Oligonucleotide, oligonucleotide conjugate, composition, and use thereof

Abstract

A single-stranded oligonucleotide. Each nucleotide in the single-stranded oligonucleotide is independently a modified or unmodified nucleotide, wherein the single-stranded oligonucleotide has a length and composition that enable the single-stranded oligonucleotide to inhibit the expression of PSD3 mRNA in animals by means of an RNAi mechanism. Disclosed are a double-stranded oligonucleotide comprising 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 Metabolic-associated fatty liver disease (MAFLD), or metabolic dysfunction-associated steatosis (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is defined as fatty liver disease (FLD) with at least one component of metabolic syndrome, excluding excessive alcohol consumption and other causes that may lead to fatty liver. Fatty liver disease (FLD), or steatosis (SLD), is a growing health problem and a leading cause of liver damage worldwide. Fat accumulation in the liver is the hallmark of FLD, which encompasses a range of conditions from simple steatosis to liver inflammation and fibrosis. Progression of FLD to advanced fibrosis can lead to cirrhosis and hepatocellular carcinoma. Treatment of metabolic-associated steatohepatitis (MASH) is a more severe inflammatory phase of MAFLD that requires aggressive intervention. Blocking or reversing MASH is the most critical strategic window to prevent its progression to cirrhosis and hepatocellular carcinoma. Currently, there are very few targeted drugs for MAFLD, with only the thyroid hormone beta receptor agonist Resmetirom approved by the US FDA for MASH. Although various drugs are being developed for MAFLD, clinically, MAFLD patients require a comprehensive assessment of the severity of liver inflammation and / or fibrosis to select appropriate liver injury treatments. Traditional small molecule inhibitors or antibody drugs struggle to target multiple pathogenic sites simultaneously and are easily affected by liver metabolism, limiting their efficacy. Therefore, there remains an urgent need to develop more targeted drugs for the treatment of metabolic-related fatty liver disease. Summary of the Invention This disclosure provides a single-stranded oligonucleotide capable of specifically inhibiting PSD3 mRNA expression in cells, comprising a double-stranded oligonucleotide with the single-stranded oligonucleotide of this disclosure as the antisense strand, an oligonucleotide conjugate, a pharmaceutically acceptable salt, and a pharmaceutical composition. The oligonucleotide and oligonucleotide conjugate of this disclosure can effectively reach hepatocytes and exhibit good pharmaceutical activity and stability. In one aspect, this disclosure provides a single-stranded oligonucleotide, wherein each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein the single-stranded oligonucleotide has a length and composition that enable it to inhibit the expression of animal PSD3 mRNA via an RNAi mechanism. In another aspect, this disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, wherein the sense strand is 15-28 nucleotides in length, each nucleotide in the sense strand is a modified or unmodified nucleotide, and the sense strand and the antisense strand are at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide 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 a group formed by removing one or more atoms or groups of atoms from a single-stranded or double-stranded oligonucleotide provided 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 an active ingredient and pharmaceutically acceptable excipients, said active ingredient comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and pharmaceutically acceptable salts described in this disclosure. In another aspect, this disclosure also provides the use of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts or pharmaceutical compositions of this disclosure in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with PSD3 mRNA levels. In another aspect, this disclosure also provides a method for treating and / or preventing diseases or symptoms associated with PSD3 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 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 one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure for the treatment and / or prevention of diseases or symptoms associated with PSD3 mRNA levels. In another aspect, this disclosure also provides a method for regulating the expression level of the PSD3 gene 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 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 Double-stranded oligonucleotides, oligonucleotide conjugates, and / or pharmaceutical compositions containing the single-stranded oligonucleotides described herein as antisense strands have high activity in regulating PSD3 mRNA, for example, they have good stability and PSD3 mRNA inhibitory activity in cells and in animal models, and therefore have good application prospects for the prevention and / or treatment of MAFLD / MASH. The siRNA, conjugates, and / or pharmaceutical compositions of this disclosure containing the antisense strand of this disclosure exhibit excellent PSD3 mRNA inhibitory effects. For example, in in vitro experiments, the conjugates of this disclosure show excellent inhibitory effects on PSD3 mRNA. The conjugates of this disclosure exhibit high inhibition rates in HEK293A cells; for example, at a concentration of 5 nM, the inhibition rate of the conjugates of this disclosure remains above 50%, reaching a maximum of 71.9%; in some embodiments, the inhibition rate of the conjugates of this disclosure can reach up to 82% at a concentration of 50 nM. As another example, the conjugates of this disclosure exhibit high inhibition rates in primary monkey liver cells expressing the PSD3 gene. At a concentration of 12.5 nM, the inhibitory rate of the conjugate disclosed herein is above 63%, reaching a maximum of 85.9%; at a concentration of 2.5 nM, the inhibitory rate is above 53%, reaching a maximum of 81.7%; and at a concentration of 0.5 nM, the inhibitory rate is above 46%, reaching a maximum of 79.8%. For example, in primary mouse liver cells expressing the PSD3 gene, 48 hours after transfection at a concentration of 50 nM, the inhibitory rate of the conjugate disclosed herein is above 64%, reaching a maximum of 93.2%; and 48 hours after transfection at a concentration of 5 nM, the inhibitory rate is above 56%, reaching a maximum of 88.0%. For example, in primary human liver cells expressing the PSD3 gene, the conjugates disclosed herein exhibited significant inhibitory effects on PSD3 mRNA expression at three different concentrations: 0.5 nM, 5 nM, and 50 nM, with the inhibition rate showing an overall concentration-dependent increase. Even at the relatively low concentration of 0.5 nM, the minimum inhibition rate of PSD3 mRNA expression reached 49.0%, and the maximum reached 85.3%, demonstrating its highly efficient inhibitory effect on PSD3 mRNA expression. The conjugates provided in this disclosure exhibit significant PSD3 mRNA inhibitory activity in vivo. For example, at a single dose of 9 mg / kg, the conjugates provided in this disclosure showed good inhibitory effects on PSD3 mRNA in C57BL / 6J mice on day 8 post-administration, with inhibition rates exceeding 77%. As another example, the conjugates provided in this disclosure showed good inhibitory effects in rats; at a single dose of 9 mg / kg, on day 8 post-administration, the conjugates showed good inhibitory effects on PSD3 mRNA in rats, with inhibition rates exceeding 57%. This demonstrates that the conjugates disclosed herein exhibit excellent pharmaceutical activity in the preparation of remedies for the treatment and / or prevention of diseases or symptoms related to PSD3 mRNA expression, and thus show great promise for development. Incorporate by reference All publications mentioned in this specification, including patents, patent applications, or non-patent documents, are incorporated herein by reference to the same extent that each individual publication 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, PSD3 mRNA refers to the mRNA transcribed from the gene expressing the PSD3 protein in an animal. In some embodiments, PSD3 mRNA refers to the mRNA transcribed from the gene expressing the PSD3 protein in a mammal. In some embodiments, PSD3 mRNA refers to human PSD3 mRNA, specifically the mRNA with the sequence shown in GenBank accession number NM_015310.4, wherein any T may optionally be replaced with U. Further, unless otherwise specified, the term "PSD3 gene" as used in this disclosure refers to the gene that transcribes the aforementioned PSD3 mRNA. definition 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 structure, each base on one strand forms a hydrogen bond with a base on 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, "mismatch" or "base mismatch" in this field means that the bases at corresponding positions between the two single-stranded nucleic acids involved 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 of nucleic acids: between a single-stranded oligonucleotide and PSD3 mRNA; between a single-stranded oligonucleotide and a continuous nucleotide sequence m of PSD3 mRNA; between the sense and antisense strands of a double-stranded oligonucleotide; and between the antisense strand of a double-stranded oligonucleotide and PSD3 mRNA. Unless otherwise specified, "at least partially anti-complementary" means that within a hypothetical or actual double-stranded region, there is no more than 50% base mismatch 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 is 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 is 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. 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 composed 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 capable of forming a double-stranded region may 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 anti-complementary" means that there is no more than 50% base mismatch between the two nucleotide sequences; "substantially anti-complementary" means that there are no more than 3 base mismatches between the two nucleotide sequences; "truly anti-complementary" means that there is no more than 1 base mismatch between the two nucleotide sequences; and "completely anti-complementary" means that there are no base mismatches between the two nucleotide sequences. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of the same length, and the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of each nucleotide sequence, and the overhanging ends of the two nucleotides are of the same length. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of different lengths, and the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of a 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 a longer nucleotide sequence. The double-stranded nucleic acid structure includes a double-stranded region and a dangling end in the antisense strand. 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 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. Various protecting groups, such as hydroxyl or amino protecting groups, may be used in this disclosure. As stated above and below, protecting groups insensitize chemical functional groups to specific reaction conditions and can be added to and removed from such functional groups 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,” a double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate may be administered to a subject at risk of developing a specific disease (e.g., MAFLD or MASH), 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 reducing or eliminating the risk of a specific disease by intervening in the level of PSD3 mRNA or PSD3 protein in a subject at risk of developing the specific disease before the risk progresses to a defined disease course. 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 may also refer to a pharmaceutically acceptable salt of the conjugate. The single-stranded oligonucleotides disclosed herein PSD3 (pleckstrin and Sec7 domain containing 3) is an intracellular protein located on the endoplasmic reticulum membrane. It is widely expressed and primarily found in the brain, heart, liver, adrenal glands, and ovaries. Downregulation of the PSD3 gene has a protective effect against the entire FLD profile in mice and against lipid accumulation in primary human hepatocytes and human and rodent hepatocellular carcinoma cells. In one aspect, this disclosure provides a single-stranded oligonucleotide, wherein each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein the single-stranded oligonucleotide has a length and composition that enable it to inhibit the expression of animal PSD3 mRNA via an RNAi mechanism. In this disclosure, by regulating the expression level of PSD3 mRNA and / or altering the protein level, it is possible to treat or prevent diseases, particularly MAFLD or MASH, that are associated with the expression level and / or protein level of PSD3 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 PSD3 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. As previously described, the length and composition of the single-stranded oligonucleotides disclosed herein enable them to inhibit the expression of animal PSD3 mRNA via RNAi. In some embodiments, the single-stranded oligonucleotides disclosed herein are sufficiently complementary to mammalian PSD3 mRNA. In some embodiments, the single-stranded oligonucleotides disclosed herein are sufficiently complementary to human PSD3 mRNA. In the context of this disclosure, "sufficiently complementary" means that the complementarity between the single-stranded oligonucleotides disclosed herein and PSD3 mRNA is sufficient to reduce or eliminate the production of the protein encoded by the PSD3 mRNA through RNAi. In some embodiments, "sufficiently complementary" means that the single-stranded oligonucleotides disclosed herein are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence m in human PSD3 mRNA, the length of nucleotide sequence m is not greater than the length of the single-stranded oligonucleotide, and the length of nucleotide sequence m is the same as, differs from, the length of the single-stranded oligonucleotide by no more than 8 nucleotides, or differs from the length of the single-stranded oligonucleotide by 1-5 nucleotides. In some embodiments, the two "fully complementary" nucleotide sequences may include completely anticomplementary internal regions (e.g., completely anticomplementary within a double-stranded region of at least 6, 8, or 10 nucleotides in length). In some embodiments, the single-stranded oligonucleotide of this disclosure is completely anticomplementary to nucleotide sequence m 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, in which case the single-stranded oligonucleotide of this disclosure can better mediate RNAi and suppress the level of PSD3 mRNA. As previously stated, nucleotide sequence m is a continuous nucleotide sequence in human PSD3 mRNA. In some embodiments, the length of nucleotide sequence m is at least 16 nucleotides. In some embodiments, the length of nucleotide sequence m is 16-25 nucleotides. In some embodiments, the length of nucleotide sequence m is 18-23 nucleotides. In some embodiments, the length of nucleotide sequence m is 19-21 nucleotides. In some embodiments, the length of nucleotide sequence m is 19, 20, 21, 22, or 23 nucleotides. In some embodiments, the length of nucleotide sequence m is 19, 21, or 23 nucleotides. In some embodiments, nucleotide sequence m is a nucleotide sequence from any one of the nucleotide sequences shown in Table 15, SEQ ID NO:295-SEQ ID NO:311. Table 15 Sequence fragments in PSD3 mRNA In some embodiments, the single-stranded oligonucleotide of this disclosure has the same length as nucleotide sequence m, and at least the nucleotide sequence other than the terminal nucleotide of the single-stranded oligonucleotide is completely anticomplementary to nucleotide sequence m. In this case, the single-stranded oligonucleotide of this disclosure can further improve the inhibition efficiency of PSD3 mRNA. In some embodiments, the nucleotide sequence other than the first position of the single-stranded oligonucleotide of this disclosure is completely anticomplementary to nucleotide sequence m in the 5'-3' direction. In some embodiments, all nucleotides of the single-stranded oligonucleotide of this disclosure are completely anticomplementary to nucleotide sequence m. In some embodiments, the single-stranded oligonucleotide of this disclosure is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to at least 15, at least 16, at least 17, at least 18, or 19 consecutive nucleotides of any one of the sequences shown in Table 1 below (SEQ ID NO:1-SEQ ID NO:38). In some embodiments, the unmodified equivalent sequence of the single-stranded oligonucleotide has at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides with any of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76 in Table 1, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference. In some embodiments, at least nucleotides 2-19 of the unmodified equivalent sequence of the single-stranded oligonucleotide have no more than 1 base difference or no base difference with nucleotides 2-19 of the nucleotide sequences shown in any of SEQ ID NO:39-SEQ ID NO:76 in the 5'-3' direction. 