between the first to last nucleotides of one nucleotide sequence and the first to last nucleotides of the other nucleotide sequence. The double-stranded oligonucleotide disclosed herein can be any double-stranded oligonucleotide that regulates AGT mRNA expression. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or downregulates AGT mRNA expression, such as siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or upregulates AGT mRNA expression, for example, saRNA. In some embodiments, the double-stranded oligonucleotide is siRNA. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises a sense strand and an antisense strand, wherein the sense strand contains nucleotide sequence I and the antisense strand contains nucleotide sequence II, wherein nucleotide sequence I is of the same length as the nucleotide sequence shown in SEQ ID NO:1 and differs from it by no more than 3 bases, and nucleotide sequence II is of the same length as the nucleotide sequence shown in SEQ ID NO:2 and differs from it by no more than 3 bases. 5'-GUUUCUCCUUGGUCUAAGZ1-3' (SEQ ID NO: 1); 5'-Z2CUUAGACCAAGGAGAAAC-3'(SEQ ID NO:2), Wherein, Z1 is U, A or ia, Z2 is A or U, the nucleotide sequence I contains nucleotide Z3 corresponding to Z1, the nucleotide sequence II contains nucleotide Z4 corresponding to Z2, and Z4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, the nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO:1 by no more than one base, and / or the nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one base. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 may include a difference at the Z3 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 may include a base difference at the Z3 position and / or a base difference at a nucleotide position adjacent to Z3. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 is a base difference at the Z3 position; preferably, Z3 is a reverse debased deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 includes a difference at the Z4 position, where Z4 is selected from C or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 is a difference at the Z4 position, where Z4 is selected from C or G. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to AGT mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I; or, a base mismatch exists between the second nucleotide of nucleotide sequence II and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high AGT mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide in length, oriented from 5' to 3', with C as the base of sequence III and G as the base of sequence IV; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides in length, with CC as the base composition of sequence III and GG as the base composition of sequence IV, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being GCC and that of nucleotide sequence IV being GGC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being AGCC and that of nucleotide sequence IV being GGCU, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being CC and that of nucleotide sequence IV being GG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GG or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2, nucleotide sequence I consists of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is GG in the direction from the 5' end to the 3' end. In some embodiments, the sense and antisense strands of the double-stranded oligonucleotide are of equal length to the sense and antisense strands of one of siRNAa1, siRNAa2, siRNAa3, and siRNAa4 shown in Table 1 below, and the number of base differences is no more than 3, no more than 1, or there are no base differences. In some embodiments, the double-stranded oligonucleotide is one of siRNAa1, siRNAa2, siRNAa3, and siRNAa4 shown in Table 1 below: Table 1. siRNA sequences disclosed herein. In this context, uppercase letters C, G, U, A, and T represent the base composition of a nucleotide; lowercase letter o indicates that the uppercase letter to the left of o represents an alkoxy-modified nucleotide; lowercase letter f indicates that the uppercase letter to the left of f represents a fluorinated nucleotide; uppercase letter combinations enclosed in parentheses (NS) indicate that the uppercase letter to the left of s represents a substituted alkoxy-modified nucleotide N, where N is C, G, U, A, or T; lowercase letter s indicates that the two uppercase letters to the left and right of s, or the closest uppercase letters to the left and right of s, are linked by phosphate thioester groups to the nucleotide represented by ia. ia represents a reverse debased deoxynucleotide; each lowercase x independently indicates that the nucleotides represented by the two uppercase letters to its left and right are linked by a thiophosphate group or a phosphate group; the lowercase d indicates that the nucleotide represented by the uppercase letter to its right is a deoxyribonucleotide; P1 indicates that the nucleotide represented by the uppercase letter to its right is a 5'-hydroxynucleotide or a 5'-vinyl phosphate (VP) modified nucleotide; ia represents a reverse debased deoxynucleotide; and each U in the above sequence can be replaced by T, and / or each C can be replaced by 5mC, which substitution does not significantly reduce the gene expression regulatory activity and / or off-target effect inhibition ability of the double-stranded oligonucleotide. In some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide is a 2'-O-methoxyethyl-modified nucleotide represented by moe. In some embodiments, each P1 is independently a 5'-hydroxynucleotide or a 5'-vinyl phosphate (E-VP) modified nucleotide. In some implementations, each lowercase 'x' independently represents a phosphate thioester linkage between the nucleotides represented by the two uppercase letters to its left and right. In some implementations, each 'N' independently represents a 'G'. The antisense and / or double-stranded oligonucleotides provided in this disclosure can be obtained using conventional oligonucleotide preparation methods in the art (e.g., solid-phase synthesis and liquid-phase synthesis). Solid-phase synthesis is already available as a commercially available custom service. Modified nucleotide groups can be introduced into the antisense and / or double-stranded oligonucleotides described in this disclosure using appropriately modified nucleoside monomers. Methods for preparing appropriately modified nucleoside monomers and for introducing modified nucleotide groups into antisense and / or double-stranded oligonucleotides are also well known to those skilled in the art. All modified nucleoside monomers are commercially available or prepared using known methods. The single-stranded oligonucleotides and double-stranded oligonucleotides provided in this disclosure can be used alone, or in combination with a pharmaceutically acceptable carrier to form a pharmaceutical composition, or in combination with a delivery group to form an oligonucleotide conjugate, or in any other suitable form. Contacting cells with an effective amount of the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate can regulate AGT mRNA expression, or administering an effective amount of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition to a subject can regulate AGT mRNA expression, thereby achieving the purpose of treating pathological conditions or diseases associated with AGT mRNA expression levels. Oligonucleotide conjugates In another aspect, this disclosure provides an oligonucleotide conjugate comprising a double-stranded oligonucleotide group and a delivery group conjugated to the double-stranded oligonucleotide group, the double-stranded oligonucleotide group being independently formed by removing one or more atoms or groups of atoms from a double-stranded oligonucleotide provided in this disclosure. An oligonucleotide group, such as an siRNA group, refers to a chemical portion formed by removing one or more atoms or groups of atoms from a single-stranded or double-stranded oligonucleotide (e.g., siRNA) molecule. Those skilled in the art will understand that the RNAi activity of the oligonucleotide group formed by this removal is at least the same as or equivalent to the RNAi activity of the single-stranded or double-stranded oligonucleotide itself. In some embodiments, the removal of one or more atoms or groups of atoms does not impair the inhibitory activity or stability of the oligonucleotide (e.g., siRNA) against the target mRNA. In some embodiments, the oligonucleotide group is formed by removing one atom or group of atoms (e.g., a hydrogen atom, a hydroxyl group, or a phosphate ester group) from a single-stranded or double-stranded oligonucleotide provided in this disclosure. For example, the siRNA group can be a chemical part formed by removing hydrogen atoms from the phosphate ester bond of siRNA, or a chemical part formed by removing hydrogen atoms from the 5' hydroxyl group of the 5' terminal nucleotide of the sense or antisense strand of siRNA, or a chemical part formed by removing hydrogen atoms from the 3' hydroxyl group of the 3' terminal nucleotide of the sense or antisense strand of siRNA. In the context of this disclosure, unless otherwise stated, "conjugation" means the covalent connection between two or more chemical parts, each having a specific function (however, without theoretical limitation, the individual components within the functional chemical part—such as a double-stranded oligonucleotide or a metal ion-ligand chelate—may not necessarily be covalently connected); correspondingly, "conjugation" refers to a compound formed by the covalent connection of the individual chemical parts. Further, "oligonucleotide conjugation" refers to a compound formed by the covalent attachment of one or more functional chemical parts to an oligonucleotide. Oligonucleotide conjugation should be understood, depending on the context, as a collective term for multiple oligonucleotide conjugations or an oligonucleotide conjugation represented by a particular chemical formula. In the context of this disclosure, "conjugated molecule" should be understood as a specific compound that can be reactively conjugated to an oligonucleotide to ultimately form the oligonucleotide conjugation of this disclosure. The delivery group is a group for delivering a single-stranded or double-stranded oligonucleotide group into cells expressing AGT mRNA. In some embodiments, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the single-stranded or double-stranded oligonucleotide group, the linker group, and the targeting group are covalently or non-covalently linked in sequence, each of the targeting groups being selected from ligands capable of binding to receptors on the surface of hepatocytes or groups capable of increasing tissue compatibility. In some embodiments, the targeting group targets the liver. In some embodiments, at least one or each targeting group is independently selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, the number of targeting groups is 1-6. In one embodiment, the number of targeting groups is 2-4. The oligonucleotide group can be non-covalently or covalently conjugated to the delivery group, for example, it can be covalently conjugated to the delivery group. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the conjugation site between the double-stranded oligonucleotide group and the delivery group can be at the 3' or 5' end of the sense strand of the double-stranded oligonucleotide, at the 5' end of the antisense strand, or within the internal sequence of the double-stranded oligonucleotide. In some embodiments, the conjugation site between the double-stranded oligonucleotide group and the delivery group is at the 3' end of the sense strand of the double-stranded oligonucleotide. In some embodiments, the delivery group can be attached to any position on the nucleotide, such as a phosphate group, a 2', 3', or 5'-hydroxyl group of the ribose, or a base. When the delivery group is attached to the 3' or 5' end of the positive strand of a single-stranded or double-stranded oligonucleotide, the delivery group is typically attached to the oxygen atom formed by removing a hydrogen atom from the 3' or 5'-hydroxyl group of the nucleotide; when the delivery group is attached to the inner sequence of a single-stranded or double-stranded oligonucleotide, the delivery group is typically attached to a phosphate group, a ribose ring, or a base. In some embodiments, the delivery group can be attached to the 3'-hydroxyl group of an inner sequence nucleotide of a single-stranded or double-stranded oligonucleotide, in which case the nucleotides are linked by a 2'-5' phosphodiester bond. Various connection methods can be found in the following non-patent literature: Muthiah Manoharan et al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5): 1181-7. The entire contents of this article are incorporated herein by reference. In some embodiments, the oligonucleotide and the delivery group are linked by acid-labile or reducible chemical bonds that can degrade in the acidic environment of the endosome, thereby converting the oligonucleotide group into a free oligonucleotide. For non-degradable conjugations, the delivery group can be attached to the positive and negative strands of a single-stranded or double-stranded oligonucleotide group to minimize the impact of the conjugation on the activity of the single-stranded or double-stranded oligonucleotide group. The targeting group can be linked to the oligonucleotide group via a suitable linker. Those skilled in the art can select a suitable linker based on the specific type of the targeting group. For example, when the targeting group is a group that targets receptors on the surface of hepatocytes, the types of these linkers, the types of targeting groups, and the way they are linked to the oligonucleotide can be found in the disclosure of WO2015006740A2, the entire disclosure of which is incorporated herein by reference. In some embodiments, the targeting group