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 positions 1-5 of nucleotide sequence A correspond to positions 2-6 of nucleotide sequence B 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 refers to the base differences calculated from the first nucleotide without base differences to the last nucleotide without base differences in the nucleotide sequence segment using the alignment method with the fewest base differences. In some embodiments, the number of base differences between two identical and perfectly aligned nucleotide sequences 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 identical nucleotide sequences means that, in the same direction, the two nucleotide sequences are perfectly aligned, and 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. In the preceding and following text, "there are X consecutive identical nucleotides between nucleotide sequence A and nucleotide sequence B, and the consecutive identical nucleotides have no more than Y base differences or no base differences" means that nucleotide sequence A contains a continuous nucleotide sequence A' of length X, which is consecutively identical to a continuous nucleotide sequence B' of length X in nucleotide sequence B, and there are no more than Y base differences or no base differences between nucleotide sequence A' and nucleotide sequence B'. In some embodiments, the unmodified equivalent sequence of the single-stranded oligonucleotide of this disclosure includes a first nucleotide sequence having at least 16, at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides between the first nucleotide sequence and any one of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base differences. In some embodiments, at least the 2nd to 19th nucleotides of the first nucleotide sequence in the 5'-3' orientation include no more than one base difference or no base difference between the 2nd to 19th nucleotides of any one of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76. In some embodiments, the unmodified equivalent sequence of the single-stranded oligonucleotide further includes a second nucleotide sequence, which is 1-3 nucleotides in length and located at the 3' end of the single-stranded oligonucleotide, forming the 3' overhang of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the second nucleotide sequence is 2 nucleotides in length, which are two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or completely reverse complementary to human PSD3 mRNA. In some embodiments, the unmodified equivalent sequence of the single-stranded oligonucleotide is of the same length as any of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76 listed in Table 1, and has no more than one base difference or no base difference. In some embodiments, the unmodified equivalent sequence of the single-stranded oligonucleotide is any of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76 listed in Table 1. Modifying nucleotides can improve the stability of oligonucleotides and reduce immunogenicity and off-target effects. siRNA stabilization modification and its delivery system are two key technologies in small RNA drug development. In the drug development of oligonucleotides, including single-stranded and double-stranded oligonucleotides, the improvement of oligonucleotide modification has never ceased. In single-stranded oligonucleotides, such as ASO and ssRNAi, and in double-stranded oligonucleotides, such as the antisense strand of siRNA, the type, position, and amount of modification can significantly affect key properties such as pharmacodynamic activity, stability, and long-lasting effect. Although existing technologies disclose numerous oligonucleotide modification schemes, how to improve the modification of oligonucleotides, especially single-stranded and double-stranded oligonucleotides' antisense strands, to obtain oligonucleotides with higher activity, higher stability, and / or long-lasting effect remains a research direction in this field. In some embodiments, at least one nucleotide in the single-stranded oligonucleotides described herein is a modified nucleotide. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotides described herein is no more than one, or each nucleotide is a modified nucleotide. In this context, "unmodified nucleotide" refers to an unmodified ribonucleotide (RNA), i.e., the 2' position of the ribose sugar in the nucleotide is an unprotected hydroxyl group (2'-OH). Accordingly, "modified nucleotide" refers to a nucleotide in which the hydroxyl group at the 2' position of the ribose sugar is replaced by another atom or group, or refers to a nucleotide analogue. In some embodiments, in the single-stranded oligonucleotides of this disclosure, at least one nucleotide is nucleotide X or a fluorinated nucleotide; and, in the 5'-3' direction, at least one nucleotide X or fluorinated nucleotide is located after the 8th nucleotide of the single-stranded oligonucleotide, and is spaced 4-7 nucleotides apart from the 8th nucleotide of the single-stranded oligonucleotide, that is, at least one nucleotide X or fluorinated nucleotide is located in one of the 13th-16th nucleotides of the single-stranded oligonucleotide counting from the 5' end; and, if, in the 5'-3' direction, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X or a fluorinated nucleotide, and the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of ribose 2'-alkoxy modified nucleotides, ribose 2'-substituted alkoxy modified nucleotides, alkyl modified nucleotides, substituted alkyl modified nucleotides, amine modified nucleotides, heat-labile nucleotides, and BNA. Each nucleotide X is independently selected from deoxynucleotides or unmodified nucleotides. 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, for ease of synthesis, each ribose 2'-alkoxy modified nucleotide is independently a 2'-methoxy modified nucleotide (2'-OMe), as shown in Formula (8). In some embodiments, each ribose 2'-substituted alkoxy modified nucleotide is independently a 2'-O-methoxyethyl modified nucleotide (2'-MOE), as shown in Formula (9). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in Formula (10). Wherein, Base represents a nucleic acid base, independently selected from A, U, G, C, 5mC (5-methylcytosine) or T; This indicates the site where the group is covalently linked. 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 thermally unstable modifications described in this paragraph. In some embodiments, the single-stranded oligonucleotides described in this disclosure do not contain thermally unstable nucleotides. BNA refers to a restricted or inaccessible nucleotide. BNA can contain a bridging structure with a "fixed" C3'-endoglucan condensation, consisting of a five-membered, six-membered, 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, BNA can be LNA, ENA, cET BNA, etc., where LNA is shown in formula (12), ENA in formula (13), and cET BNA in formula (14), where Base represents a nucleic acid base: In some embodiments, each BNA in the single-chain oligonucleotides described in this disclosure refers to an LNA or cET BNA. In some embodiments, BNA is not present in the single-chain oligonucleotides described in this disclosure. In some embodiments, in the single-stranded oligonucleotides of this disclosure, at least one nucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide; and, in the 5'-3' direction, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and is spaced 4-7 nucleotides apart from the 8th nucleotide of the single-stranded oligonucleotide, that is, at least one nucleotide X is located in one of the 13th-16th nucleotides of the single-stranded oligonucleotide counting from the 5' end; and, if, in the 5'-3' direction, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X, and the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of ribose 2'-alkoxy modified nucleotides, ribose 2'-substituted alkoxy modified nucleotides, and BNA. Each nucleotide X is independently selected from deoxynucleotides or unmodified nucleotides. The inventors have specifically discovered that the single-stranded oligonucleotides disclosed herein, by including fluorinated nucleotides and nucleotide X, can effectively maintain the high inhibitory activity of double-stranded oligonucleotides and oligonucleotide conjugates against PSD3 mRNA while maintaining stability. In some embodiments, the number of nucleotides X is 1-3, for example, 1 or 2. In some embodiments, each nucleotide X is located after the 8th nucleotide in the single-stranded oligonucleotide in the 5'-3' direction; and in the 5'-3' direction, each nucleotide X is separated from the 8th nucleotide in the single-stranded oligonucleotide by 3, 5, or 7 nucleotides; that is, in the 5'-3' direction, each of the nucleotides X is independently the 12th, 14th, or 16th nucleotide in the single-stranded oligonucleotide. In some embodiments, one of the nucleotides X is separated from the 8th nucleotide by 5 nucleotides; that is, in the 5'-3' direction, one of the nucleotides X is the 14th nucleotide X in the single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide contains only one nucleotide X, which is spaced 5 nucleotides away from the 8th nucleotide in the single-stranded oligonucleotide along the 5'-3' direction; that is, nucleotide X is the 14th nucleotide in the single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide contains two nucleotides X, wherein one nucleotide X is spaced 5 nucleotides away from the 8th nucleotide in the single-stranded oligonucleotide, and the other nucleotide X is spaced 3 or 7 nucleotides away from the 8th nucleotide in the single-stranded oligonucleotide; in other words, the 12th and 14th nucleotides, or the 14th and 16th nucleotides, in the single-stranded oligonucleotide are nucleotides X. Each nucleotide X is independently selected from deoxyribonucleotides or unmodified nucleotides. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide, along the 5'-3' orientation, are nucleotide X, and the other nucleotides are modified nucleotides. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide, along the 5'-3' orientation, is a deoxyribonucleotide, and the other nucleotides are modified nucleotides. In some embodiments, the number of modified nucleotides accounts for more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide of this disclosure; or, the number of unmodified nucleotides in the single-stranded oligonucleotide does not exceed 5, 4, or 3. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, all nucleotides in the single-stranded oligonucleotide are modified nucleotides. As previously stated, in addition to nucleotide X, the single-stranded oligonucleotides described in this disclosure also include fluorinated nucleotides. In some embodiments, the number of fluorinated nucleotides is 2-7. In some embodiments, with respect to the 5'-3' orientation, the fluorinated nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides of the single-stranded oligonucleotide. In some embodiments, with respect to the 5'-3' orientation, the fluorinated nucleotides are 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-stranded oligonucleotide. In some embodiments, with respect to the 5'-3' orientation, the fluorinated nucleotides are the 2nd, 6th, and 16th nucleotides of the single-stranded oligonucleotide. In some embodiments, with respect to the 5'-3' orientation, the fluorinated nucleotides are the 2nd, 5th, 7th, 12th, and 16th nucleotides of the single-stranded oligonucleotide. In some embodiments, the fluorinated nucleotides, with respect to the 5'-3' orientation, are the 2nd, 7th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure does not contain nucleotide X, but contains at least one fluorinated nucleotide. In some embodiments, the single-stranded oligonucleotide contains 5-10 fluorinated nucleotides, and in the 5'-3' orientation, the 2nd and 14th nucleotides of the antisense strand are fluorinated nucleotides, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, and one of the 15th-17th nucleotides is a fluorinated nucleotide. In some embodiments, in the 5'-3' orientation, the 2nd and 14th nucleotides of the single-stranded oligonucleotide are fluorinated nucleotides, the 5th nucleotide is a fluorinated nucleotide, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, one of the 15th-17th nucleotides is a fluorinated nucleotide, and the 18th or 19th nucleotide is a fluorinated nucleotide. In some embodiments, each modified nucleotide other than nucleotide X and the fluorinated nucleotide is independently selected from ribose 2'-alkoxy-modified nucleotides or ribose 2'-substituted alkoxy-modified nucleotides. In some embodiments, the number of ribose 2'-substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed three. In some embodiments, the number of ribose 2'-substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed two. In some embodiments, the number of ribose 2'-substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is one. In some embodiments, in the single-stranded oligonucleotide, when not nucleotide X or a fluorinated nucleotide, the 3rd, 5th, and 13th nucleotides are all ribose 2'-substituted alkoxy-modified nucleotides or ribose 2'-substituted alkoxy-modified nucleotides in the 5'-3' direction. In some embodiments, in the single-stranded oligonucleotide, when not nucleotide X or a fluorinated nucleotide, one or two of the 3rd, 5th, and 13th nucleotides are each