may be a ligand commonly used in the field of double-stranded oligonucleotide drug delivery, such as the various ligands described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of the target groups is selected from ligands capable of binding to cell surface receptors expressing AGT mRNA. In some embodiments, at least one or each of the target groups is selected from small molecule ligand groups capable of affinity for desialylate glycoprotein receptors on the surface of hepatocytes. In some embodiments, at least one or each of the target groups is selected from any ligand capable of binding to cell surface receptors of cells expressing AGT mRNA. In some embodiments, each of the target groups is independently a ligand with affinity for desialyl glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, each of the target groups is independently a desialyl glycoprotein or a sugar. In some embodiments, each of the target groups is independently selected from D-mannose, L-mannose, D-arabinose, D-xylfuranose, L-xylfuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannose, β-D-mannose, α-D-mannose, β-D-mannose, α-D-glucose, β-D-glucose, α-D-glucose, β-D-glucose. α-D-Furfural, β-D-Furfural, α-D-Fructose, α-D-Galactopyranose, α-D-Galactopyranose, β-D-Galactopyranose, α-D-Galactopyranose, β-D-Galactopyranose, Glucosamine, Sialic acid, Galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-butyrylgalactosamine, N-isobutyrylgalactosamine, 2 -Amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfonamido-D-glucopyranose, N-ethanolyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4 One of the following: tri-O-acetyl-1-thio-6-O-triphenylmethyl-α-D-glucopyranoside methyl ester, 4-thio-β-D-galactopyranose, 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucopyranoside ethyl ester, 2,5-dehydrated-D-alosulfonyl, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose. In some embodiments, at least one or each of the target groups is galactose or N-acetylgalactosamine. In some embodiments, the double-stranded oligonucleotide group is capable of regulating the expression level of AGT mRNA in hepatocytes. The delivery group in the oligonucleotide conjugates disclosed herein can be any of the various delivery groups known to those skilled in the art of oligonucleotide pharmaceuticals. In some embodiments, the linker group in the oligonucleotide conjugate of this disclosure has a structure as shown in formula (301): Where k is an integer from 1 to 5, Indicates the site of covalent linkage of groups; all L A Connect to L C The same atom in; or, each L A Independently connected to L C Different atoms in it. In some implementations, L C It has -NH-C(H) n301 (CH2O-) k The structure shown is such that k is an integer from 1 to 3, and n301 = 3 - k; L B The length is 5-20 atoms. In some implementations, each L A Independently, it is a straight-chain alkylene group with a length of 5-20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, 1,2,3-triazole subunit, succinimide subunit. In some implementations, L A Having a structure containing amide bonds as shown in formula (302), L B It has a structure as shown in equation (303): Where, n 302 q 302 and p 302 Each is an independent integer from 2 to 6; optionally, n 302 q 302 and p 302 Each can be 2 or 3 independently; n 303 n is an integer between 4 and 16, optionally n 303 For integers between 8 and 12, This indicates the site where the group is covalently linked. In some embodiments, the linking group has a structure as shown in formula (304) or formula (305): In the linking group, each L A Each of the target groups is connected via an ether bond and via L C The oxygen atom of the hydroxyl group in some of the middle groups is related to L. C Partially linked by ether bonds; L B Through the carbonyl group in formula (303) and L CThe nitrogen atom of the amino group in some of them forms an amide bond and is connected to the double-stranded oligonucleotide group through the oxygen atom in formula (303) by forming a phosphate ester bond or a thiophosphate ester bond. In some embodiments, the oligonucleotide conjugates provided in this disclosure have a structure as shown in formula (305A): Wherein, Nu represents an oligonucleotide group formed from single-stranded or double-stranded oligonucleotides provided in this disclosure. In some embodiments, the linker group in the oligonucleotide conjugate of this disclosure has the structure shown in formula (306): Where, n 306 For each p, the integer is between 0 and 3. 306 Independently, integers from 1 to 6. The site indicates a covalently linked group; the linking group is connected to the target group by an ether bond formed by an oxygen atom marked with *; the linking group is connected to the double-stranded oligonucleotide by at least one of the oxygen atoms marked with # forming a phosphate ester bond or a thiophosphate ester bond, and the remaining oxygen atoms marked with # are connected to hydrogen atoms to form hydroxyl groups, or connected to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugates of this disclosure have a structure as shown in formula (307): Wherein, Nu represents an oligonucleotide group formed from single-stranded or double-stranded oligonucleotides provided in this disclosure. In some embodiments, the oligonucleotide conjugates of this disclosure have the structure shown in formula (308): in, n 308 The integers are selected from 2 to 4; Each m 308 Independently selected as an integer from 2 to 5; Each R 308 Independently, it can be a hydrogen atom, a methyl group, or an ethyl group, or two R atoms attached to the same carbon atom. 308 Together with this carbon atom, they form a carbonyl group; One of the groups independently represented by A0 is an oligonucleotide group, which is a group formed by removing an atom or group of atoms from a single-stranded or double-stranded oligonucleotide as described in this disclosure; the remaining A0s are independently target groups, and each target group may be the same or different, and their definition and selection range are as described above. In some embodiments, each target group is independently selected from a ligand that has an affinity for the desialylate glycoprotein receptor on the surface of mammalian hepatocytes. Each L1 is independently a divalent linker with a length of 1-70 atoms; This indicates the site where the group is covalently linked. In some embodiments, each L1 is independently a straight-chain alkylene group with a length of 1-70 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenyl, C2-C 10 Ethyne group, C6-C 10 Aromatic, C3-C 18 Heterocyclic groups and C5-C 10 Heteroaryl; and the linear alkylene group may optionally have substituents of any one or more of the group consisting of: C1-C 10 Alkyl, C6-C 10 Aryl, C5-C 10 heteroaryl, C1-C 10 Halogenated alkyl, -OC1-C 10 Alkyl, OC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-OH, -OC1-C 10 Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10 Alkyl) (C1-C 10 alkyl), -NH(C1-C 10 Alkyl), N(C1-C) 10 Alkyl) (C1-C 10 alkylphenyl), NH(C1-C 10 Alkylphenyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 Alkyl), -CON (C1-C) 10 Alkyl) (C1-C 10 Alkyl), -CONH (C1-C) 10 Alkyl groups, -CONH2, -NHC(O) (C1-C) 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10Alkyl)C(O)(C1-C 10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (Halogenated alkyl groups). Those skilled in the art will understand that, although for convenience, L1 is defined as a linking group formed by substitution or substitution of a linear alkylene group, it may not be a linear group or may have a different name, such as an amine or alkenyl group resulting from the aforementioned substitution and / or substitution. Unless otherwise stated, in the chemical structural formulas described in this disclosure, the “length” of any group refers to the number of atoms in the longest atomic chain of that group, excluding hydrogen atoms; in the calculation of group length, when multiple connections are involved between two atoms (e.g., two atoms belong to the same cyclic group, and thus at least two atomic chains contain the two atoms), the length is calculated according to the shortest atomic chain between the two atoms. For example, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4-phenylene, and 1,4-piperazindiyl are all calculated as having a length of 4 atoms, while 1,2-cyclopentadiyl is calculated as having a length of only 2 atoms. The function of L1, covalently linked to A0 representing the oligonucleotide group, is to covalently link the oligonucleotide group to the target group. This allows the oligonucleotide conjugate containing the oligonucleotide group to enter the cell expressing mRNA through the targeting effect of the target group, without affecting the regulatory effect of the oligonucleotide group on AGT mRNA levels after entering the cell. Therefore, in some embodiments, the length of L1 covalently linked to A0 representing the oligonucleotide group is 3-20 atoms, 4-15 atoms, or 5-12 atoms. In some embodiments, L1 covalently linked to A0 representing the oligonucleotide group is selected from one or more of A1, A2, A4, A5, A10, A16, A18, and A19, combined with a phosphate ester group or a modified phosphate ester group. Where j1 is an integer between 2 and 10; This indicates the site where the group is covalently linked. In some embodiments, R2 is selected from at least two of A1, A2, A4, A10 and A16 connected with a phosphate ester group or a modified phosphate ester group; in some embodiments, R2 is selected from at least two of A1, A2, A10 connected with a phosphate ester group or a modified phosphate ester group. In some embodiments, L1, covalently linked to A0 representing an oligonucleotide group, has a structure as shown in formulas (B1), (B2), (B3), or (B4): in, L represents the site where groups are covalently linked. B1 and L B2 Whether identical or different, independently selected from one of the following groups or any combination thereof: -(CH2) q1 -、-CH(OH)-、-CH(CH2OH)-、-NH-、-O-、-S-、1,4-cyclohexanediyl、1,4-piperidinidyl、1,4-phenylene、1,4-piperazinidyl、pyrrolidinediyl、where q1 is an integer from 1 to 6, L B1 and L B2 The length of each is independently 1-20 atoms. In some embodiments, L B1 and L B2 The length of each is independently 1-10 atoms. In some embodiments, L B1 and L B2 The length of each atom is 1-6 atoms. L B3 A group selected from phosphate ester groups, thiophosphate ester groups, and dithiophosphate ester groups is covalently linked to the 5' hydroxyl group at the 5' position of the ribose of the sense or antisense strand of the double-stranded oligonucleotide group, or the oxygen atom remaining after removing one hydrogen atom from the 3' hydroxyl group at the 3' position of the ribose of the 3' terminal nucleotide. In some embodiments, L B3 It is a phosphate ester group, covalently linked to the 5' hydroxyl group of the ribose at the 5' end of the positive strand of the double-stranded oligonucleotide group, or the oxygen atom remaining after removing one hydrogen atom from the 3' hydroxyl group of the ribose at the 3' end of the positive strand of the double-stranded oligonucleotide group. In some embodiments, when the oligonucleotide conjugates of this disclosure are prepared by a solid-phase synthesis process, L1, covalently linked to A0 representing an oligonucleotide group, needs to simultaneously contain a linking site for N-linking on a nitrogen-containing backbone, a linking site for linking to an oligonucleotide group, and a functional group capable of linking to a solid-phase support. In some embodiments, the N-linking site on the nitrogen-containing backbone in L1, covalently linked to A0 representing an oligonucleotide group, forms an amide bond with N, is covalently linked to the oligonucleotide group via a phosphate ester bond, and the functional group capable of linking to the solid-phase support is a hydroxyl or amino group. In some embodiments, R2 is B5, B6, B5', or B6'. in, This indicates the site where a group is covalently bonded. The value of q2 can be an integer from 1 to 10. In some implementations, q2 is an integer from 1 to 5. The function of L1 covalently linked to A0, representing the target group, is to position the target group in a suitable spatial location, thereby better binding to receptors on the surface of mammalian hepatocytes, and thus specifically targeting and entering the hepatocytes. Therefore, any L1 covalently linked to A0, representing the target group, can be used in this disclosure as long as it has an appropriate length and its chemical properties do not significantly affect delivery. In some embodiments, each L1 covalently linked to A0, representing the target group, is independently a divalent linker with a length of 3-25 atoms. In some embodiments, each L1 covalently linked to A0, representing the target group, has a length of 4-15 atoms. In some embodiments, each L1 covalently linked to A0, representing the target group, has a length of 5-10 atoms. In some embodiments, the length of each L1 covalently linked to A0, representing the target group, is the same. In some embodiments, each L1 covalently linked to A0 representing a target group may be the same or different, and is independently selected from the group consisting of the groups represented by formulas (L3)-(L18) and any combination thereof: Where each j1 is an integer from 2 to 10; each R' is independently a hydrogen atom or a C1-C3 alkyl group. This indicates the site where the group is covalently linked. For ease of synthesis and / or chemical stability, in some embodiments, each L1 covalently linked to A0 representing a target group is independently a combination of at least two linking units, each linking unit independently having a structure shown in any one of formulas (L3)-(L7). In some embodiments, each linking unit independently has a structure shown in any one of formulas (L3), (L4), and (L7). For ease of synthesis, in some embodiments, each L1 covalently linked