independently ribose 2'-substituted alkoxy-modified nucleotides or ribose 2'-substituted alkoxy-modified nucleotides in the 5'-3' direction. In some embodiments, the single-stranded oligonucleotide does not contain ribose 2'-substituted alkoxy-modified nucleotides. In some embodiments, the single-stranded oligonucleotides of this disclosure are 19-23 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X, two of the 5th-7th and 19th nucleotides, as well as the 2nd, 12th, and 16th nucleotides, are fluorinated nucleotides, the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and the 5th nucleotide, if not fluorinated, is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotides of this disclosure are 19-23 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X, the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-substituted alkoxy-modified nucleotide or BNA, the 3rd or 5th nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotides of this disclosure are 19-23 nucleotides in length, and in the 5'-3' direction, the 2nd and 14th nucleotides are fluorinated nucleotides, the 5th nucleotide is a fluorinated nucleotide, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, one of the 15th-17th nucleotides is a fluorinated nucleotide, the 18th or 19th nucleotide is a fluorinated nucleotide, the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in a 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a ribose 2'-alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and the 2nd, 5th, 7th, 12th, 14th, 16th, and 19th nucleotides are fluorinated nucleotides in the 5'-3' direction, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy modified nucleotide. In some embodiments, each ribose 2'-alkoxy modified nucleotide of the present disclosure is a ribose 2'-C1-C3 alkoxy modified nucleotide, such as a ribose 2'-methoxy modified nucleotide. In some embodiments, each ribose 2'-substituted alkoxy modified nucleotide of the present disclosure is a ribose 2'-C1-C3 alkoxy modified nucleotide with a substituent, wherein the substituent can be any suitable substituent, such as a C1-C3 alkoxy. In some embodiments, each ribose 2'-substituted alkoxy modified nucleotide of the present disclosure is a ribose 2'-O-methoxyethyl modified nucleotide. In some embodiments, at least two of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide of this disclosure are phosphate groups with modifying groups. In some embodiments, one to four of the linking groups between adjacent nucleotides in the 5' end (1-5 nucleotides) of the single-stranded oligonucleotide of this disclosure are phosphate groups with modifying groups. In some embodiments, one to four of the linking groups between adjacent nucleotides in the 3' end (1-5 nucleotides) of the single-stranded oligonucleotide of this disclosure are phosphate groups with modifying groups. In some embodiments, two or four linking groups between adjacent nucleotides in the 5' end (1-3 nucleotides) of the single-stranded oligonucleotide of this disclosure are phosphate groups with modifying groups. In some embodiments, two or four linking groups between adjacent nucleotides in the 3' end (1-3 nucleotides) of the single-stranded oligonucleotide of this disclosure are phosphate groups with modifying groups. In some embodiments, in the single-stranded oligonucleotides of this disclosure, if unmodified nucleotides are present, one or both of the two linking groups between each unmodified nucleotide and its adjacent nucleotides are phosphate ester groups with modified groups. Modified phosphate ester groups can enhance the resistance of the single-stranded oligonucleotides of this disclosure to exonuclease activity and improve their stability in the body. In some embodiments, each of at least two linking groups between adjacent nucleotides in the single-stranded oligonucleotides of this disclosure is independently a phosphate ester group with modified groups. In some embodiments, 2-6 linking groups between adjacent nucleotides in the single-stranded oligonucleotides are phosphate ester groups with modified groups. In some embodiments, 3 or 4 linking groups between adjacent nucleotides in the single-stranded oligonucleotides are phosphate ester groups with modified groups. In some embodiments, each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the single-stranded oligonucleotide, and each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 3' end, is independently a phosphate ester group with modified groups. In some embodiments, the phosphate group having the modifying group is a thiophosphate group having the structure shown in formula (28): In some embodiments, the 5'-terminal nucleotide of the single-stranded oligonucleotide of this disclosure 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 5'-vinylphosphonate (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 5'-vinylphosphonate (5'-(E)-vinylphosphonate, E-VP) modification. In some embodiments, the 5'-terminal nucleotide being a vinylphosphonate (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, with the 14th nucleotide being nucleotide X and being a deoxynucleotide in the 5'-3' direction, the 2nd, 5th, 7th, 12th and 16th nucleotides being fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide being independently ribose 2'-methoxy modified nucleotides; each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end being independently thiophosphate groups, and each of the linking groups between adjacent nucleotides in the remaining adjacent nucleotides being independently phosphate groups; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, with the 14th nucleotide being nucleotide X and being a deoxynucleotide in the 5'-3' direction, the 2nd, 7th, 12th, 16th and 19th nucleotides being fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide being independently ribose 2'-methoxy modified nucleotides; each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end being independently thiophosphate groups, and each of the linking groups between adjacent nucleotides in the remaining adjacent nucleotides being independently phosphate groups; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, with the 14th nucleotide being nucleotide X and being a deoxynucleotide in the 5'-3' direction, the 2nd, 6th, 12th, 16th and 19th nucleotides being fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide being independently ribose 2'-methoxy modified nucleotides; each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end being independently thiophosphate groups, and each of the linking groups between adjacent nucleotides in the remaining adjacent nucleotides being independently phosphate groups; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, with the 14th nucleotide being nucleotide X and being a deoxynucleotide in the 5'-3' direction, the 2nd, 6th and 16th nucleotides being fluorinated nucleotides, the 13th nucleotide being a ribose 2'-O-methoxyethyl modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide being an independently ribose 2'-methoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end being an independently thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides being an independently phosphate group; the 5' terminal nucleotide being a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, with the 2nd, 5th, 7th, 12th, 14th, 16th and 19th nucleotides being fluorinated nucleotides in the 5'-3' direction, and each of the remaining nucleotides being independently ribose 2'-methoxy modified nucleotides; each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end being independently thiophosphate groups, and each of the linking groups between adjacent nucleotides being independently phosphate groups; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). In some embodiments, the single-stranded oligonucleotide of this disclosure has at least 16, 17, 18, 19, 20, or 21 consecutive identical nucleotides with any one of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference. In some embodiments, along the 5'-3' direction, at least the 2nd to 19th nucleotides of the single-stranded oligonucleotide of this disclosure have no more than 1 base difference with the 2nd to 19th nucleotides of any one of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2, or no base difference. In some embodiments, the single-chain oligonucleotides described herein are any one of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2. In some embodiments, the single-chain oligonucleotides described herein are any one of the nucleotide sequences shown in SEQ ID NO:223-SEQ ID NO:274 listed in Table 3. 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. 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, wherein the sense strand is 15-28 nucleotides in length, each nucleotide in the sense strand is independently modified or unmodified, and the sense strand and antisense strand are at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide described above in this disclosure. In the double-stranded oligonucleotides of this disclosure, the length of the sense strand is 15-28 nucleotides. 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 19-23 nucleotides, and the length of the antisense strand is 19-26 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 difference between the sense strand and the antisense strand is 0-5 nucleotides. In some embodiments, the length of the sense strand is no greater than the length of the antisense strand. In some embodiments, the sense strand and antisense strand are of the same length, each independently being 19, 20, or 21 nucleotides. In some embodiments, the sense strand is 19-21 nucleotides long, the antisense strand is 20-24 nucleotides long, and the antisense strand is 1-3 nucleotides longer than the sense strand. In some embodiments, the antisense strand is 2 nucleotides longer than the sense strand. In some embodiments, for ease of synthesis, the sense strand is 19, 20, or 21 nucleotides long, and the antisense strand is 19-23 nucleotides long. In some embodiments, the sense and antisense strands are of the same length, each independently being 19, 20, or 21 nucleotides; or the sense strand is 19 nucleotides long and the antisense strand is 20-24 nucleotides long; or the sense strand is 20 nucleotides long and the antisense strand is 21-24 nucleotides long; or the sense strand is 21 nucleotides long and the antisense strand is 22-24 nucleotides long. In some embodiments, the sense strand is 19 nucleotides long and the antisense strand is 21 nucleotides long. In some embodiments, both the sense and antisense strands are 21 nucleotides long. In some embodiments, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long. In the double-stranded oligonucleotides described in this disclosure, the sense strand and antisense strand are at least partially anticomplementary to form a double-stranded region. In some embodiments, the double-stranded oligonucleotides of this disclosure consist of a substantially anticomplementary or fully 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 oligonucleotides of this disclosure consist of a substantially anticomplementary or fully anticomplementary double-stranded region and one dangling end of the antisense strand. In some embodiments, the double-stranded oligonucleotides of this disclosure consist of a substantially anticomplementary or fully anticomplementary double-stranded region and one dangling end at the 3' end of the antisense strand, the dangling end comprising 1-3 nucleotides. In some embodiments, the length of the double-stranded region formed by the sense and antisense strands is at least 16 nucleotides. In some embodiments, the length of the double-stranded region formed by the sense and antisense strands is 16-23 nucleotides. In some embodiments, the length of the double-stranded region formed by the sense and antisense strands is 18, 19, 20, or 21 nucleotides. 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 of 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 some embodiments, the unmodified equivalent sequence of the positive strand is identical to any one of the sequences shown in SEQ ID NO:1-SEQ ID NO:38 listed in Table 1 for at least 15, at least 16, at least 17, at least 18, or 19 consecutive nucleotides, and the consecutive identical nucleotides have a difference of no more than 3 bases, no more than 1 base, or no base difference. In some embodiments, in the 5'-3' direction, at least the first 18 nucleotides of the unmodified equivalent sequence of the positive strand include a difference of no more than 1 base or no base difference between the first 18 nucleotides of the nucleotide sequence shown in any one of SEQ ID NO:1-SEQ ID NO:38 listed in Table 1. In some embodiments, in the double-stranded oligonucleotides of this disclosure, the unmodified equivalent sequence of the positive strand is of the same length as any one of the nucleotide sequences shown in SEQ ID NO:1-SEQ ID NO:38 in Table 1, and has no more than one base difference or no base difference. In some embodiments, in the double-stranded oligonucleotides of this disclosure, the unmodified equivalent sequence of the positive strand is any one of the nucleotide sequences shown in SEQ ID NO:1-SEQ ID NO:38 in Table 1. In some embodiments, in the double-stranded oligonucleotides of this disclosure, the unmodified equivalent sequence of the double-stranded oligonucleotide is compared with any of the unmodified siRNAs listed in Table 1, wherein the unmodified equivalent sequence of the sense strand is at least 15, at least 16, at least 17, at least 18, or 19 consecutive identical nucleotides between the sense strand of the unmodified equivalent sequence of the double-stranded oligonucleotide and any of the siRNAs listed in Table 1, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference; the unmodified equivalent sequence of the antisense strand of the double-stranded oligonucleotide is at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides between the unmodified equivalent sequence of the antisense strand of the double-stranded oligonucleotide and the antisense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference. In some embodiments, in the 5'-3' orientation, at least the first 1-18 nucleotides of the unmodified equivalent sequence of the sense strand of the double-stranded oligonucleotide include no more than one base difference or no base difference between the first 1-18 nucleotides of the sense strand of any one of the siRNAs in Table 1 (siRNA1-siRNA38); at least the second 19 nucleotides of the unmodified equivalent sequence of the antisense strand of the double-stranded oligonucleotide include no more than one base difference or no base difference between the second 19 nucleotides of the antisense strand of the siRNA. In some embodiments, the unmodified equivalent sequence of the double-stranded oligonucleotide has the same length as the sense and antisense strands of any one of the siRNAs shown in Table 1 (siRNA1-siRNA38), and differs from the sense and antisense strands of that siRNA by one base or has no base difference. In some embodiments, the unmodified equivalent sequence of the double-stranded oligonucleotide is any one of the siRNAs shown in Table 1 (siRNA1-siRNA38). Table 1 Unmodified double-stranded oligonucleotides In some embodiments, in the double-stranded oligonucleotides of this disclosure, 2-3 of the 11th-13th nucleotides of the positive strand in the 3'-5' direction are fluorinated nucleotides, and the first and / or last nucleotide of the positive strand is a ribose 2'-alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having the structure shown in formula (35)). In some embodiments, in the 3'-5' direction, the first nucleotide of the positive strand is a ribose 2'-alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide. In some embodiments, apart from the fluorinated and inverted abasic deoxyribonucleotides described above, each remaining nucleotide in the positive strand is independently a non-fluorinated nucleotide, and each non-fluorinated nucleotide is independently selected from one of ribose 2'-alkoxy-modified nucleotides, alkyl-modified nucleotides, amine-modified nucleotides, and thermally unstable nucleotides. In some embodiments, the 3' terminal nucleotide and / or 5' terminal nucleotide of the positive strand of the double-stranded oligonucleotide are the reverse debased deoxynucleotides. 