to A0 representing a target group includes a carbonyl group bonded to a nitrogen atom shown in formula (308). In some embodiments, each L1 covalently linked to A0 representing a target group independently has the structure shown in formula (L20) or (L21): Where j2 is an integer from 4 to 9, and j3 is 1 or 2. In some embodiments, j2 is 5, 6, or 7, and j3 is 1. In some embodiments, each L1 covalently linked to A0 representing the target group is identical. In the conjugates disclosed herein, the number of targeting groups and the spacing between them are the number and spacing that provide a suitable spatial configuration of multiple targeting groups. For this purpose, n308 and each m308 are independently integers selected from 2 to 4. In some embodiments, n308 is 3 or 4, so that the number of targeting groups in the conjugates of this disclosure is 3 or 4, which enables better binding to hepatocyte surface receptors. In some embodiments, n308 is 3, and each m308 is independently 3 or 4. Those skilled in the art will understand that each R 308 When the individual atoms are hydrogen atoms, methyl groups, or ethyl groups, the delivery effect of the oligonucleotide conjugate is not affected, and the objectives of this disclosure can still be achieved. In some embodiments, for ease of synthesis, each R... 308 Each is an independent hydrogen atom. In the conjugates disclosed herein, each targeting group may be the same or different, and is independently selected from a ligand having an affinity for a receptor on the surface of mammalian hepatocytes. In some embodiments, at least one or each targeting group is a ligand having an affinity for the desialylate glycoprotein receptor (ASGPR) on the surface of mammalian hepatocytes. In some embodiments, each targeting group is a galactose group or an N-acetylgalactosamine group formed by removing an atom or group from galactose or N-acetylgalactosamine (GalNAc). In some embodiments, the oligonucleotide conjugates of this disclosure have the structures shown in formulas (403), (404), (405), (406), (407), (408), (409), (410), (411), (412), (413), (414), (415), (416), (417), (418), (419), (420), (421), or (422): Wherein, Nu represents an oligonucleotide group, such as a single-stranded oligonucleotide group or a double-stranded oligonucleotide group formed from a single-stranded oligonucleotide or a double-stranded oligonucleotide provided in this disclosure. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom shown in the above structural formula is covalently linked to the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group. In some embodiments, the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group is a reverse debased deoxynucleotide, and the P atom shown in the above structural formula is covalently linked to the double-stranded oligonucleotide group by substituting a hydrogen atom in the hydroxyl group of the 3' terminal reverse debased deoxynucleotide of the positive strand of the double-stranded oligonucleotide group represented by Nu, which is connected to the ribose ring via a methylene group. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom remaining after removing one hydrogen atom from the 3' position hydroxyl group of the ribose ring of the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group represented by Nu. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom of the reverse debased deoxynucleotide ia (as shown in formula (35)) at the 3' end of the positive strand of the siRNA represented by Nu, thereby covalently linking it to the positive strand of the siRNA. In some embodiments, the oligonucleotide conjugate of this disclosure has the structure shown in formula (403). In some embodiments, the oligonucleotide conjugates of this disclosure may contain siRNA groups formed by removing an atom or group of atoms from siRNA; in this case, the oligonucleotide conjugates of this disclosure are also referred to as siRNA conjugates. In some embodiments, the double-stranded oligonucleotide groups contained in the oligonucleotide conjugates of this disclosure may be siRNA groups formed from, for example, the siRNAs listed in Table 1. siRNA conjugates containing these siRNA groups exhibit excellent stability and high AGT mRNA inhibitory activity. In this context, an siRNA group refers to a chemical portion formed by removing one or more atoms or groups of atoms from an siRNA molecule. Those skilled in the art will understand that the RNAi activity of the siRNA group formed by this removal is at least the same as or equivalent to that of the siRNA itself. In some embodiments, the removal of one or more atoms or groups of atoms does not impair the inhibitory activity or stability of the siRNA against the target mRNA. In some embodiments, the siRNA group is a group formed by removing one atom or group of atoms (e.g., a hydrogen atom, a hydroxyl group, or a phosphate ester group) from the siRNA provided in this disclosure. For example, the siRNA group may be a chemical portion formed by removing a hydrogen atom from a phosphate ester bond in the siRNA, or a chemical portion formed by removing a hydrogen atom from the 5' hydroxyl group of the 5' terminal nucleotide of the sense or antisense strand in the siRNA, or a chemical portion formed by removing a hydrogen atom from the 3' hydroxyl group of the 3' terminal nucleotide of the sense or antisense strand in the siRNA. This disclosure relates to the preparation of oligonucleotide conjugates. Those skilled in the art can prepare the oligonucleotide conjugates described herein using various suitable methods. For example, by solid-phase synthesis, when linking nucleoside monomers one by one according to the sequence and modification scheme of the sense and antisense strands of the double-stranded oligonucleotides described herein, a delivery group can be introduced using methods already described in detail in the prior art to synthesize the oligonucleotide conjugates described herein. For example, WO2015006740A2 describes in detail various methods for preparing oligonucleotide conjugates. When the double-stranded oligonucleotide is siRNA, the oligonucleotide conjugates of this disclosure can also be obtained using methods well known to those skilled in the art. For example, WO2014025805A1 describes a method for preparing the structure shown in formula (305A), and Rajeev et al. describe a method for preparing the structure shown in formula (307) in ChemBioChem 2015, 16, 903-908. Chinese patent application CN110959011A also discloses in detail a method for preparing the oligonucleotide conjugate shown in formula (308). The contents of the above-mentioned documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts In another aspect, this disclosure also provides pharmaceutically acceptable salts of the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described herein. Pharmaceutically acceptable salts are known to those skilled in the art. By forming salts, the pharmaceutically acceptable salts of the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described herein may exhibit better solubility, bioavailability, or stability than the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates themselves. In some embodiments, in the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described in this disclosure, each adjacent nucleotide is linked by a phosphodiester bond or a phosphothiodiester bond. The non-bridging oxygen or sulfur atom in the phosphodiester bond or phosphothiodiester bond carries a negative charge and can exist in the form of a hydroxyl or mercapto group. The hydrogen ion in the hydroxyl or mercapto group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, ammonium ion (NH4+). + The delivery group may contain one of the organic ammonium cations. Further, the delivery group may also contain a salt-forming group, such as a phosphate group. For the purpose of improving solubility and / or bioavailability, in some embodiments, the pharmaceutically acceptable salt is a partial or complete water-soluble salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the water-soluble salt may be one or more of an amine salt, an alkali metal salt, or an alkaline earth metal salt. In some embodiments, the amine salt is selected from one or more of ammonium salts, methylamine salts, tertiary amine salts, and quaternary ammonium salts; the alkali metal salt is selected from potassium or sodium salts; and the alkaline earth metal salt is selected from calcium or magnesium salts. In some embodiments, the tertiary amine salt is one or more of triethylamine salt, triisopropylamine salt, or N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a mixture of the methylamine salt and the ammonium salt of the double-stranded oligonucleotide or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a sodium salt or a partial sodium salt of the double-stranded oligonucleotide or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a salt or a partial salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate, wherein the salt or partial salt is one or more of sodium, calcium, and magnesium salts. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a calcium salt or a partial calcium salt of the double-stranded oligonucleotide or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate, wherein the salt is one or more of methylamine, triethylamine, sodium, or calcium salts. Pharmaceutical Composition In another aspect, this disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and pharmaceutically acceptable salts provided in this disclosure, and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are one or more of the various components commonly used in the art, such as solvents, protectants, osmotic pressure regulators, and one or more other pharmaceutically acceptable carriers. For example, when the pharmaceutical composition is an injection, the pharmaceutically acceptable excipient is a solvent, such as deionized water, water for injection, physiological saline, ethanol, aqueous ethanol solution, or a pH buffer. The pH buffer may be a tris(hydroxymethyl)aminomethane hydrochloride buffer with a pH of 7.5-8.5 and / or a phosphate buffer with a pH of 5.5-8.5, for example, a phosphate buffer with a pH of 5.5-8.5. The amount of solvent used is adjusted according to the required solution concentration. Based on the oligonucleotide groups in the double-stranded oligonucleotide, the concentration of the oligonucleotide conjugate in the injection solution can be 0.01 mg / mL-20 mg / mL, 0.1 mg / mL-10 mg / mL, or 0.5 mg / mL-5 mg / mL. The protective agent may be at least one selected from inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. Based on the total weight of the pharmaceutical composition, the content of the protective agent may be 0.01-30% by weight. The osmotic pressure regulator may be sodium chloride and / or potassium chloride. The content of the osmotic pressure regulator results in an osmotic pressure of 200-700 milliosm / kg (mOsm / kg) for the pharmaceutical composition. The content of the osmotic pressure regulator can be readily determined by those skilled in the art based on the desired osmotic pressure. In some embodiments, the dosage of the formulation made from the pharmaceutical composition may be adjusted during administration depending on the route of administration. In some embodiments, the pharmaceutical composition may be a liquid formulation, such as an injection; or it may be a lyophilized powder for injection, which is mixed with liquid excipients to form a liquid formulation for administration. The liquid formulation may be administered subcutaneously, intramuscularly, or intravenously, or may be delivered via a spray to the lungs, or via a spray to other organs (such as the liver), or orally. In some embodiments, the pharmaceutical composition is administered via subcutaneous injection. Other pharmaceutically acceptable carriers may be carriers conventionally used in the field of oligonucleotide drug delivery, such as, but not limited to, magnetic nanoparticles (e.g., Fe3O4 or Fe2O3-based nanoparticles), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&L-lactic / glycolic acid) copolymer (PLGA), and poly(2-aminoethyl ethylene) phosphate. One or more of the following: phosphate), PPEEA, and poly(2-dimethylaminoethyl methacrylate), PDMAEMA, and their derivatives. In some embodiments, there are no particular requirements for the content of oligonucleotides and pharmaceutically acceptable carriers in the pharmaceutical composition. In some embodiments, the weight ratio of oligonucleotides to pharmaceutically acceptable carriers can be 1:(1-500), and in some embodiments, the weight ratio is 1:(1-50). In some embodiments, the pharmaceutical composition may be in the form of a liposomal formulation. In some embodiments, the pharmaceutically acceptable carrier used in the liposomal formulation comprises an amine-containing transfection compound (hereinafter also referred to as an organic amine), a cofactor lipid, and / or a polyethylene glycol-modified lipid. The organic amine, cofactor lipid, and polyethylene glycol-modified lipid may be selected from one or more of the amine-containing transfection compounds or their pharmaceutically acceptable salts or derivatives, cofactor lipids, and polyethylene glycol-modified lipids described in Chinese patent application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine may be a compound of formula (201) as described in Chinese patent application CN103380113A, or a pharmaceutically acceptable salt thereof: in: X 101 and X 102 Each can be independently O, S, NA, or CA, where A is hydrogen or C1-C. 20 hydrocarbon chain; Y 101 and Z 101 Each can be independently C=O, C=S, S=O, CH-OH, or SO2; R 101 R 102 R 103 R 104 R 105 R 106 and R 107 Each is independently hydrogen, cyclic or acyclic, substituted or unsubstituted, branched or straight aliphatic group, cyclic or acyclic, substituted or unsubstituted, branched or straight heteroaliphatic