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 second nucleotide starting from the 3' end 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 second nucleotide starting from the 3' end 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 in Formula (35) that is connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the second nucleotide starting from the 5' end of the positive strand. In some embodiments, the oxygen atom in Formula (35) that is connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the second nucleotide starting from the 5' end of the positive strand, and the oxygen atom in Formula (35) that is 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 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 in the 3'-5' orientation are fluorinated nucleotides, the first nucleotide and / or the last nucleotide of the sense strand is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy-modified nucleotide. In some embodiments, each ribose 2'-alkoxy-modified nucleotide is independently a ribose 2'-methoxy-modified nucleotide. In some embodiments, in the positive strand, at least one of the linking groups between adjacent nucleotides is a phosphate group with a modifying group, and the phosphate group with the modifying group is present at least once between 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 some embodiments, 1 to 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand, and / or 1 to 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand are phosphate groups with modifying groups. In some embodiments, all four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand are phosphate groups with modifying groups. In some embodiments, all four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand are phosphate groups with modifying groups. In some embodiments, the linking group connecting two adjacent nucleotides in the 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 5' and / or 3' ends of the sense strand is a phosphate ester group with a modifying group. In some embodiments, each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3rd nucleotides at the 5' end of the sense strand, and / or each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3rd nucleotides at the 3' end of the sense strand, is independently a phosphate ester group with a modifying group. The definition and selection range of the phosphate ester group with a modifying group are the same as those described above for the antisense strand of this disclosure. In some embodiments, each phosphate ester group with a modifying group is a thiophosphate ester group having the structure shown in formula (28). 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 in the 3'-5' direction are fluorinated nucleotides, the first and / or last nucleotide of the sense strand is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; 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 thiophosphate groups. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 5' end and / or 3' end of the sense strand is a thiophosphate group, and the linking groups between the remaining adjacent nucleotides in the sense strand are phosphate groups. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 5' end of the positive strand is a phosphate ester 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 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 3' end of the positive strand is a phosphate ester group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. 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 3'-5' direction, the 1st and / or the last nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3th nucleotides at the 5' end of the sense strand, and / or each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3rd nucleotides at the 3' end of the sense strand, is independently a phosphate ester group with a modifying group, and the remaining... Each linker group between adjacent nucleotides is independently a phosphate ester group; in the antisense strand, in the 5'-3' direction, the 14th nucleotide is nucleotide X, two of the 5th-7th and 19th nucleotides, as well as the 2nd, 12th, and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and if the 5th nucleotide is not a fluorinated nucleotide, it is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy-modified nucleotide; or, in the 5'-3' direction, the 14th nucleotide is nucleotide X, the 5 ... Nucleotides 2, 6, and 16 are fluorinated nucleotides; the 13th nucleotide is a ribose 2'-substituted alkoxy-modified nucleotide or BNA; the 3rd or 5th nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide; and each of the remaining nucleotides is independently a ribose 2'-alkoxy-modified nucleotide; or, in the 5'-3' direction, the 2nd and 14th nucleotides are fluorinated nucleotides; the 5th nucleotide is fluorinated nucleotide; one of the 6th-8th nucleotides is fluorinated nucleotide; one of the 11th-13th nucleotides is fluorinated nucleotide; one of the 15th-17th nucleotides is fluorinated nucleotide; and the 18th nucleotide... Alternatively, the 19th nucleotide may be a fluorinated nucleotide, the 3rd nucleotide may be a ribose 2'-alkoxy modified nucleotide or a ribose 2'-substituted alkoxy modified nucleotide, and each of the remaining nucleotides may be independently a ribose 2'-alkoxy modified nucleotide; and each of the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end, may be independently a phosphate ester group with a modifying group, and each of the linking groups between adjacent nucleotides may be independently a phosphate ester group; and the 5' terminal nucleotide of the antisense strand may be a 5'-hydroxy nucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide. 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, the 11th and 13th nucleotides are fluorinated nucleotides along the 3'-5' direction, the first nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the sense strand is independently a phosphate thioester group, and the remaining adjacent... Each linker group between nucleotides is independently a phosphate ester group; in the antisense strand, along the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; or, in the antisense strand, along the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, and the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides. Each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; or, in the antisense strand, along the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxynucleotide, the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated modified nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; or, in the antisense strand, along the 5'-3' direction, the 2nd, 5th, 7th, 12th, 14th, 16th, and 19th nucleotides are fluorinated modified nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; Each nucleotide is independently a ribose 2'-methoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 3' end, is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate 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). 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 in the 3'-5' direction are fluorinated nucleotides, the first nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the 1-5 or 1-3 nucleotides at the 5' end of the sense strand is independently a thiophosphate group, and each of the linking groups between adjacent nucleotides is independently a phosphate group; in the antisense strand, nucleotide 14 in the 5'-3' direction is nucleotide X and is The deoxynucleotide, wherein the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-O-methoxyethyl nucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; each of the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end, is independently a thiophosphate group, and each of the linking groups between adjacent nucleotides is independently a phosphate group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate nucleotide of formula (31). The double-stranded oligonucleotides disclosed herein, through the aforementioned modification schemes, achieve a good balance between gene expression regulatory activity and in vivo stability. In the context of this disclosure, "modification scheme" refers to a combination of different numbers, positions, and types of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications 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 schemes, can maintain excellent stability without significantly reducing the original drug activity of the double-stranded oligonucleotide, thereby achieving a good balance between gene expression regulatory activity and in vivo stability. In some embodiments, the double-stranded oligonucleotide of this disclosure is siRNA. By having the above-described modification scheme, the double-stranded oligonucleotide of this disclosure can maintain excellent stability without significantly reducing the original RNAi activity of siRNA, thereby achieving a good balance between PSD3 mRNA inhibitory activity and in vivo stability. In some embodiments, compared with any of the modified siRNAs listed in Table 2, the double-stranded oligonucleotide of this disclosure has at least 15, at least 16, at least 17, at least 18, or 19 consecutive identical nucleotides between the sense strand of the double-stranded oligonucleotide of this disclosure and the sense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference; the antisense strand of the double-stranded oligonucleotide has at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides between the antisense strand of the double-stranded oligonucleotide and the antisense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference. In some embodiments, in the double-stranded oligonucleotide, at least the first to 18 nucleotides of the sense strand of the double-stranded oligonucleotide, in the 5'-3' orientation, have a base difference of no more than one or no base difference between the first to 18 nucleotides of the sense strand of the modified siRNA listed in Table 2; at least the second to 19 nucleotides of the antisense strand of the double-stranded oligonucleotide have a base difference of no more than one or no base difference between the second to 19 nucleotides of the antisense strand of the modified siRNA. In some embodiments, the sense and antisense strands of the double-stranded oligonucleotide are of equal length to the sense and antisense strands of any of the modified siRNAs shown in Table 2, and there is a difference of one base or no base difference between the sense and antisense strands of the siRNA and the original siRNA. In some embodiments, the double-stranded oligonucleotide is any of the modified siRNAs listed in Table 2. In some embodiments, the double-stranded oligonucleotide corresponds to the double-stranded oligonucleotide group contained in any of the conjugates 1-52 listed in Table 3. Table 2 Modified double-stranded oligonucleotides In this context, uppercase letters C, G, U, A, and T represent the base composition of nucleotides; uppercase letter Z independently represents either U or T; lowercase letter o indicates that the nucleotide represented by the uppercase letter to its left is a ribose 2'-alkoxy modified nucleotide; lowercase letter f indicates that the nucleotide represented by the uppercase letter to its left is a 2'-fluoro modified nucleotide; lowercase letter s indicates that the nucleotide represented by the two closest uppercase letters to the left and right of s is linked by a phosphate ester group with a modifying group; lowercase letter x indicates that the nucleotide represented by the two closest uppercase letters to the left and right of x is linked by a phosphate ester group with a modifying group. The two capital letters represent nucleotides linked by a phosphate ester group with a modifying group; the lowercase letter d indicates that the nucleotide represented by the capital letter to the right of d is a deoxyribonucleotide; the lowercase letter e indicates that the nucleotide represented by the capital letter to the left of e is a ribose 2'-substituted alkoxy-modified nucleotide; ia indicates a reverse debased deoxynucleotide; P1 indicates that the nucleotide represented by the capital letter to the right of ia is a 5'-hydroxynucleotide, a 5'-phosphate nucleotide, or a 5'-vinyl phosphate nucleotide. In some embodiments, each Z is independently T. In some embodiments, each x is independently a thiophosphate ester group. In some embodiments, each phosphate ester group with a modifying group is independently a thiophosphate ester group. In some embodiments, each ribose 2'-alkoxy-modified nucleotide is independently selected from ribose 2'-methoxy-modified nucleotides. In some embodiments, each ribose 2'-substituted alkoxy-modified nucleotide is independently selected from ribose 2'-O-methoxyethyl-modified nucleotides. In some implementations, each P1 independently represents a nucleotide modified with 5'-vinyl phosphate (VP) represented by a capital letter on the right. The single-stranded 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 single-stranded 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 single-stranded 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 and / or double-stranded oligonucleotides provided in this disclosure can be used alone, or combined with a delivery group to form oligonucleotide conjugates, or combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition, or used in any other suitable form. Contacting an effective amount of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition with cells to modulate the expression of a target gene, or administering an effective amount of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition to a subject to modulate the expression of a target gene, thereby achieving the purpose of treating a pathological condition or disease associated with the level of target gene expression. The oligonucleotide conjugates disclosed herein In another aspect, this disclosure provides 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 of atoms from a single-stranded or double-stranded oligonucleotide provided in this disclosure. An oligonucleotide 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 an oligonucleotide group into a cell expressing PSD3 mRNA. In some embodiments, the cells expressing PSD3 mRNA are hepatocytes, and the delivery group comprises a linker and a pharmaceutically acceptable target group, wherein the oligonucleotide group, the linker, and the target group are covalently or non-covalently linked in sequence, and at least one or each of the target groups is independently selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, there are 1-6 target groups. In one embodiment, there are 2-4 target groups. 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. When the oligonucleotide group is a double-stranded oligonucleotide group, 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 3' or 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 double-stranded oligonucleotide chain, it 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 the double-stranded oligonucleotide group, it 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 the double-stranded oligonucleotide group, 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 double-stranded 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, such as the delivery group being attached to the positive and negative strands of the double-stranded oligonucleotide group, the impact of the conjugation on the activity of the double-stranded oligonucleotide group can be minimized. The targeting group can be linked to the double-stranded oligonucleotide group via a suitable adapter. Those skilled in the art can select a suitable adapter based on the specific type of the targeting group. For details on these adapters, the types of targeting groups, and the connection methods with the double-stranded oligonucleotide, please refer to 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 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 independently a ligand with affinity for desialyl glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, at least one or each of the target groups is independently a desialyl glycoprotein or a sugar. In some embodiments, at least one or each of the target groups is independently selected from D-mannopyranoside, L-mannopyranoside, D-arabinose, D-xylfuranose, L-xylfuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannopyranoside, β-D-mannopyranoside, α-D-mannopyranoside, β-D-mannopyranoside, α-D-glucose pyranopyranoside, β-D-glucose pyranopyranoside, α-D-glucose pyranopyranoside, β-D-glucose pyranopyranoside. 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-tri-O-acetyl-1 -One of the following: 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 a group formed by removing an atom or group from L-4-thioribose. In some embodiments, at least one or each of the target groups is a galactose or N-acetylgalactosamine group formed by removing an atom or group from galactose or N-acetylgalactosamine. 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 linkers in the oligonucleotide conjugates of this disclosure have 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 LC 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 is independently 2 or 3; 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 connector has a structure as shown in formula (304) or formula (305): In the aforementioned connector, 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 C The 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 (309): Wherein, Nu represents the oligonucleotide group formed by the oligonucleotides provided in this disclosure. In some embodiments, the linkers in the oligonucleotide conjugates of this disclosure have 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 the oligonucleotide group formed by the 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 a hydrogen atom, methyl or ethyl, 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 represented by A0 is an oligonucleotide group, which is a double-stranded oligonucleotide group formed by removing an atom or group of atoms from the oligonucleotide described in this disclosure; each of the remaining groups represented by A0 is an independent target group, and each target group may be the same or different, and its definition and selection range are as described above. Each L1 is independently a divalent linker with a length of 3-70 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-C10 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 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 10alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (Halogenated alkyl groups). As used herein, “alkyl” refers to a straight-chain and branched saturated hydrocarbon group having a specified number of carbon atoms, typically from 1 to 30 carbon atoms, such as 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C1-C6 alkyl groups comprise straight-chain and branched alkyl groups having 1 to 6 carbon atoms. When referring to an alkyl residue having a specific number of carbon atoms, it is intended to encompass all branched and straight-chain forms having that number of carbon atoms; thus, for example, “butyl” means including n-butyl, sec-butyl, isobutyl, and tert-butyl; “propyl” includes n-propyl and isopropyl. Alkylene is a subset of alkyl groups, referring to residues identical to alkyl groups but with two bonding sites. As used herein, “saturated hydrocarbon group” refers to a hydrocarbon group in which all carbon atoms are linked by single bonds and which does not contain carbon-carbon double bonds and / or carbon-carbon triple bonds. 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, "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 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. "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: 1,2,3-triazolyl, aziridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, and 1,4-benzodioxalkyl. ioxanyl), benzonaphthylfuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophenyl, benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cinnolinyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H- Cyclopentano[4,5]thieno[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, dibenzothienoyl, 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, purineyl, pyrroleyl, pyrazolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4]pyrimidinyl -d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinoxalinyl, quinoxalinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinoxalinyl, 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 The compounds include pyridyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl (thieno[2,3-c]pridinyl), and thiophenyl / thienyl. 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. In the foregoing or hereinafter, "substituted" groups include substituted alkyl groups, substituted alkoxy groups, substituted amino groups, substituted aliphatic groups, substituted heteroaliphatic groups, substituted acyl groups, substituted aryl groups, or substituted heteroaryl groups. Unless otherwise specified, a "substituted" group refers to a group formed by replacing one or more hydrogen atoms in the group with one or more substituents. For example, "substituted alkoxy" refers to a group formed by replacing one or more hydrogen atoms in the alkoxy group with a substituent. Those skilled in the art will understand that compounds applicable to the present disclosure may contain various substituents, as long as the introduction of such substituents does not affect the function of the present disclosure and achieves the purpose of the present 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-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), -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 10Alkyl, -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. 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 cells expressing PSD3 mRNA through the targeting effect of the target group, without affecting the regulatory effect of the oligonucleotide group on PSD3 mRNA levels after entering the cells. 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 independently 1-6 atoms. L B3Selected from one of the following: phosphate ester group, thiophosphate ester group, and dithiophosphate ester group; when the oligonucleotide group is a double-stranded oligonucleotide group, L B3 The oxygen atom remaining after removing one hydrogen atom from the 5' hydroxyl group of the 5' terminal nucleotide of the sense or antisense strand of the double-stranded oligonucleotide group is covalently linked to the 3' hydroxyl group 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 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 an independent 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 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 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, Nu represents an siRNA group. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the 3' terminal nucleotide of the positive strand of the siRNA group. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom remaining after removing a hydrogen atom from the 3' hydroxyl group of the ribose of the 3' terminal nucleotide of the positive strand of the siRNA group represented by Nu. In some embodiments, the 3' terminal nucleotide of the positive strand of the siRNA group is a reverse debased deoxynucleotide, and the P atom shown in formulas (403)-(422) is covalently linked to the siRNA group by substituting a hydrogen atom in the hydroxyl group of the 3' terminal reverse debased deoxynucleotide of the positive strand of the siRNA group represented by Nu through a methylene group linked to the ribose ring. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom of the reverse debased deoxynucleotide ia shown in formula (35) at the 3' end of the positive strand of the siRNA group represented by Nu, thereby covalently linking it to the positive strand of the siRNA group. 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 any of the modified siRNAs shown in Table 2. In some embodiments, the double-stranded oligonucleotide groups contained in the oligonucleotide conjugates are siRNA groups contained in any one of conjugates 1-52 shown in Table 3. In some embodiments, the oligonucleotide conjugates are any one of conjugates 1-52 shown in Table 3. siRNA conjugates containing these siRNA groups exhibit excellent stability and high PSD3 mRNA inhibitory activity. This disclosure relates to the preparation of oligonucleotide conjugates. Those skilled in the art can prepare the oligonucleotide conjugates described herein by various suitable methods. For example, 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 by solid-phase synthesis, delivery groups can be introduced by 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 by methods well known to those skilled in the art. For example, WO2014025805A1 describes a method for preparing the structure shown in formula (309), 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. Those skilled in the art can use various suitable methods to separate and purify the conjugates of this disclosure, such as ultrafiltration, column chromatography, reversed-phase column chromatography, or ion-exchange chromatography. Depending on the separation and purification method, the obtained conjugate may be an oligonucleotide conjugate or a different pharmaceutically acceptable salt thereof. In some embodiments, the conjugates of this disclosure are purified by sodium ion-exchange chromatography to obtain the sodium salt of the oligonucleotide conjugate. The pharmaceutically acceptable salts disclosed herein 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 herein, each adjacent nucleotide is linked by a phosphodiester bond or a thiophosphate diester bond, the non-bridging oxygen or sulfur atom in the phosphodiester bond or thiophosphate diester bond being negatively charged. This phosphodiester bond or thiophosphate diester bond may be present in the form of a hydroxyl or mercapto group, and the hydrogen ion in the hydroxyl or mercapto group may be partially or completely replaced by a cation. The cation may be any cation, such as a metal cation, ammonium ion (NH4+). +The delivery group may contain a salt-forming group, such as a phosphate group. For improved 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 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 salts or sodium salts; and the alkaline earth metal salt is selected from calcium salts or magnesium salts. In some embodiments, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or an N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt is a salt or a partial salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or the oligonucleotide conjugate disclosed herein, wherein the salt or partial salt is one or more of a methylamine salt, a triethylamine salt, or a sodium salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate described in this disclosure is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate described in this disclosure is a mixture of a methylamine salt and an ammonium salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate. The pharmaceutical compositions disclosed herein In another aspect, this disclosure also provides a pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and their 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 solution, the pharmaceutically acceptable excipient is a solvent, such as deionized water, water for injection, physiological saline, ethanol, aqueous ethanol solution, or 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 oligonucleotide conjugate, 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 double-stranded 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 double-stranded oligonucleotides and pharmaceutically acceptable carriers in the pharmaceutical composition. In some embodiments, the weight ratio of double-stranded 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 any 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) to (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 oligonucleotides or oligonucleotide conjugates of this disclosure and the aforementioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm. 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 by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide to all lipids (e.g., organic amines, auxiliary lipids and / or polyethylene glycol-modified lipids) is in the range of about 1:1 to about 1:50, about 1:1 to about 1:30, about 1:3 to about 1:20, about 1:4 to about 1:18, about 1:5 to about 1:17, about 1:5 to about 1:15, about 1:5 to about 1:12, about 1:6 to about 1:12 or about 1:6 to about 1:10. For example, the weight ratio of the oligonucleotide to all lipids of the present disclosure 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, except that the oligonucleotide or oligonucleotide conjugate provided in this disclosure is used instead of the existing double-stranded oligonucleotide; 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 (based on 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 oligonucleotides or oligonucleotide conjugates 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 oligonucleotides or oligonucleotide conjugates is 1:(2-5). 