group, substituted or unsubstituted, branched or straight acyl group, substituted or unsubstituted, branched or straight aryl group, substituted or unsubstituted, branched or straight heteroaryl group; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; where, if m = p = 0, then R 102 It is hydrogen; Furthermore, if at least one of n or m is 2, then R 103 The nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): In this context, g, e, and f are each an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some implementations, R 103 It is a polyamine. In other embodiments, R 103 It is a ketal. In some embodiments, R in formula (201) 101 and R 102 Each of them is independently an arbitrary substituted or unsubstituted, branched or straight-chain alkyl or alkenyl group having 3 to 20 carbon atoms, such as 8 to 18 carbon atoms, and 0 to 4 double bonds, such as 0 to 2 double bonds. In some implementations, if each of n and m independently has a value of 1 or 3, then R 103 It can be any one of the following equations (204)-(213): In equations (204)-(213), g, e, and f are each independent integers from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * indicates R.103 Possible connection points with nitrogen atoms in equation (201), wherein each H at any * position can be replaced to achieve connection with nitrogen atoms in equation (201). Those skilled in the art can obtain the compound represented by formula (201) by any reasonable method. In some embodiments, the compound represented by formula (201) can be prepared according to the description in Chinese patent application CN103380113A. In some embodiments, the organic amine is an organic amine as shown in formula (214) and / or an organic amine as shown in formula (215): The auxiliary lipid is cholesterol, cholesterol analogues and / or cholesterol derivatives; The PEGylated lipid is 1,2-dipalmitoyl-sn-glycerol-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio of the organic amine, the auxiliary lipid, and the polyethylene glycol-modified lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed from the double-stranded oligonucleotide of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, and more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm. For example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, in the pharmaceutical composition formed from the oligonucleotide or oligonucleotide conjugate of this disclosure and the aforementioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide or oligonucleotide conjugate (based on oligonucleotide groups) to all lipids (e.g., organic amines, auxiliary lipids, and / or polyethylene glycol-modified lipids) is from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:3 to about 1:20, from about 1:4 to about 1:20, from about 1:3 ...30, from about 1:3 to about 1:30, from about 1:3 to about 1:30, from The ratio of oligonucleotides or oligonucleotide conjugates (based on oligonucleotide groups) of this disclosure to total lipids is in the range of about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10. For example, the weight ratio of the oligonucleotides or oligonucleotide conjugates (based on oligonucleotide groups) of this disclosure to total lipids is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, or 1:18. In some embodiments, the components of the pharmaceutical composition may exist independently when sold, and may be in liquid form when used. In some embodiments, the pharmaceutical composition formed by the oligonucleotide or oligonucleotide conjugate provided in this disclosure and the above-described pharmaceutically acceptable carrier can be prepared according to various known methods, simply by replacing existing oligonucleotides with the oligonucleotide or oligonucleotide conjugate provided in this disclosure; in some embodiments, it can be prepared according to the following method: An organic amine, auxiliary lipid, and polyethylene glycol-modified lipid are suspended in an alcohol at the above molar ratio and mixed to obtain a lipid solution. The amount of alcohol used is such that the total mass concentration of the resulting lipid solution is 2-25 mg / mL, for example, 8-18 mg / mL. The alcohol is selected from pharmaceutically acceptable alcohols, such as alcohols that are liquid near room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400, for example, ethanol. The oligonucleotide or oligonucleotide conjugate provided in this disclosure is dissolved in a buffer salt solution to obtain an aqueous solution of the oligonucleotide or oligonucleotide conjugate. The concentration of the buffer salt solution is 0.05-0.5M, for example, 0.1-0.2M. The pH of the buffer salt solution is adjusted to 4.0-5.5, for example, 5.0-5.2. The amount of buffer salt solution used is such that the concentration of oligonucleotide groups in the oligonucleotide or oligonucleotide conjugate does not exceed 0.6 mg / mL, for example, 0.2-0.4 mg / mL. The buffer salt is selected from one or more of soluble acetate and soluble citrate, for example, sodium acetate and / or potassium acetate. The lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate are mixed, and the resulting product is incubated at 40-60°C for at least 2 minutes, for example, 5-30 minutes, to obtain the incubated liposome formulation. The volume ratio of the lipid solution to the aqueous solution of the oligonucleotide or oligonucleotide conjugate is 1:(2-5), for example, 1:4. The incubated liposome formulation is concentrated or diluted, impurities are removed, and sterilization is performed to obtain the pharmaceutical composition provided in this disclosure. Its physicochemical parameters are: pH value of 6.5-8, encapsulation efficiency of not less than 80%, particle size of 40-200 nm, polydispersity index of not more than 0.30, and osmotic pressure of 250-400 mOsm / kg; for example, the physicochemical parameters can be: pH value of 7.2-7.6, encapsulation efficiency of not less than 90%, particle size of 60-100 nm, polydispersity index of not more than 0.20, and osmotic pressure of 300-400 mOsm / kg. Concentration or dilution can be performed before, after, or simultaneously with impurity removal. Impurity removal can be achieved using various existing methods, such as ultrafiltration at 100 kDa using a tangential flow system or hollow fiber column, with the ultrafiltration exchange solution being phosphate-buffered saline (PBS) at pH 7.4. Sterilization can be achieved using various existing methods, such as filtration sterilization through a 0.22 μm filter. The use of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions disclosed herein. This disclosure also provides for the use of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein in medicaments for treating and / or preventing diseases or symptoms associated with AGT mRNA levels. In some embodiments, the diseases or symptoms associated with AGT mRNA levels are hypertension and hypertension-related diseases. This disclosure also provides a method for treating and / or preventing diseases or symptoms associated with AGT mRNA levels, the method comprising administering to a subject in need an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure. In some embodiments, the disease or symptom associated with AGT mRNA levels is hypertension and hypertension-related diseases. Furthermore, this disclosure also provides a method for regulating the expression level of AGT mRNA in cells, the method comprising contacting the cells with an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure. As used herein, the term "administration" refers to the delivery of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a subject via a method or route that at least partially targets one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a desired site to produce a desired effect. Routes of administration suitable for the methods of this disclosure include local administration and systemic administration. Generally, local administration results in the delivery of more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a specific site compared to the subject's entire body; while systemic administration results in the delivery of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to substantially the entire body of the subject. The medication may be administered to the subject via any suitable route known in the art, including but not limited to: oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and local administration (including oral and sublingual administration). Administration frequency may be once or more daily, weekly, bi-weekly, bi-weekly, monthly, or annually. The dosage of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure can be conventional in the art, and the dosage can be determined based on various parameters, particularly the age, weight, and sex of the subject. Toxicity and efficacy can be determined in cell culture or laboratory animals using standard pharmaceutical procedures, such as determining the LD50 (the dose that causes 50% of the population to die) and ED50 (the dose that elicits 50% of the maximum response intensity in a quantitative response, and the dose that elicits a positive response in 50% of the subjects in a qualitative response). The range of human dosages can be derived based on data obtained from cell culture analysis and animal studies. When administering one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure, for example, to male or female C57BL / 6J or C3H / HeNCrlVr mice, aged 6-12 weeks and weighing 18-25 g, the amount of oligonucleotide in one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions may be 0.001-100 mg / kg body weight, in some embodiments 0.01-50 mg / kg body weight, in further embodiments 0.05-20 mg / kg body weight, in even further embodiments 0.1-15 mg / kg body weight, and in still further embodiments 0.1-10 mg / kg body weight. The above-mentioned amounts are preferred when administering one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure. The method provided in this disclosure inhibits AGT mRNA expression in cells. The amount of one or more oligonucleotides from the categories of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions used is readily determined by those skilled in the art based on the desired effect. For example, in some embodiments, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the provided siRNA conjugate is sufficient to reduce AGT mRNA expression and result in an extracellular concentration of 1 pM to 1 μM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM, or about 5 nM at the surface of target cells. The amount required to achieve this local concentration will vary with various factors, including the delivery method, delivery site, the number of cell layers between the delivery site and the target cells or tissue, and whether the delivery is local or systemic. The concentration at the delivery site can be significantly higher than the concentration at the surface of the target cells or tissue. Reagent test kit This disclosure provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions disclosed herein. In some embodiments, the kit described herein may provide one or more of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions in a single container. In some embodiments, the kit described herein may include a container providing a pharmaceutically acceptable excipient. In some embodiments, the kit may also include other components, such as stabilizers or preservatives. In some embodiments, the kit described herein may contain at least one other therapeutic agent in a container other than the container providing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein. In some embodiments, the kit may include instructions for mixing one or more of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions with pharmaceutically acceptable carriers and / or excipients or other ingredients (if any). In the kits disclosed herein, one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and / or pharmaceutically acceptable excipients, may be provided in any form, such as liquid, dry, or lyophilized. In some embodiments, the double-stranded oligonucleotides and pharmaceutically acceptable carriers and / or excipients, as well as the pharmaceutical compositions and / or oligonucleotide conjugates and optional pharmaceutically acceptable excipients, are substantially pure and / or sterile. In some embodiments, sterile water may be provided in the kits disclosed herein. The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited thereto. Without intending to be limiting, the invention is further described in detail below in the embodiments and in exemplary embodiments relating to small interfering RNA (siRNA) in pharmaceutical compositions and / or oligonucleotide conjugates of this disclosure. In this context, the double-stranded oligonucleotides, pharmaceutical compositions, and oligonucleotide conjugates of this disclosure are siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates, respectively. In the context of this disclosure, for ease of description, the siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates in these embodiments are also referred to as the siRNA, pharmaceutical compositions, and siRNA conjugates of this disclosure. This does not mean that the double-stranded oligonucleotides of this disclosure can only be siRNA; rather, the double-stranded oligonucleotides can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA), etc. It is contemplated that, based on the detailed description of siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates, other double-stranded oligonucleotides will similarly function when used alone or in the formation of the pharmaceutical compositions and / or oligonucleotide conjugates described in this disclosure. Example Unless otherwise specified, the reagents and culture media used in the following examples are all commercially available products, and the nucleic acid electrophoresis, real-time PCR and other operations used