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. Applications of the oligonucleotides, oligonucleotide conjugates and pharmaceutical compositions disclosed herein This disclosure also provides the use of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with PSD3 mRNA levels of a target gene. In some embodiments, the disease or symptom associated with PSD3 mRNA levels is MAFLD. In some embodiments, the MAFLD is selected from one or more of simple steatosis, MASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma. In some embodiments, the disease or symptom associated with PSD3 mRNA levels is one or more of MASH or MASH-induced cirrhosis. In some embodiments, MASH is selected from one or more of fatty liver, hepatitis, cirrhosis, and hepatocellular carcinoma. This disclosure also provides a method for treating and / or preventing diseases or symptoms associated with PSD3 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 and their pharmaceutically acceptable salts, and pharmaceutical compositions 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 one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure for the treatment and / or prevention of diseases or symptoms associated with PSD3 mRNA levels. In addition, this disclosure also provides a method for regulating the expression level of the PSD3 gene 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, and pharmaceutically acceptable salts and pharmaceutical compositions of the present disclosure. As used herein, the term "administration" refers to the delivery of a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutically acceptable salt thereof, a pharmaceutical composition, and / or an oligonucleotide conjugate into a subject by means of a method or route that at least partially positions a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutically acceptable salt thereof, a pharmaceutical composition, and / or an oligonucleotide conjugate at 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 single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, and / or oligonucleotide conjugates and their pharmaceutically acceptable salts to a specific site compared to the entire body of the subject; while systemic administration results in the delivery of said single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, and / or oligonucleotide conjugates and their pharmaceutically acceptable salts 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 dosages of the single-stranded oligonucleotides, double-stranded oligonucleotides, and / or oligonucleotide conjugates, and their pharmaceutically acceptable salts and / or pharmaceutical compositions described in this disclosure are conventional dosages in the art, 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). Ranges of human dosages can be derived based on data obtained from cell culture analysis and animal studies. When administering the oligonucleotides, pharmaceutical compositions, and / or oligonucleotide conjugates 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, when the oligonucleotides described in this disclosure are siRNAs, the amount of siRNA in the siRNA, pharmaceutical composition, and / or siRNA conjugate is as follows: for siRNA conjugates formed by siRNA and pharmaceutically acceptable conjugate molecules, the amount of siRNA 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 amounts are preferred when administering the siRNA, pharmaceutical composition, and / or siRNA conjugates described in this disclosure. The methods provided in this disclosure for inhibiting PSD3 gene expression in cells utilize oligonucleotides, including single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, and / or oligonucleotide conjugates and their pharmaceutically acceptable salts. The amount of oligonucleotides 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 PSD3 mRNA levels 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 target cell surface. The amount required to achieve this local concentration will vary depending on various factors, including the delivery method, delivery site, the number of cell layers between the delivery site and the target cell 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 cell or tissue. The reagent kit disclosed herein In another aspect, this disclosure also provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions provided in this disclosure. In some embodiments, the kit described herein may provide one or more of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and their pharmaceutically acceptable salts and pharmaceutical compositions in a single container. In some embodiments, the kit described herein may include a container providing pharmaceutically acceptable excipients. In some embodiments, the kit may also contain 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 the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions and / or conjugates and their pharmaceutically acceptable salts described herein. In some embodiments, the kit may include instructions for mixing one or more of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and their pharmaceutically acceptable salts and pharmaceutical compositions with a pharmaceutically acceptable carrier and / or excipients or other ingredients (if any). In the kits disclosed herein, the single-stranded oligonucleotides, double-stranded oligonucleotides, and pharmaceutically acceptable carriers and / or excipients, as well as the pharmaceutical compositions and / or oligonucleotide conjugates, and / or pharmaceutically acceptable excipients, may be provided in any form, such as liquid, dry, or lyophilized. In some embodiments, the single-stranded oligonucleotides, 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, this disclosure is further described in detail below in examples of embodiments and exemplary embodiments where the double-stranded oligonucleotides in the pharmaceutical compositions and / or oligonucleotide conjugates of this disclosure are small interfering RNAs (siRNAs). In these examples, the double-stranded oligonucleotides, pharmaceutical compositions, and oligonucleotide conjugates of this disclosure are siRNAs, siRNA-containing pharmaceutical compositions, and siRNA conjugates, respectively. In the context of this disclosure, for ease of description, the siRNAs, siRNA-containing pharmaceutical compositions, and siRNA conjugates in these embodiments are also referred to as the siRNAs of this disclosure, the pharmaceutical compositions of this disclosure, and the siRNA conjugates of this disclosure. This does not mean that the double-stranded oligonucleotides of this disclosure can only be siRNAs; rather, the double-stranded oligonucleotides can be other variants disclosed herein or known to those skilled in the art, such as small activating RNAs (saRNAs), etc. It is contemplated that, based on the detailed description of siRNAs, 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 cell culture, real-time PCR and other operations used are all performed in accordance with the methods described in Molecular Cloning (Cold Spring Harbor Laboratory (1989)). Preparation Example 1: Synthesis of siRNA conjugates 1-52 provided in this disclosure Following the preparation method described in Preparation Example 14 of CN110959011A, conjugates 1-52 as shown in Table 3 were prepared, with the only difference being that the sense and antisense strands of the siRNA contained in each siRNA conjugate are shown in Table 3. For nucleic acid sequences containing the sense and antisense strand sequences of siRNAs numbered as conjugates 1-52 in Table 3, nucleoside phosphoramide monomers were linked one by one to synthesize the sense and antisense strands of the siRNA conjugates. After single-chain synthesis, the sense and antisense chains of conjugates 10-12 and 51-52 were first purified by self-packed column ionization using strong anion exchange packing material, and then purified by desalting using a HiPrep 26 / 13 Desalting pre-packed column. After annealing, conjugates 10-12 and 51-52 were sodium salts of compounds having the structure shown in formula (403). The sense and antisense chains of other conjugates 1-9 and 13-50 were purified by centrifugal ultrafiltration using 3K (MWCO) ultrafiltration tubes. After annealing, conjugates 1-9 and 13-50 were mixtures of methylamine and ammonium salts of compounds having the structure shown in formula (403). Conjugates 1-52 are compounds having the structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the oxygen atom at the 3' end of the positive strand of the siRNA group represented by Nu, as shown in formula (35), and connected to the positive strand of the siRNA group via a methylene ring. Furthermore, the siRNA group contained in this siRNA conjugate has the siRNA sequence corresponding to conjugates 1-52 in Table 3. Table 3. siRNA sequences in siRNA conjugates In this context, uppercase letters C, G, U, and A 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 a ribose 2'-methoxy modified nucleotide; lowercase letter f indicates that the nucleotide represented by the uppercase letter to the left of f is a 2'-fluoro modified nucleotide; lowercase letter s indicates that the nucleotides represented by the two uppercase letters to the left and right of s are linked by a thiophosphate group; lowercase letter d indicates that the nucleotide represented by the uppercase letter to the right of d is a deoxyribonucleotide; the letter combination moe indicates that the nucleotide represented by the uppercase letter to the left of moe is a ribose 2'-O-methoxyethyl modified nucleotide; the letter combination VP indicates that the nucleotide represented by the uppercase letter to the right of VP is a 5'-vinyl phosphate (VP) modified nucleotide; and ia indicates a reverse debased deoxynucleotide. 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℃)). The molecular weight of some conjugates was then determined using liquid chromatography-mass spectrometry (LC-MS, Waters Corporation, model: LCT Premier). The results are shown in Table 4. The measured values ​​are consistent with the theoretical values, indicating that the synthesized conjugates contain the designed double-stranded nucleic acid sequence. Table 4 shows the molecular weights of some of the conjugates. Comparative Preparation Example 1: Synthesis of Reference Conjugates 1-2 Following the same method used in Preparation Example 1 for preparing conjugate 1, reference conjugates 1-2 as shown in Table 3 were prepared by solid-phase synthesis. Reference conjugates 1-2 are mixtures of the methylamine salt and ammonium salt of a compound with the structure shown in formula (403), wherein the conjugate group is attached to the 3' position of the ribose of the 3' terminal nucleotide of the positive strand of the siRNA group represented by Nu. Furthermore, the siRNA group contained in reference conjugates 1-2 has the negative control siRNA sequence corresponding to reference conjugates 1-2 in Table 3, which is a negative control sequence that is not homologous to any known human, mouse, rat, or monkey mRNA. Experimental Example 1: Inhibitory activity of the disclosed conjugate in HEK293A cells Experimental Example 1-1 This experimental example determined the lipofectamine content. TM Activity of conjugate 13-50 transfected with 2000 in HEK293A cells. HEK293A cells (purchased from Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60436) were cultured in DMEM containing 10% FBS (referred to as complete medium). Cells were digested with trypsin, and the cell concentration was adjusted to 1×10⁶ cells / year using complete medium. 5 Cells were seeded at a density of 1 mL / well in 12-well plates, with 1 mL of cell culture per well. The 12-well plates were then incubated at 37°C in a CO2 incubator (containing 5% CO2 and 95% air) for 24 hours. Before transfection, all complete culture medium was removed from each well and replaced with 1 mL of Opti-MEM medium per well. The conjugate 13-50 obtained in Preparation Example 1 was prepared into a 20 μM conjugate storage solution using PBS. Preparation of 1A0 solution: 1A0 solution contains 3 μL of the above conjugate storage solution and 97 μL of Opti-MEM culture medium. Preparation of 1B0 solution: 1B0 solution contains 1 μL of Lipofectamine TM 2000 and 99 μL of Opti-MEM culture medium. For each conjugate to be tested, one part of 1A0 solution was mixed with one part of 1B0 solution and incubated at room temperature for 20 min to obtain transfection complex 1X. The 1B0 solution was mixed with 100 μL of Opti-MEM culture medium and incubated at room temperature for 20 min to obtain blank transfection complex 1X'. In three culture wells (each containing HEK293A cells and 1 mL of Opti-MEM medium, the same below), 200 μL of transfection complex 1X was added to each well to obtain a transfection mixture with a final concentration of 50 nM (based on the amount of siRNA), which was designated as test group 1X. 13 -1X 50 In the other three culture wells, 200 μL of transfection complex 1X' was added to each well to obtain a transfection mixture that did not contain the siRNA conjugate, which was designated as the blank control group. Transfection mixtures containing and without the conjugate were introduced into separate wells and incubated with cells in a 12-well plate in a CO2 incubator. Four hours after transfection, 1 mL of complete culture medium was added to each well. The above test group 1X... 13 -1X 50 Both the control and blank control groups were placed in a CO2 incubator and incubated overnight at 37°C. 24 hours after transfection, the culture was completed, and total RNA was extracted from the cells using TRIZOL (purchased from SIGMA, Cat. No. T9424) according to the method described in the instructions. For each well of cells, 1 μg of total RNA was taken and transduced using the reagents provided by the Promega Reverse Transcription Kit (Promega, Cat. No. A3500), with Oligo(dT) selected as the primary RNA. 17 As primers, a 20 μL reverse transcription reaction system was prepared according to the reverse transcription procedure in the kit instructions, and the total RNA from each well was reverse transcribed. The reverse transcription conditions were as follows: each reverse transcription reaction 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 DEPC water was added to each 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, and 20 μL of qPCR reaction system was prepared using the reagents provided by the SYBR Select Master Mix kit (Thermo, catalog number 4472908). The PCR primer sequences used to amplify the target gene PSD3 and the internal reference gene GAPDH are shown in Table 5, and the final concentration of each primer is 0.25 μM. Table 5 Primer Information Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument and amplified using a three-step method. 