are all performed in accordance with the methods described in Molecular Cloning (Cold Spring Harbor LBboratory Press (1989)). Preparation Example 1: Synthesis of siRNA conjugates 1-4 provided in this disclosure Following the preparation method described in Example 13 of CN110959011A, conjugates 1-4 as shown in Table 2 were prepared, differing only in that the sense and antisense strands of the siRNA contained in the conjugates are as shown in Table 2. Nucleoside phosphoramide monomers were sequentially linked to nucleic acid sequences containing the sense and antisense strand sequences of the siRNA in conjugates 1-4 as shown in Table 2 to synthesize the sense and antisense strands of the siRNA conjugates. After synthesis, the conjugates were purified by centrifugation and ultrafiltration using a 3K (MWCO) ultrafiltration tube. Conjugates 1-4 are mixtures of methylamine and ammonium salts of compounds with the structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the inverse debased deoxynucleotide ia shown in formula (35) at the 3' end of the positive strand of the siRNA represented by Nu, and the oxygen atom is linked to the ribose ring via a methylene group, thereby covalently linking to the positive strand of the siRNA. Furthermore, the siRNA contained in these siRNA conjugates has the siRNA sequences corresponding to conjugates 1-4 in Table 2. Each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (based on siRNA) using ultrapure water (Milli-Q ultrapure water system, resistivity 18.2 MΩ*cm (25℃)). Molecular weight was then determined using liquid chromatography-mass spectrometry (LC-MS, Waters Corporation, model: LCT Premier). The theoretical molecular weight of the positive strand of conjugate 1 was 7324.22, and the measured molecular weight was 7323.60; the theoretical molecular weight of the antisense strand was 7194.91, and the measured molecular weight was 7194.27. For conjugate 2, the theoretical molecular weight of the positive strand was 7292.11, and the measured molecular weight was 7291.54; the theoretical molecular weight of the antisense strand was 7194.91, and the measured molecular weight was 7194.37. The theoretical molecular weight of the positive strand of conjugate 3 was 735... The measured molecular weight of the conjugate 1-4 was 7355.83, while the theoretical molecular weight of the antisense strand was 7194.91 and the measured molecular weight was 7194.26. The theoretical molecular weight of the sense strand of conjugate 4 was 7324.23 and the measured molecular weight was 7323.58, while the theoretical molecular weight of the antisense strand was 7141.96 and the measured molecular weight was 7141.23. The measured values ​​were consistent with the theoretical values, indicating that the synthesized conjugates 1-4 contained the target double-stranded nucleic acid sequence. Table 2. siRNA sequences in siRNA conjugates In this context, uppercase letters C, G, U, A, and T represent the base composition of the nucleotide; lowercase letter m indicates that the nucleotide represented by the uppercase letter to the left of m is 2'-methoxy modified; lowercase letter f indicates that the nucleotide represented by the uppercase letter to the left of f is 2'-fluoro modified; lowercase letter s indicates that the linking group between the two uppercase letters to the left and right of s is a thiophosphate group; lowercase letter d indicates that the nucleotide represented by the uppercase letter to the right of d is a deoxynucleotide; the letter combination in parentheses (MOE) indicates that the nucleotide represented by the uppercase letter to the left of MOE is 2'-methoxyethyl modified; the letter combination VP indicates that the nucleotide represented by the uppercase letter to the right of VP is vinyl phosphate modified; and ia indicates a reverse debased deoxynucleotide. Preparation Example 5: Synthesis of Conjugate 5 provided in this disclosure Following the preparation method described in Example 13 of CN110959011A, conjugate 5 as shown in Table 2 was prepared. The only difference was that the sense and antisense strands of the siRNA contained in the conjugate were as shown in Table 2. For nucleic acid sequences containing siRNA with sense and antisense strand sequences according to the sense and antisense strand sequences of conjugate 5 in Table 2, nucleoside phosphoramidide monomers were linked one by one to synthesize the sense and antisense strands of the siRNA conjugate. After synthesis, the synthesized product was first purified by ion packing using a Source15Q strong anion exchange column, and then purified by desalting using a HiPrep 26 / 13 Desalting pre-packed column. The resulting conjugate 5 was the sodium salt of a compound with the structure shown in formula (403). The linking method of conjugate 5 was the same as that of conjugates 1-4. The molecular weight was determined according to the methods in Preparation Examples 1-4. The theoretical molecular weight of the sense strand of conjugate 5 was 7356.35, and the measured molecular weight was 7356.6. The theoretical molecular weight of the antisense strand was 7217.95, and the measured molecular weight was 7218.0. The measured values ​​were consistent with the theoretical values, indicating that the synthesized conjugate 5 is the target double-stranded nucleic acid sequence. Synthesis of the reference conjugate in Comparative Preparation Example 1 The reference conjugate, designated as Reference Conjugate 1 in Table 2, was synthesized by solid-phase synthesis using the same method as in Preparation Example 1. Experimental Example 1: In vitro inhibitory activity of the disclosed conjugate. This experiment investigated the inhibitory activity of conjugate 4 and reference conjugate 1 on the AGT gene in Huh-7 cells in vitro. The specific steps are as follows: [1] Cell culture Huh-7 human hepatocellular carcinoma cells (Cells-0120) were cultured at 37°C in an incubator containing 5% CO2 / 95% air using DMEM complete medium (purchased from Zhongke Maichen (Beijing) Technology Co., Ltd., catalog number: CM15019) supplemented with 10% fetal bovine serum (FBS, purchased from GIBCO, catalog number 10099-141C). Huh-7 cells were fed at a concentration of 0.5 × 10⁻⁶. 5 Cells were seeded into 24-well plates at 0.5 mL of cell culture per well. After culturing for 16 h, the culture medium in the wells was aspirated, and 0.5 mL of Opti-MEM medium (purchased from GIBCO, catalog number 31985-070) was added to each well. The cells were then cultured for another 1.5 h. [2] Transfection For each siRNA conjugate to be tested, a 20 μM solution of each siRNA conjugate was prepared using PBS. Starting from this solution, the solutions were sequentially diluted 4-fold to obtain 11 different concentrations of siRNA conjugate working solutions: 5 μM, 1.25 μM, 0.312 μM, 0.0781 μM, 0.0195 μM, 0.00488 μM, 0.00122 μM, 0.000305 μM, 0.0000763 μM, 0.0000191 μM, and 0.00000477 μM (based on the amount of siRNA in the siRNA conjugate). The siRNA conjugates used were conjugate 4 and reference conjugate 1. Prepare 3A solutions, each containing 3 μL of siRNA conjugate working solution and 97 μL of cell maintenance culture medium, to make 11 different concentrations of 3A1-3A11 solutions. Prepare 3B solution, each serving containing 2 μL of Lipofectamine. TM 2000 (Invitrogen) and 98 μL Opti-MEM medium. For conjugate 4, one part of solution 3A and one part of solution 3B were mixed to obtain transfection complex 3X1. In the culture wells (all containing Huh-7 cells and 0.5 mL of Opti-MEM medium, hereinafter the same), 100 μL of transfection complex 3X1 for each siRNA conjugate was added and mixed thoroughly, yielding transfection mixtures with concentrations of 50 nM (based on siRNA content), 12.5 nM, 3.13 nM, 0.781 nM, 0.195 nM, 0.0488 nM, 0.0122 nM, 0.00305 nM, 0.000763 nM, 0.000191 nM, and 0.0000477 nM, respectively. Each siRNA conjugate transfection complex 3X1 was transfected into two culture wells to obtain transfection mixtures containing siRNA conjugate 4, designated as test groups 2X1-2X11. For reference conjugate 1, one part of solution 3A and one part of solution 3B were mixed to obtain transfection complex Y1. In each culture well (all containing Huh-7 cells and 0.5 mL of Opti-MEM medium, hereinafter the same), one portion of transfection complex Y1 of reference conjugate 1 was added and mixed thoroughly. The addition volume was 100 μL / well, resulting in transfection mixtures with concentrations of 50 nM (based on siRNA), 12.5 nM, 3.13 nM, 0.781 nM, 0.195 nM, 0.0488 nM, 0.0122 nM, 0.00305 nM, 0.000763 nM, 0.000191 nM, and 0.0000477 nM, respectively. Each reference conjugate 1 transfection complex Y1 was transfected into two culture wells to obtain a transfection mixture containing reference conjugate 1, denoted as test group 2Y1-2Y11. One portion of solution 3B was mixed with 100 μL of cell maintenance medium to obtain blank transfection mixture B. Blank transfection mixture B was then added to another well at a volume of 100 μL / well to obtain a transfection mixture without siRNA conjugates, designated as blank control group 2B. The test groups 2X1-2X11, 2Y1-2Y11 and the blank control group 2B were placed in an incubator with an air atmosphere containing 5% CO2 and cultured at 37°C for 24 hours. [3] Detection Total RNA was extracted from cells in each well using TRIZOL reagent (purchased from Sigma, catalog number: T9424-200 mL). For each well of cells, 1 μg of total RNA was taken and reverse transcribed into cDNA using the Reverse Transcription System (Promega, catalog number A3500) according to the manufacturer's instructions. The provided reagents included Oligo(dT)15 as the primer. A 20 μL reverse transcription reaction system was prepared according to the kit's instructions. The reverse transcription conditions were as follows: for each reaction system, the system was incubated at 70°C for 10 min, then at 42°C for 30 min, and finally at 95°C for 5 min. After the reaction, 80 μL of RNase-free water was added to the system to obtain the cDNA-containing solution. For each reverse transcription reaction system, 5 μL of the above-mentioned cDNA-containing solution was used as a template. A 20 μL qPCR reaction system was prepared using the reagents provided in the SYBR Select Master Mix kit (purchased from Applied Biosystems, catalog number 4472908). The PCR primer sequences for amplifying the target gene AGT and the internal reference gene GAPDH are shown in Table 3, with a final concentration of 10 μM for each primer. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and a three-step amplification method was used. The amplification program was: 95℃ pre-denaturation for 10 min, followed by 95℃ denaturation for 30 s, 60℃ annealing for 30 s, and 72℃ extension for 30 s. This denaturation, annealing, and extension process was repeated 40 times to obtain product W1 containing amplified target gene AGT and internal reference gene GAPDH. Product W1 was then subjected to a gradient temperature increase to 95℃ for 15s, 60℃ for 1min, and then to 95℃ with fluorescence signals collected every 0.3℃. After 15s at 95℃, the melting curves of the target gene and the internal reference gene GAPDH in product W1 were collected by a real-time quantitative PCR instrument to obtain the Ct values ​​of the target gene AGT and the internal reference gene GAPDH. Table 3 Primer Information The relative quantitative calculation of the expression level of the target gene AGT mRNA in each test group was performed using the Ct(ΔΔCt) method. The calculation method is as follows: ΔCt(test group) = Ct(target gene in test group) – Ct(internal reference gene in test group) ΔCt(control group) = Ct(target gene in control group) – Ct(internal reference gene in control group) ΔCt(test group) = ΔCt(test group) - ΔCt(control group average) ΔCt(control group) = ΔCt(control group) - ΔCt(control group average) Here, ΔCt (control group average) is the arithmetic mean of ΔCt (control group) for each of the two culture wells in the control group. Therefore, each culture well in both the test and control groups corresponds to a ΔCt value. The expression level of AGT mRNA in the test group was normalized based on the average value of the control group, with the average value of AGT mRNA expression in the control group defined as 100%. The relative expression level of AGT mRNA in the test group was 2. - ΔΔCt(测试组) ×100% AGT mRNA inhibition rate in the test group = (1 - relative expression level of AGT mRNA in the test group) × 100% Based on the relative expression levels of human AGT mRNA in Huh-7 cells after transfection with different concentrations of the target siRNA conjugate, the nonlinear regression analysis function of Graphpad Prism 8.0 software was used to fit the log (inhibitor) vs. response-variable slope (four parameters) dose-response curve, and the values ​​of Bot, Top, and Hillslope parameters were obtained. Based on the function corresponding to the fitted dose-response curve, calculate the IC50 of the target sequence of the siRNA conjugate. 50 The value, the function is as follows, In the formula: Y is the ratio R, which represents the relative residual activity of Renilla. X represents the logarithm of the siRNA transfection concentration. Bot is the Y value at the bottom of the steady-state period. Top is the Y value at the peak of the steady-state period. X' is the X value when Y is halfway between the bottom and the top, while HillSlope is the slope of the curve at X'. Based on the dose-response curve and the corresponding function, determine X when Y = 50%. 50 The IC50 values ​​of each siRNA conjugate were calculated. 50 Value = 10^X 50 (nM), IC 50 The fitting curves are shown in Figures 1A and 1B. Figure 1A shows the IC50 of the siRNA conjugate 4 disclosed herein. 50 Fitted curves; Figure 1B shows the IC of reference conjugate 1. 50 Fitting curves. As shown in Figures 1A and 1B, the IC50 values ​​of the siRNA conjugate 4 and the reference conjugate 1 disclosed herein are... 50 The values ​​were 0.021 nM and 0.027 nM, respectively, indicating that the siRNA conjugate disclosed in this invention has a smaller IC50 value. 50 The value indicates that the siRNA conjugate disclosed herein has a higher AGT mRNA inhibition efficiency compared to the reference conjugate. Experimental Example 2: In vitro inhibitory activity of the disclosed conjugate. This experiment investigated the activity of conjugates 1-3 in primary hepatocytes of hAGT mice. [1] Cell culture Primary hepatocytes were obtained from fresh liver tissue of human AGT transgenic mice (B6.Cg-Tg(hAGT)2041Sig / J, grade: SPF, age: 6-8 weeks, purchased from Jackson Lab). The density of the primary hepatocytes was adjusted to 2x10⁻⁶ cells in Opti-MEM (1X) medium (GIBCO, catalog number 31985-70). 5 To obtain a suspension of primary mouse liver cells, the cells were measured at 1 x 10⁶ cells / mL. 5 Cells were seeded into 12-well plates with 1 mL of cell culture per well. After culturing for 16 h, the culture medium in the wells was aspirated, and 1 mL of Opti-MEM medium (GIBCO) was added to each well. The cells were then cultured for another 1.5 h. [2] Transfection Working solutions of conjugates 1-3 at concentrations of 0.8 μM and 4 μM were prepared using PBS buffer. 0.3 μL of each concentration of working solution and PBS were added to two culture wells (each containing primary mouse liver cells and Opti-MEM as described above). 99.7 μL of DMEM was then added to each well to obtain transfection mixtures with final concentrations of 0.2 nM and 1 nM, respectively. The group with 0.2 nM conjugate working solution was designated as test group 1, the group with 1 nM conjugate working solution as test group 2, and the group with PBS as the blank control group. The 12-well plates were then incubated in a CO2 incubator for 24 hours. [3] Detection Total RNA was extracted from cells in each well using TRIZOL reagent (purchased from Sigma, catalog number: T9424-200 mL). For each well of cells, 1 μg of total RNA was taken and reverse transcribed into cDNA using the Reverse Transcription System (Promega, catalog number: A3500) according to its instructions, yielding a solution containing cDNA, of which Oligo(dT) was selected. 15 As primers, a 20 μL reverse transcription reaction system was prepared according to the reverse transcription procedure in the kit instructions to reverse transcribe total RNA from cells in each well. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the system was incubated at 70°C for 10 min, then at 42°C for 30 min, and finally at 95°C for 5 min. After the reaction was completed, 80 μL of RNase-free water was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above-mentioned cDNA-containing solution was used as a template. A 20 μL qPCR reaction system was prepared using the reagents provided in the SYBR Select Master Mix kit (purchased from Applied Biosystems, catalog number 4472908). The PCR primer sequences for amplifying the target gene hAGT and the internal reference gene mGAPDH are shown in Table 4, with a final concentration of 10 μM for each primer. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and a three-step amplification method was used. The amplification program was: 95℃ pre-denaturation for 10 min, followed by 95℃ denaturation for 30 s, 60℃ annealing for 30 s, and 72℃ extension for 30 s. This denaturation, annealing, and extension process was repeated 40 times to obtain product W1 containing amplified target gene AGT and internal reference gene GAPDH. Product W1 was then subjected to a gradient temperature increase to 95℃ for 15s, 60℃ for 1min, and then to 95℃ with fluorescence signals collected every 0.3℃. After 15s at 95℃, the melting curves of the target gene and the internal reference gene GAPDH in product W1 were collected by a real-time quantitative PCR instrument to obtain the Ct values ​​of the target gene AGT and the internal reference gene GAPDH. Table 4 Primer sequence information The Ct(ΔΔCt) method was used, and the calculation was performed according to the method in Experimental Example 1. The results are shown in Table 5 below. Table 5 shows the inhibition rate of AGT mRNA in primary mouse liver cells after transfection with 0.2 nM and 1 nM concentrations of the conjugates 1-3 of this disclosure, respectively. Table 5. Inhibition rate of AGT mRNA in primary mouse liver cells As shown in Table 5, in primary liver cells of hAGT transgenic mice, the conjugate provided in this disclosure can inhibit the target gene AGT mRNA by more than 72% at a concentration of 0.2 nM, and can reach 98.5% or even 99% at a concentration of 1 nM, demonstrating excellent in vitro inhibitory activity. Experimental Example 3: Activity Assay of siRNA Conjugates in Mice (in vivo) In this experimental example, conjugate 4 and reference conjugate 2 were dissolved in PBS to obtain solutions with a concentration of 0.6 mg / mL (based on the amount of siRNA). Reference conjugate 2 is an siRNA conjugate, designated AD85481 in Table 5 of the specification of US Patent Publication US11,015,201B2, obtained by the method described in Example 1 of the patent publication. This siRNA conjugate has the structure shown in formula (305), wherein the conjugating group is linked to the 3' position of the ribose of the 3' terminal nucleotide of the sense strand of the siRNA represented by Nu. Furthermore, the siRNA contained in this siRNA conjugate has the sense and antisense strand sequences shown in Table 6 below: Table 6. siRNA sequence of reference conjugate 2 Note: (gn) indicates that the nucleotide represented by the uppercase letter on the left is a GNA-modified nucleotide. Twenty mice (human AGT transgenic mice (B6.Cg-Tg(hAGT)2041Sig / J); grade: SPF; age: 6-8 weeks, purchased from Jackson Lab) were randomly divided into three groups of 6 mice each, with half males and half females in each group: test group 1, control group 2, and blank group. Mice in test group 1 and control group 2 were administered 0.6 mg / mL of conjugate 4 solution or reference conjugate 2 solution via subcutaneous abdominal injection. Mice in the blank group were administered PBS solution. The weight of mice in each group was recorded before administration and administered the drug according to body weight. The single dose was 5 mL / kg of mouse body weight. Using the drug administration time point as day 1, blood samples were collected from mice on days 8, 15, 22, 29, and 43 post-administration. The expression levels of hAGT protein in the serum of the test and control groups were detected using the Abcam hAGT ELISA kit (ab108823) (purchased from Xi'an Zhuangzhi Biotechnology Co., Ltd.) according to the instructions. The decrease rate of hAGT protein expression in mouse serum was calculated by normalization with the expression level of hAGT protein in the blank control group at the corresponding time point as 100%. The results are shown in Table 7. Table 7. Inhibition rate of hAGT protein in mice As shown in Table 7, during the 43-day experimental period, mice treated with conjugate 4 exhibited a higher inhibition rate of hAGT protein expression than mice treated with reference conjugate 2. This high inhibition rate was maintained throughout the entire experimental period, remaining close to 80% on day 43. Considering that reference conjugate 2 is the most effective siRNA conjugate in the prior art (US 11,015,201 B2) and is protected by patent, the above results indicate that the conjugate containing the antisense strand of this disclosure can inhibit AGT mRNA expression for a prolonged period, thereby reducing serum hAGT protein expression, and exhibits significantly higher inhibition efficiency than one of the most preferred compounds in the art. Experiment 4: In vivo activity test of siRNA conjugates in mice. This experiment investigated the activity of different concentrations of the disclosed conjugate 4 in mice. The experiment was conducted according to the method in Example 3, with the only difference being that the siRNA conjugate used was conjugate 4. Two concentrations of solutions, 0.6 mg / mL and 1.8 mg / mL, were prepared and administered to mice in different test groups, while the blank group was given PBS solution. The single dose was 5 mL / kg of mouse body weight. Based on the mouse body weight, the dosages were calculated to be 3 mg / kg and 9 mg / kg, respectively. Blood samples were collected from mice at the time of administration and on days 8, 15, 22, 36, and 43 post-administration for analysis. The results are shown in Table 8. Table 8. Inhibition rate of hAGT protein in mice As shown in Table 8, during the 43-day experimental period, mice treated with conjugate 4 of this disclosure exhibited a high inhibition rate of hAGT protein expression, with the highest inhibition rate reaching 96.5%. Furthermore, this high inhibition rate was maintained throughout the entire experimental period; at a dose of 9 mg / kg, the inhibition rate of hAGT protein expression remained at a maximum of 90.3% on day 43. This demonstrates that the conjugate of this disclosure, containing the antisense strand, can reduce serum hAGT protein expression for a prolonged period, exhibiting a dose-dependent effect. The conjugate of this disclosure demonstrates significant and long-lasting pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to AGT mRNA expression, showing excellent development potential. Experimental Example 5: Activity test of the disclosed conjugate in mice (in vivo) The conjugates 1 and 3 prepared above were dissolved in PBS to prepare solutions with a concentration of 0.2 mg / mL (based on the amount of siRNA). Human AGT transgenic mice (B6.Cg-Tg(hAGT)2041Sig / J, grade: SPF, age: 6-8 weeks, purchased from Jackson Lab) were randomly divided into 4 groups of 6 mice each, with half males and half females in each group: test group 1, test group 2, and blank control group. Each mouse in test group 1 was administered 0.2 mg / mL of conjugate 1 solution via subcutaneous abdominal injection; each mouse in test group 2 was administered 0.2 mg / mL of conjugate 3 solution; and mice in the blank control group were administered PBS solution. Mice in all groups were weighed and their body weight was recorded before administration. The dosage was 5 mL / kg of mouse body weight per administration. Using the drug administration time point as day 1, blood samples were collected from mice on days 15, 43, and 71 post-administration. The expression levels of hAGT protein in the serum of the test group and the blank control group were detected using the Abcam hAGT ELISA kit (ab108823) (purchased from Xi'an Zhuangzhi Biotechnology Co., Ltd.) according to the instructions. The decrease rate of hAGT protein expression in mouse serum was calculated by normalization with the expression level of hAGT protein in the blank control group at the corresponding time point as 100%. The results are shown in Table 9. Table 9. Inhibition rate of hAGT protein in mice As shown in Table 9, during the 71-day experimental period, mice given the conjugate of this disclosure exhibited a high inhibition rate of hAGT protein expression. On day 15, the inhibition rate of hAGT protein expression was above 90%, and on day 71, the inhibition rate of hAGT protein expression was still close to or reached 70%. This indicates that the conjugate of this disclosure containing the antisense strand of this disclosure can inhibit the expression of AGT mRNA for a long time, thereby reducing the level of hAGT protein expression in serum. Experiment Example 6: Activity Assay of siRNA Conjugates in Mice (in vivo) In this experimental example, conjugate 5 was dissolved in PBS to prepare solutions with concentrations of 0.6 mg / mL and 0.2 mg / mL (based on the amount of siRNA). Eighteen mice (human AGT transgenic mice (B6.Cg-Tg(hAGT)2041Sig / J); grade: SPF; age: 6-8 weeks, purchased from Jackson Lab) were randomly divided into two groups of 6 mice each, with half males and half females in each group, designated as test group 1, test group 2, and blank group. Mice in test group 1 were administered 0.6 mg / mL of conjugate 5 solution via subcutaneous abdominal injection, and mice in test group 2 were administered 0.2 mg / mL of conjugate 5 solution. Mice in the blank group were administered PBS solution. For all groups of mice, their weight was recorded before administration. The dosage was based on body weight, with a single dose of 5 mL / kg of mouse body weight. The dosages for test group 1 and test group 2 were 3 mg / kg and 1 mg / kg, respectively. Using the drug administration time point as day 1, blood samples were collected from mice on days 15, 43, and 70 post-administration. The expression level of hAGT protein in the serum of the test group mice was detected using the Abcam hAGT ELISA kit (ab108823) (purchased from Xi'an Zhuangzhi Biotechnology Co., Ltd.) according to the instructions. The decrease rate of hAGT protein expression in mouse serum was calculated by normalization with the expression level of hAGT protein in the blank group mice at the corresponding time points as 100%. The results are shown in Table 10. Table 10. Inhibition rate of hAGT protein in mice As shown in Table 10, mice treated with the conjugate 5 of this disclosure exhibited a high inhibition rate of hAGT protein expression during the 71-day experimental period, maintaining a high inhibition rate throughout the entire experimental period. On day 71 of administration, the inhibition rate of hAGT protein expression was 56% at a dose of 1 mg / kg; at a dose of 3 mg / kg, the inhibition rate still reached 70%. Therefore, the conjugate of this disclosure, containing the antisense strand, can inhibit AGT mRNA expression for a prolonged period, thereby reducing serum hAGT protein expression levels. Some embodiments of this disclosure have been described in detail above. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure. It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately. Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.