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 W containing amplified target gene PSD3 and internal reference gene GAPDH. Product W was then incubated sequentially at 95℃ for 1 min, 55℃ for 30 s, and 95℃ for 30 s. The melting curves of target gene PSD3 and internal reference gene GAPDH in product W were collected using a real-time quantitative PCR instrument, and the Ct values ​​of target gene PSD3 and internal reference gene GAPDH were obtained. The relative quantification of the target gene PSD3 mRNA in each test group was performed using the Ct(ΔΔCt) method, 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 three culture wells in the blank control group. Therefore, each culture well in both the test group and the blank control group corresponds to a ΔCt value. The expression level of PSD3 mRNA in the test group was normalized based on the mean of the blank control group, and the mean of PSD3 mRNA expression level in the blank control group was defined as 100%. The relative expression level of PSD3 mRNA in the test group = 2 - ΔΔCt(test group) × 100% The inhibition rate of PSD3 mRNA in the test group = (1 - relative expression level of PSD3 mRNA in the test group) × 100%. The inhibition rates of each conjugate on PSD3 mRNA are shown in Table 6A. Table 6 shows the inhibition rate of conjugate A on PSD3 mRNA in HEK293A cells. As shown in Table 6A, the conjugate disclosed herein exhibits a high mRNA inhibition rate in HEK293A cells. At a concentration of 50 nM, the conjugate disclosed herein can inhibit PSD3 mRNA by up to 82%. Experimental Examples 1-2: These experimental examples determined the lipofectamine content. TM Activity of conjugates 1-9 transfected with 2000 in HEK293A cells. Using the same method as in Experiment 1-1, the inhibition rate of conjugates 1-9 on PSD3 mRNA in HEK293A cells was determined. The difference was that the test conjugates were conjugates 1-9 prepared in Preparation Example 1 and reference conjugate 2 prepared in Comparative Preparation Example 1. The final transfection concentration (based on the amount of siRNA) of each conjugate was 50 nM and 5 nM, respectively. The inhibition rate of each conjugate on PSD3 mRNA is shown in Table 6B. Table 6 shows the inhibition rate of conjugate B on PSD3 mRNA in HEK293A cells. As shown in Table 6B, the conjugate disclosed herein exhibits a high inhibition rate in HEK293A cells. At a concentration of 5 nM, the inhibition rate of the conjugate disclosed herein remains above 50%, reaching a maximum of 71.9%. Experimental Example 2: Inhibitory activity of the disclosed conjugate in primary monkey liver cells Primary monkey liver cells were purchased from Myosun (Shanghai) Biotechnology Co., Ltd. (Catalog No.: CCH-100CYS-PQ). Cell resuscitation was performed according to the provided culture medium and reagents, following the manufacturer's instructions. 40 mL of resuscitation medium (Catalog No. HTS-R-40) was preheated to 37°C. Cryopreservation tubes containing cells were placed in a 37°C water bath and gently agitated until some ice crystals thawed. The cell suspension was then poured into the preheated resuscitation medium, rinsed, and mixed thoroughly. The cell suspension was centrifuged at 180 g for 1 min at room temperature, the supernatant was discarded, and the cells were resuspended in 20 mL of plating medium (Catalog No. HPM-R-40). After cell counting, the cells were plated. Prepare collagen-coated cell culture plates in advance. Add 1.7 mg of rat tail collagen type I (catalog number: AR0001-02) to 40 mL of basal medium (catalog number: HCM-BM-40) and mix well to obtain the coating medium. Add 1 mL of the above coating medium to each well of a 12-well plate and incubate at 37°C for 0.5-2 hours. Dilute cells to 1×10⁻⁶ using plating medium.5 Cells / mL (live cell count), discard the coating medium in a 12-well plate, add 1 mL of cell culture to each well, shake well, and incubate at 37°C in an incubator containing 5% CO2 / 95% air. After 4-6 hours of cell attachment, discard the coating medium, add 1 mL of maintenance medium (product number: HMM-R-40) to each well, and incubate at 37°C in an incubator containing 5% CO2 / 95% air until transfection. Use Lipofectamine TM RNAiMAX (Thermo, catalog number 13778150) was used to transfect test conjugates 1-9 and reference conjugate 1 into primary monkey liver cells. The final concentrations of each conjugate were 12.5 nM, 2.5 nM, and 0.5 nM (based on siRNA), with two replicates per concentration. Cells untreated with any conjugate served as a blank control. Cells treated with reference conjugate 1 served as a negative control. The 12-well plates containing transfected cells were placed in an incubator containing 5% CO2 / 95% air and cultured at 37°C for 24 hours. The inhibition rates of conjugates 1-9 on PSD3 mRNA in primary monkey liver cells were determined using the same detection method as in Experiment 1-1, with the following differences: 1) the PCR primers used for amplifying PSD3 and GAPDH as an internal reference gene are shown in Table 7; 2) each test group consisted of primary monkey liver cells transfected with conjugates 1-9, the negative control group consisted of primary monkey liver cells transfected with reference conjugate 1, and the blank control group consisted of primary monkey liver cells not transfected with any conjugate. The inhibition rates of each conjugate on PSD3 mRNA are shown in Table 8. Table 7 Primer Information Table 8. Inhibition rate of conjugates on PSD3 mRNA in primary monkey liver cells As shown in Table 8, the conjugates disclosed herein exhibit high inhibition rates in primary monkey liver cells expressing the PSD3 gene. At a concentration of 12.5 nM, the inhibition rates of the conjugates disclosed herein are all above 63%, with a maximum of 85.9%; at a concentration of 2.5 nM, the inhibition rates are above 53%, with a maximum of 81.7%; and at a concentration of 0.5 nM, the inhibition rates are above 46%, with a maximum of 79.8%. Experimental Example 3: Inhibitory activity of the disclosed conjugate in primary mouse liver cells Liver tissues from perfused C57BL / 6J mice (SPF grade, 6-8 weeks old, male, purchased from Spiford (Beijing) Biotechnology Co., Ltd.) were washed with calcium-magnesium HBSS (manufacturer: Zhongke Maichen, catalog number CCo16) and transferred to sterile culture dishes. The liver capsule was torn open, and cells were gently released by agitation in DMEM (manufacturer: Zhongke Maichen, catalog number CM15o19) containing 10% FBS and 1% penicillin antibiotics. Cells were filtered through a 70-75 μm cell sieve, centrifuged at 500 rpm for 3 minutes, and the supernatant was discarded. The cells were washed once with DMEM and resuspended in Opti-MEM. 20 μL of the cell suspension was mixed with an equal volume of trypan blue, and the viability was counted after 3 minutes (viable cells / total cells × 100%). Based on the viable cell concentration, the cells were diluted with Opti-MEM to 1 × 10⁻⁶. 5 Cells / mL were seeded at 1 mL / well into collagen-coated 12-well plates for subsequent cell transfection. Use Lipofectamine TM RNAiMAX transfected C57BL / 6J mouse primary liver cells with conjugates 4, 5, 7, and 8, respectively, at final concentrations of 50 nM and 5 nM (based on siRNA), with two replicates per concentration. Cells untreated with any conjugate served as blank controls. The test group and blank control group, transfected with different concentrations of conjugates, were harvested at 24 and 48 hours post-transfection, respectively, and RNA was extracted for Real-time PCR detection. Using the same detection method as in Experiment 1-1, the inhibition rates of conjugates 4, 5, 7, and 8 on PSD3 mRNA in primary mouse liver cells were determined. The difference lies in the PCR primer sequences used to amplify the target gene mPSD3 and the internal reference gene mGAPDH, as shown in Table 9. Table 9 Primer Information The inhibition rates of each conjugate on PSD3 mRNA are shown in Table 10. Table 10. Inhibition rate of conjugates on PSD3 mRNA in primary liver cells of C57BL / 6J mice. As shown in Table 10, the conjugate disclosed herein exhibits a high inhibition rate in primary mouse liver cells expressing the PSD3 gene. At a concentration of 50 nM, 48 hours after transfection, the inhibition rate of the conjugate disclosed herein is above 64%, reaching a maximum of 93.2%; at a concentration of 5 nM, 48 hours after transfection, the inhibition rate of the conjugate disclosed herein is above 56%, reaching a maximum of 88.0%. Experimental Example 4: Inhibitory activity of the disclosed conjugate in primary human liver cells This experiment investigated the inhibitory activity of conjugates 1-5 and 7-8 on PSD3 mRNA in primary human liver cells. Human primary liver cells were obtained from BioIVT (catalog number: M00995-SCERT). Cell resuscitation was performed according to the provided culture medium and reagents, following the manufacturer's instructions. 5 mL of culture medium (purchased from BioIVT, catalog number Z990029) was preheated to 37°C. The cryovials containing cells were placed in a 37°C water bath and gently inverted until the contents were completely thawed. The cell suspension was poured into preheated plating medium, the cryovials were rinsed, and the cell suspension was mixed thoroughly. The cells were gently inverted to ensure complete resuscitation. After cell counting, the cells were plated. The cell suspension was then spread at a ratio of 2 × 10⁶ cells / mL. 5 Cells were seeded in 24-well plates (supplier: Corning, catalog number: 3527), with 400 μL of seeding medium added to each well. After 24 hours of incubation, the medium was replaced with 500 μL of maintenance medium (purchased from BioIVT, catalog number Z990009), and the plates were incubated at 37°C in a 5% CO2 / 95% air incubator until transfection. Use Lipofectamine TM RNAiMAX transfected human primary liver cells with test conjugates 1-5 and 7-8, respectively, at final concentrations of 50 nM, 5 nM, and 0.5 nM (based on siRNA levels); cells without any conjugate treatment served as blank controls. The test group and blank control group were transfected with different concentrations of conjugates. 48 h after transfection, the cells were harvested and RNA was extracted for Real-time PCR detection. Total RNA was extracted from cells in each well using Buffer RLT (Qiagen, catalog number 79216) according to the manufacturer's instructions. For each well, 0.1 μg of total RNA was taken and reverse transcribed using the iScript cDNA synthesis kit (BioRad, catalog number 1708891) according to the manufacturer's instructions to obtain 20 μL of cDNA-containing solution. The reverse transcription conditions were as follows: for each reverse transcription reaction system, incubation was performed at 25°C for 5 min, then at 46°C for 20 min, and finally at 95°C for 1 min. For each reverse transcription reaction system, 2 μL of the above-mentioned cDNA-containing solution was used as a template, and 10 μL of qPCR reaction system was prepared using reagents provided by SsoAdvanced Universal Probes Supermix (supplier: Bio-Rad, catalog number: 1725280). The PCR primers for amplifying the target gene PSD3 were purchased from Applied Biosystems (catalog number: 4331182, assay number: Hs00939867_m1), and the PCR primers for the internal reference gene GAPDH were purchased from Bio-Rad (catalog number: 10031230, assay number: qHsaCEP0041396). Each qPCR reaction system was placed on a real-time quantitative PCR instrument (purchased from Bio-Rad, model CFX Opus 96). The amplification program was 95℃ polymerase activation for 30s, 95℃ denaturation for 10s, and 60℃ annealing / extension for 20s. The above denaturation, annealing / extension process was repeated for a total of 40 times to obtain the Ct values ​​of the target gene PSD3 and the internal reference gene GAPDH. The expression level of the target gene PSD3 mRNA in each test group was relatively quantitatively calculated using the Ct(ΔΔCt) method. The same calculation method as in Experiment 1-1 was used. All experimental data are expressed as averages. The inhibition rate of different conjugates on PSD3 mRNA is shown in Table 11. Table 11 Inhibition rate of conjugates on PSD3 mRNA in primary human liver cells As shown in Table 11, under three different concentrations of 0.5 nM, 5 nM, and 50 nM, all conjugates exhibited significant inhibitory effects on PSD3 mRNA expression, with the inhibition rate generally increasing in a concentration-dependent manner. Even at the relatively low concentration of 0.5 nM, the minimum inhibition rate on PSD3 mRNA expression reached 49.0%, and the maximum reached 85.3%, demonstrating its highly efficient inhibitory effect on PSD3 mRNA expression. Experiment 5: Activity test of the conjugate in mice (in vivo) This experiment investigated the inhibitory efficiency of conjugates 4, 10, 11, 12 and 51 on PSD3 mRNA expression in C57BL / 6J mice. Thirty male C57BL / 6J mice (SPF grade, 6-8 weeks old; purchased from SPAF (Beijing) Biotechnology Co., Ltd.) were randomly divided into 6 groups of 5 mice each. All animals were given the drug via subcutaneous injection after calculating the dosage based on body weight. The test groups were administered conjugates 4, 10, 11, 12, and 51 at a dose of 9 mg / kg (based on siRNA). Each conjugate was provided in PBS aqueous solution at a dose of 1.8 mg / mL (based on siRNA), with an administration volume of 5 mL / kg. Another group of mice was given PBS (purchased from Zhongke Maichen (Beijing) Technology Co., Ltd., catalog number: CC008; the same applies to PBS mentioned above and below) at a dose of 5 mL / kg, serving as the blank control group. Day 1 was marked as the day of drug administration. Mice were sacrificed on day 8, and liver tissue was collected from each mouse. The liver tissue was preserved using RNA later (Sigma Aldrich), homogenized using a tissue homogenizer, and then total RNA was extracted from the liver tissue of each mouse using the MagaBio Plus RNA Purification Kit II (purchased from Hangzhou Borui Technology Co., Ltd., catalog number: BSC69L1E) according to the operating steps described in the instructions. Using the same detection method as in Experiment 1-1, the expression level of PSD3 mRNA in the livers of mice given different conjugates was detected by quantitative real-time PCR. For each mouse, 1 μg of total RNA extracted from liver tissue was used for reverse transcription. The difference was that the PCR primer sequences used to amplify the target gene mPSD3 and the internal reference gene mGAPDH were shown in Table 9 above. The expression level of the target gene PSD3 mRNA in each test group was relatively quantitatively calculated using the Ct(ΔΔCt) method. The same calculation method as in Experiment 1-1 was used. All experimental data are expressed as mean ± standard deviation. The inhibition rate of different conjugates on PSD3 mRNA is shown in Table 12. Table 12 Inhibition rate of each conjugate on PSD3 mRNA in C57BL / 6J mice As shown in Table 12, the conjugates provided in this disclosure showed good inhibitory effects on PSD3 mRNA in C57BL / 6J mice on day 8 after a single dose of 9 mg / kg, with inhibition rates exceeding 77%. Experiment 6: Activity test of the conjugate in rats (in vivo) This experimental example used the same method as Experiment 5 to investigate the inhibitory efficiency of conjugates 4, 10, 11, 12, and 51 on PSD3 mRNA expression in rats (purchased from Spiford (Beijing) Biotechnology Co., Ltd.). Rats were used instead of mice in this experiment, and the dosage remained at a single dose of 9 mg / kg. The difference was that the PCR primer sequences used to amplify the target gene rat PSD3 and the internal reference gene rat GAPDH are shown in Table 13. The inhibition rates of each conjugate on PSD3 mRNA in rats are shown in Table 14. Table 13 Primer Information Table 14 Inhibition rate of each conjugate on PSD3 mRNA in rats As shown in Table 14, the conjugates provided in this disclosure, at a single dose of 9 mg / kg, exhibited good inhibitory effects on PSD3 mRNA in rats on day 8 after administration, with inhibition rates all greater than 57%. 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 all such simple modifications 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, wherein each nucleotide in the single-stranded oligonucleotide is independently a modified or unmodified nucleotide, wherein, This single-stranded oligonucleotide has a length and composition that enable it to suppress the expression of animal PSD3 mRNA via an RNAi mechanism.