Claims

1. A single-stranded oligonucleotide having a length of 16-30 nucleotides, wherein the composition of the single-stranded oligonucleotide enables it to inhibit the expression of AGT mRNA via an RNAi mechanism; wherein each nucleotide in the single-stranded oligonucleotide is independently modified or unmodified, wherein, At least one nucleotide in the single-stranded oligonucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide. Furthermore, in the direction from the 5' end to the 3' end, the 13th nucleotide of the single-stranded oligonucleotide is a substituted alkoxy modified nucleotide; the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X; and each of the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide is independently a modified nucleotide. Each nucleotide X is independently a deoxynucleotide or an unmodified nucleotide.

2. The single-chain oligonucleotide as described in claim 1, wherein, The single-chain oligonucleotide has a length of 17-28, 19-27, or 20-25 nucleotides; or, the single-chain oligonucleotide has a length of 19, 21, or 23 nucleotides.

3. The single-stranded oligonucleotide as described in claim 1 or 2, wherein, The number of nucleotides X is 1-3.

4. The single-chain oligonucleotide according to any one of claims 1-3, wherein, In the single-stranded oligonucleotide, the 12th and 14th nucleotides are each independently nucleotide X, in the direction from the 5' end to the 3' end; or, only the 14th nucleotide is nucleotide X.

5. The single-stranded oligonucleotide according to any one of claims 1-4, wherein, The number of unmodified nucleotides does not exceed 5, 4, 3, 2, or 1; or, each of the nucleotides in the single-stranded oligonucleotide is independently modified.

6. The single-chain oligonucleotide according to any one of claims 1-5, wherein, The number of fluorinated nucleotides is 2-7.

7. The single-chain oligonucleotide of claim 6, wherein, Fluorinated nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides in the single-stranded oligonucleotide, following the direction from the 5' end to the 3' end.

8. The single-chain oligonucleotide of claim 7, wherein, In the direction from the 5' end to the 3' end, the fluorinated nucleotides refer to one or two of the 2nd and 12th nucleotides, one or two of the 5th to 7th nucleotides, and 0 to 2 of the 16th to 19th nucleotides in the single-stranded oligonucleotide; Alternatively, in the direction from the 5' end to the 3' end, the fluorinated nucleotide refers to the 2nd and 6th nucleotides of the single-stranded oligonucleotide; the 2nd, 6th and 16th nucleotides; the 2nd, 5th, 7th, 12th and 16th nucleotides; the 2nd, 7th, 12th, 16th and 19th nucleotides; or the 2nd, 6th, 12th, 16th and 19th nucleotides.

9. The single-chain oligonucleotide of claim 8, wherein, In the single-stranded oligonucleotide, in the direction from the 5' end to the 3' end, except for the 13th and 14th nucleotides of the single-stranded oligonucleotide and the fluorinated nucleotide, each modified nucleotide is independently selected from one of alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, alkyl-modified nucleotides, substituted alkyl-modified nucleotides, amine-modified nucleotides, heat-labile nucleotides, and BNA.

10. The single-chain oligonucleotide of claim 9, wherein, In the direction from the 5' end to the 3' end, except for the 13th and 14th nucleotides of the single-stranded oligonucleotide and the fluorinated nucleotides, each modified nucleotide is independently selected from alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, or heat-labile nucleotides, and the number of substituted alkoxy-modified nucleotides does not exceed 3 and the number of heat-labile nucleotides does not exceed 2.

11. The single-chain oligonucleotide of claim 10, wherein, The single-stranded oligonucleotide is 19-23 nucleotides in length, and Following the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, one of the 5th to 7th nucleotides, as well as the 2nd and 16th nucleotides of the single-stranded oligonucleotide, are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and when the 5th nucleotide is not a fluorinated nucleotide, it is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide.

12. The single-stranded oligonucleotide of claim 11, wherein, The single-stranded oligonucleotide is 21 nucleotides in length, and Following the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide.

13. The single-chain oligonucleotide according to any one of claims 9-12, wherein, Each nucleotide X refers to a deoxynucleotide; Each alkoxy-modified nucleotide is a alkoxy-modified nucleotide; Each substituted alkoxy-modified nucleotide refers to a nucleotide modified with 2'-O-methoxyethyl; and / or Each thermally unstable nucleotide refers to GNA.

14. The single-stranded oligonucleotide according to any one of claims 1-13, wherein, Each of at least two of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate ester group with a modifying group.

15. The single-stranded oligonucleotide of claim 14, wherein, Each of 1-4 linking groups between adjacent nucleotides in the 5' end of the single-stranded oligonucleotide, and / or 1-4 linking groups between adjacent nucleotides in the 3' end of the single-stranded oligonucleotide, is independently a phosphate ester group with a modifying group; and / or If the single-stranded oligonucleotide contains unmodified nucleotides, each of the two linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate ester group having a modifying group; and / or In the single-stranded oligonucleotide, each of 2-6, or 3 or 4 of the linking groups between adjacent nucleotides is an independently phosphate ester group with a modifying group.

16. The single-stranded oligonucleotide of claim 14 or 15, wherein, Each of the linking groups between adjacent nucleotides in the 5' end of the first to third nucleotides of the single-stranded oligonucleotide, and each of the linking groups between adjacent nucleotides in the 3' end of the first to third nucleotides, is independently a phosphate ester group with a modifying group; and / or If the single-stranded oligonucleotide contains unmodified nucleotides, each of the two linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate ester group with a modifying group.

17. The single-stranded oligonucleotide according to any one of claims 14-16, wherein, Each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28):

18. The single-stranded oligonucleotide according to any one of claims 1-17, wherein, The 5' terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxynucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide, wherein the 5'-hydroxynucleotide has the structure shown in formula (29); the 5'-phosphate nucleotide has the structure shown in formula (30); and the 5'-phosphate analog modified nucleotide is selected from one of the nucleotides shown in formulas (31) to (34). R is selected from H, OH, OCH3 and F; Base represents a nucleic acid base, selected from A, U, C, G or T.

19. The single-stranded oligonucleotide according to any one of claims 1-18, wherein, The single-stranded oligonucleotide is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a 2'-O-methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a methoxy modified nucleotide. The linking group between any two adjacent nucleotides in the first to third nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the first to third nucleotides at the 3' end are phosphate thioester groups; The 5' terminal nucleotide is a 5'-hydroxy nucleotide as shown in formula (29) or a nucleotide modified with 5'-vinyl phosphate as shown in formula (31).

20. The single-stranded oligonucleotide according to any one of claims 1-19, wherein, The single-stranded oligonucleotide is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence m in AGT mRNA; the length of the nucleotide sequence m is not greater than the length of the single-stranded oligonucleotide, and the length of the nucleotide sequence m is the same as the length of the single-stranded oligonucleotide, or differs by no more than 8 nucleotides, or differs by 1-5 nucleotides. Alternatively, the length of the nucleotide sequence m is at least 16 nucleotides, or 16-25 nucleotides, or 18-23 nucleotides, or 19-21 nucleotides; Alternatively, the single-stranded oligonucleotide has the same length as the nucleotide sequence m, and at least the nucleotide sequence of the single-stranded oligonucleotide other than the terminal nucleotide is completely anticomplementary to the nucleotide sequence m; Alternatively, in the 5'-3' direction, the nucleotide sequence other than position 1 of the single-stranded oligonucleotide is substantially anticomplementary to the nucleotide sequence m, or the nucleotide sequence other than position 1 of the single-stranded oligonucleotide is completely anticomplementary to the nucleotide sequence m, or all nucleotides of the single-stranded oligonucleotide are completely anticomplementary to the nucleotide sequence m.

21. The single-chain oligonucleotide according to any one of claims 1-20, wherein, The single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:2 and differs from it by no more than 3 bases. 5'-Z2CUUAGACCAAGGAGAAAC-3'(SEQ ID NO:2), Wherein, Z2 is A or U, and the nucleotide sequence II contains a nucleotide Z4 at a position corresponding to Z2, wherein Z4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence.

22. The single-chain oligonucleotide of claim 21, wherein, The nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one base; Alternatively, there may be no base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:

2.

23. The single-stranded oligonucleotide of claim 21 or 22, wherein, The single-stranded oligonucleotide also contains a nucleotide sequence IV, which is attached to the 3' end of the nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in the nucleotide sequence IV is independently one of the non-fluorinated modified nucleotides. The nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to the AGT mRNA. Each of the non-fluorinated modified nucleotides is independently selected from one of the following: 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with 1-3 carbon atoms, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides, and heat-labile nucleotides. Alternatively, the length of the nucleotide sequence IV is 2 nucleotides.

24. The single-chain oligonucleotide as described in claims 21-23, wherein, The single-stranded oligonucleotide also contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II. After the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. Alternatively, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or completely reverse complementary to AGT mRNA; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1–siRNA4 shown in Table 1; Alternatively, the single-chain oligonucleotide is the antisense strand of any one of the conjugates 1-5 shown in Table 2.

25. A double-stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, wherein the sense strand and the antisense strand are at least partially anticomplementary to form a double-stranded region, wherein, The antisense strand is a single-stranded oligonucleotide as described in any one of claims 1-24.

26. The double-stranded oligonucleotide of claim 25, wherein, The length of the positive chain is 15-26, 17-24, or 19-23 nucleotides; Alternatively, the length of the justice chain is 19-21 nucleotides.

27. The double-stranded oligonucleotide of claim 26, wherein, The length difference between the sense and antisense strands is 0-5 nucleotides. Alternatively, the length of the justice chain is not greater than the length of the antisense chain; Alternatively, the sense and antisense strands may be of the same length, either 19, 20, or 21 nucleotides. Alternatively, the length of the sense strand is 19-21 nucleotides, the length of the antisense strand is 20-24 nucleotides, and the length of the antisense strand is 1-3 nucleotides longer than the length of the sense strand; or the length of the antisense strand is 2 nucleotides longer than the length of the sense strand. Alternatively, the length of the sense strand is 19 nucleotides and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides and the length of the antisense strand is 23 nucleotides.

28. The double-stranded oligonucleotide according to any one of claims 25-27, wherein, Following the direction from the 3' end to the 5' end, 2-3 of the 11th-13th nucleotides of the positive strand are fluorinated nucleotides, the first and / or the last nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, and the remaining nucleotides in the positive strand are each independently non-fluorinated nucleotides, each of which is independently selected from one of alkoxylated nucleotides, alkylated nucleotides, amine-modified nucleotides, and heat-labile nucleotides.

29. The double-stranded oligonucleotide of claim 28, wherein, In the direction from the 3' end to the 5' end, the 11th and 13th nucleotides, or the 11th to 13th nucleotides, of the positive strand are fluorinated nucleotides, the 1st and / or the last nucleotide is a reverse debased deoxynucleotide, and the nucleotides at the remaining positions of the positive strand are each independently alkoxylated nucleotides.

30. The double-stranded oligonucleotide of claim 28 or 29, wherein, Each of the alkoxy-modified nucleotides is independently a methoxy-modified nucleotide.

31. The double-stranded oligonucleotide according to any one of claims 25-30, wherein, In the positive strand, each of at least one of the linking groups connecting two adjacent nucleotides is independently a phosphate group with a modifying group, the phosphate group with the modifying group being present at least once between two adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand and between two adjacent nucleotides in the first to fifth nucleotides at the 3' end.

32. The double-stranded oligonucleotide of claim 31, wherein, One to four, or all four, of the linking groups connecting any two adjacent nucleotides from the first to the fifth nucleotide at the 5' end of the positive strand are independently phosphate groups with modifying groups; and / or, one to four, or all four, of the linking groups connecting any two adjacent nucleotides from the first to the fifth nucleotide at the 3' end of the positive strand are independently phosphate groups with modifying groups; Alternatively, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28); Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1–siRNA3 shown in Table 1; Alternatively, the single-chain oligonucleotide is the antisense strand of any one of the conjugates 1-5 shown in Table 2.

33. The double-stranded oligonucleotide according to any one of claims 25-32, wherein, The sense strand contains 19-21 nucleotides, and the antisense strand contains 21-23 nucleotides; In the positive chain, the 11th and 13th nucleotides, or the 11th to 13th nucleotides, are fluorinated nucleotides in the direction from the 3' end to the 5' end, the 1st and / or the last nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, and the nucleotides at the remaining positions are each independently alkoxylated nucleotides. Each of 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the positive strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the positive strand, is independently a phosphate ester group with a modifying group.

34. The double-stranded oligonucleotide of claim 33, wherein, The sense strand contains 19-21 nucleotides, and the antisense strand contains 21-23 nucleotides; In the positive strand, from the 3' end to the 5' end, the 11th to 13th nucleotides are fluorinated nucleotides, the first nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, and the remaining nucleotides are each independently alkoxylated nucleotides; 1 to 4 of the linking groups between adjacent nucleotides in the 1st to 5th nucleotides at the 5' end of the positive strand, and / or 1 to 4 of the linking groups between adjacent nucleotides in the 1st to 5th nucleotides at the 3' end of the positive strand, are each independently a phosphate ester group with a modifying group; In the antisense chain, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, and the 2nd, 6th and 16th nucleotides are fluorinated nucleotides. Each of the remaining nucleotides in the antisense chain is independently an alkoxy-modified nucleotide. The linking group between any two adjacent nucleotides in the 5' end of the first to third nucleotides of the antisense chain, and the linking group between any two adjacent nucleotides in the 3' end of the first to third nucleotides, are independently phosphate groups with modifying groups. The 5' end nucleotide of the antisense chain is a 5'-hydroxy nucleotide as shown in formula (29) or a 5'-vinyl phosphate-modified nucleotide as shown in formula (31).

35. The double-stranded oligonucleotide of claim 34, wherein, The sense strand contains 19 nucleotides, and the antisense strand contains 21 nucleotides; In the positive strand, from the 3' end to the 5' end, nucleotides 11-13 are fluorinated nucleotides, nucleotide 1 is a reverse debased deoxynucleotide, and the nucleotides at the remaining positions are each independently methoxylated nucleotides; the linking group between adjacent nucleotides in nucleotides 1-5 at the 5' end of the positive strand is a thiophosphate group. In the antisense strand, the 13th nucleotide is a 2'-O-methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, and the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides. Each of the remaining nucleotides in the antisense strand is an alkoxy modified nucleotide independently. The linking group between any two adjacent nucleotides in the first to third nucleotides at the 5' end of the antisense strand, and the linking group between any two adjacent nucleotides in the first to third nucleotides at the 3' end, are each independently a thiophosphate group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31).

36. The double-stranded oligonucleotide according to any one of claims 25-35, wherein, The justice chain and the antisense chain are essentially opposite complementary, substantially opposite complementary, or completely opposite complementary. Alternatively, in the 5'-3' direction, at least the nucleotide sequence other than the first and last positions of the sense strand is substantially anticomplementary or completely anticomplementary to the antisense strand; Alternatively, in the 5'-3' direction, the nucleotide sequence of the sense strand except the last nucleotide is completely anticomplementary to the antisense strand; or all nucleotides of the sense strand are completely anticomplementary to the antisense strand. Alternatively, the unmodified equivalent sequence of the positive strand may contain a nucleotide sequence of the same length as nucleotide sequence m, and differing by no more than 3 bases, no more than 1 base, or having no base difference, wherein nucleotide sequence m is a continuous nucleotide sequence in AGT mRNA, and the length of nucleotide sequence m is at least 16 nucleotides, or 16-25 nucleotides, or 18-23 nucleotides, or 19-21 nucleotides.

37. The double-stranded oligonucleotide of claim 36, wherein, The double-stranded oligonucleotide is siRNA.

38. The double-stranded oligonucleotide according to any one of claims 25-37, wherein, The sense strand contains nucleotide sequence I, and the antisense strand contains nucleotide sequence II. Nucleotide sequence I is of the same length as the nucleotide sequence shown in SEQ ID NO:1, and differs by no more than 3 bases. Nucleotide sequence II is of the same length as the nucleotide sequence shown in SEQ ID NO:2, and differs by no more than 3 bases. 5'-GUUUCUCCUUGGUCUAAGZ1-3' (SEQ ID NO: 1); 5'-Z2CUUAGACCAAGGAGAAAC-3'(SEQ ID NO:2), Wherein, Z1 is U, A or ia, Z2 is A or U, ia is a reverse debase deoxynucleotide, the nucleotide sequence I contains a nucleotide Z3 corresponding to Z1, the nucleotide sequence II contains a nucleotide Z4 corresponding to Z2, and Z4 is the first nucleotide at the 5' end of the antisense strand.

39. The double-stranded oligonucleotide of claim 38, wherein, The nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO:1 by no more than one base, and the nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one base.

40. The double-stranded oligonucleotide of claim 39, wherein, The double-stranded oligonucleotide is siRNAa1, siRNAa2, siRNAa3, or siRNAa4.

41. An oligonucleotide conjugate comprising an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, wherein the oligonucleotide group is independently formed by removing one or more atoms or groups from a single-stranded oligonucleotide of any one of claims 1-24 or a double-stranded oligonucleotide of any one of claims 25-40.

42. The oligonucleotide conjugate of claim 41, wherein, The delivery group comprises a linker group and a pharmaceutically acceptable target group, and the oligonucleotide group, the linker group, and the target group are sequentially covalently or non-covalently linked, each target group being selected from ligands capable of binding to hepatocyte surface receptors or groups capable of increasing tissue compatibility; or, Each of the target groups is selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes; Alternatively, the oligonucleotide conjugate may contain oligonucleotide groups that are siRNA groups formed from siRNAs listed in Table 1; Alternatively, the oligonucleotide conjugate has the structure shown in formula (403). In formula (403), Nu is an oligonucleotide group; or, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom is covalently linked to the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group; or, the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group is a reverse debased deoxynucleotide, and the P atom is covalently linked to the double-stranded oligonucleotide group by substituting the hydrogen atom in the hydroxyl group of the debased reverse deoxynucleotide at the 3' terminal of the positive strand of the double-stranded oligonucleotide group via the methylene group linked to the ribose ring. Alternatively, the oligonucleotide conjugate is one of conjugates 1-5 listed in Table 2.

43. A pharmaceutically acceptable salt of a single-stranded oligonucleotide as described in any one of claims 1-24, a double-stranded oligonucleotide as described in any one of claims 25-40, or an oligonucleotide conjugate as described in claim 41 or 42; Alternatively, the pharmaceutically acceptable salt is a partial or complete water-soluble salt of the double-stranded oligonucleotide or the oligonucleotide conjugate; Alternatively, the water-soluble salt is one or more of an amine salt, an alkali metal salt, and an alkaline earth metal salt; Alternatively, the amine salt is selected from one or more of ammonium salts, methylamine salts, tertiary amine salts, and quaternary ammonium salts, and the alkali metal salt is selected from potassium salts or sodium salts, and the alkaline earth metal salt is selected from calcium salts or magnesium salts; Alternatively, the tertiary amine salt is one or more of triethylamine salt, triisopropylamine salt, or N,N-diisopropylethylamine salt; Alternatively, the pharmaceutically acceptable salt is a salt or a portion of the double-stranded oligonucleotide or the oligonucleotide conjugate, wherein the salt is one or more of a methylamine salt, a triethylamine salt, or a sodium salt.

44. A pharmaceutical composition comprising one or more of the following: a single-stranded oligonucleotide according to any one of claims 1-24, a double-stranded oligonucleotide according to any one of claims 25-40, an oligonucleotide conjugate according to claim 41 or 42, and a pharmaceutically acceptable salt according to claim 43, and a pharmaceutically acceptable excipient; Alternatively, the pharmaceutically acceptable excipient is one or more of solvents, preservatives, osmotic pressure regulators, and other pharmaceutically acceptable carriers; Alternatively, the solvent is one of deionized water, water for injection, pH buffer, physiological saline, ethanol, or an aqueous solution of ethanol.

45. Use of one or more of the single-stranded oligonucleotides of any one of claims 1-24, the double-stranded oligonucleotides of any one of claims 25-40, the oligonucleotide conjugates of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical compositions of claim 44 in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with AGT mRNA levels.

46. ​​The use as described in claim 45, wherein, The diseases or symptoms associated with AGT mRNA levels are hypertension and hypertension-related diseases.

47. A method for treating and / or preventing diseases or symptoms associated with AGT mRNA levels, the method comprising administering to a subject in need an effective amount of one or more of the following: a single-stranded oligonucleotide of any one of claims 1-24, a double-stranded oligonucleotide of any one of claims 25-40, an oligonucleotide conjugate of claim 41 or 42, a pharmaceutically acceptable salt of claim 43, and a pharmaceutical composition of claim 44.

48. A method for regulating the expression level of AGT mRNA in cells, the method comprising contacting the cells with an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-24, the double-stranded oligonucleotide of any one of claims 25-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43, and the pharmaceutical composition of claim 44.

49. One or more of the following as used as a medicament: a single-stranded oligonucleotide as described in any one of claims 1-24, a double-stranded oligonucleotide as described in any one of claims 25-40, an oligonucleotide conjugate as described in claim 41 or 42, a pharmaceutically acceptable salt as described in claim 43, and a pharmaceutical composition as described in claim 44.

50. A cell expressing AGT mRNA, and the cell comprising one or more of the following: a single-stranded oligonucleotide of any one of claims 1-24, a double-stranded oligonucleotide of any one of claims 25-40, an oligonucleotide conjugate of claim 41 or 42, a pharmaceutically acceptable salt of claim 43, and a pharmaceutical composition of claim 44.

51. A kit comprising one or more of the following: a single-stranded oligonucleotide according to any one of claims 1-24, a double-stranded oligonucleotide according to any one of claims 25-40, an oligonucleotide conjugate according to claim 41 or 42, a pharmaceutically acceptable salt according to claim 43, and a pharmaceutical composition according to claim 44.

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