2. The single-chain oligonucleotide as described in claim 1, wherein, The single-chain oligonucleotide has a length of 16-30, 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 single-stranded oligonucleotide is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence m in human PSD3 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.

4. The single-chain oligonucleotide as described in claim 3, wherein, 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; or, The nucleotide sequence m is a segment of any of the nucleotide sequences shown in SEQ ID NO:295-SEQ ID NO:

311.

5. The single-stranded oligonucleotide as described in claim 3 or 4, wherein, The single-stranded oligonucleotide has the same length as the nucleotide sequence m; at least the nucleotide sequence of the single-stranded oligonucleotide other than the terminal nucleotide is completely inversely complementary to the nucleotide sequence m.

6. The single-chain oligonucleotide of claim 5, wherein, In the 5'-3' direction, the nucleotide sequence other than the first position 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.

7. The single-stranded oligonucleotide according to any one of claims 1-6, wherein the single-stranded oligonucleotide is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to at least 15, at least 16, at least 17, at least 18, or 19 consecutive nucleotides of any one of the sequences shown in SEQ ID NO:1-SEQ ID NO:38 listed in Table 1.

8. The single-stranded oligonucleotide according to any one of claims 1-7, wherein the unmodified equivalent sequence of the single-stranded oligonucleotide has at least 16, at least 17, at least 18, at least 19, at least 20 or 21 consecutive identical nucleotides between the unmodified equivalent sequence of the single-stranded oligonucleotide and the nucleotide sequences shown in any one of SEQ ID NO:39-SEQ ID NO:76 listed in Table 1, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference or no base difference.

9. The single-chain oligonucleotide of claim 8, wherein, In the 5'-3' orientation, at least the 2nd to 19th nucleotides of the unmodified equivalent sequence of the single-stranded oligonucleotide include no more than one base difference or no base difference between the 2nd to 19th nucleotides of the nucleotide sequences shown in any one of SEQ ID NO:39-SEQ ID NO:76 listed in Table 1.

10. The single-chain oligonucleotide of claim 8, wherein, The unmodified equivalent sequence of the single-stranded oligonucleotide includes a first nucleotide sequence that has at least 16, at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides with any one of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:76, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base differences.

11. The single-chain oligonucleotide of claim 10, wherein, In the 5'-3' orientation, at least the 2nd to 19th nucleotides of the first nucleotide sequence have a base difference of no more than one or no base difference between the 2nd to 19th nucleotides of any one of the nucleotide sequences shown in SEQ ID NO:39-SEQ ID NO:

76.

12. The single-stranded oligonucleotide of claim 10 or 11, wherein, The unmodified equivalent sequence of the single-stranded oligonucleotide also includes a second nucleotide sequence, which is 1-3 nucleotides in length and located at the 3' end of the single-stranded oligonucleotide, forming the 3' overhang of the antisense strand of the double-stranded oligonucleotide after its formation; or, the second nucleotide sequence is 2 nucleotides in length, which are two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or completely reverse complementary to human PSD3 mRNA.

13. The single-stranded oligonucleotide according to any one of claims 1-12, wherein the unmodified equivalent sequence of the single-stranded oligonucleotide is of equal length to the nucleotide sequence shown in any one of SEQ ID NO:39-SEQ ID NO:76 listed in Table 1, and has no more than one base difference or no base difference; or, The unmodified equivalent sequence of the single-stranded oligonucleotide is any one of the nucleotide sequences shown in Table 1, from SEQ ID NO:39 to SEQ ID NO:

76.

14. The single-stranded oligonucleotide according to any one of claims 1-13, wherein, At least one nucleotide is a modified nucleotide.

15. The single-stranded oligonucleotide of claim 14, wherein, The number of unmodified nucleotides is no more than one, or each nucleotide is a modified nucleotide.

16. The single-stranded oligonucleotide of claim 15, wherein, At least one nucleotide in the single-stranded oligonucleotide is nucleotide X or a fluorinated nucleotide; Furthermore, in the 5'-3' direction, at least one nucleotide X or a fluorinated nucleotide is located after the 8th nucleotide of the single-stranded oligonucleotide and is separated from the 8th nucleotide by 4-7 nucleotides; Furthermore, if, in the 5'-3' direction, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X or a fluorinated nucleotide, and the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of the following: ribose 2'-alkoxy modified nucleotides, ribose 2'-substituted alkoxy modified nucleotides, alkyl modified nucleotides, substituted alkyl modified nucleotides, amine modified nucleotides, heat-labile nucleotides, and BNA; each nucleotide X is independently selected from deoxynucleotides or unmodified nucleotides.

17. The single-stranded oligonucleotide of claim 15 or 16, 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 5'-3' direction, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is separated from the 8th nucleotide by 4-7 nucleotides; Furthermore, if, in the 5'-3' direction, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X, and the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of ribose 2'-alkoxy modified nucleotides, ribose 2'-substituted alkoxy modified nucleotides, and BNA; each nucleotide X is independently selected from deoxynucleotides or unmodified nucleotides.

18. The single-stranded oligonucleotide of claim 17, wherein, The number of nucleotides X is 1-3.

19. The single-stranded oligonucleotide of claim 17 or 18, wherein, In the 5'-3' orientation, each nucleotide X is located after the 8th nucleotide in the single-stranded oligonucleotide; and in the 5'-3' orientation, each nucleotide X is separated from the 8th nucleotide in the single-stranded oligonucleotide by 3, 5, or 7 nucleotides; or, one of the nucleotides X is separated from the 8th nucleotide by 5 nucleotides.

20. The single-chain oligonucleotide of claim 19, wherein, The single-stranded oligonucleotide contains only one nucleotide X, which is spaced 5 nucleotides apart from the 8th nucleotide in the single-stranded oligonucleotide in the 5'-3' orientation.

21. The single-chain oligonucleotide according to any one of claims 17-20, wherein, The number of fluorinated nucleotides is 2-7.

22. The single-chain oligonucleotide of claim 21, wherein, The fluorinated nucleotides, arranged in the 5'-3' direction, are 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th and 19th nucleotides of the single-stranded oligonucleotide.

23. The single-chain oligonucleotide of claim 22, wherein, In the 5'-3' direction, the fluorinated nucleotides are one or two of the 2nd and 12th nucleotides, one or two of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides.

24. The single-chain oligonucleotide of claim 23, wherein, The fluorinated nucleotides, in the 5'-3' orientation, are the 2nd, 6th, and 16th nucleotides of the single-stranded oligonucleotide; 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.

25. The single-stranded oligonucleotide of claim 15 or 16, wherein, The single-stranded oligonucleotide contains 5-10 fluorinated nucleotides, and in the 5'-3' direction, the 2nd and 14th nucleotides of the antisense strand are fluorinated nucleotides, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, and one of the 15th-17th nucleotides is a fluorinated nucleotide.

26. The single-chain oligonucleotide of claim 25, wherein, In the 5'-3' orientation, the 2nd and 14th nucleotides of the single-stranded oligonucleotide are fluorinated nucleotides, the 5th nucleotide is a fluorinated nucleotide, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, one of the 15th-17th nucleotides is a fluorinated nucleotide, and the 18th or 19th nucleotide is a fluorinated nucleotide.

27. The single-stranded oligonucleotide according to any one of claims 16-26, wherein, In the single-stranded oligonucleotide, each modified nucleotide other than nucleotide X and the fluorinated nucleotide is independently selected from ribose 2'-alkoxy-modified nucleotides or ribose 2'-substituted alkoxy-modified nucleotides.

28. The single-chain oligonucleotide of claim 27, wherein, The single-stranded oligonucleotide is 19-23 nucleotides in length; in the 5'-3' orientation, the 14th nucleotide is nucleotide X, two of the 5th-7th and 19th nucleotides, as well as the 2nd, 12th, and 16th nucleotides, are fluorinated nucleotides, the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and the 5th nucleotide, if not fluorinated, is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' orientation, the 14th nucleotide is nucleotide X, the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-substituted alkoxy-modified nucleotide or BNA, the 3rd or 5th nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' orientation, the 2nd and 14th nucleotides are fluorinated nucleotides, the 5th nucleotide is a fluorinated nucleotide, one of the 6th-8th nucleotides is a fluorinated nucleotide, one of the 11th-13th nucleotides is a fluorinated nucleotide, one of the 15th-17th nucleotides is a fluorinated nucleotide, the 18th or 19th nucleotide is a fluorinated nucleotide, the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide.

29. The single-chain oligonucleotide of claim 28, wherein, The single-stranded oligonucleotide is 21 nucleotides in length; in the 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides; and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides; and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' orientation, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides; the 13th nucleotide is a ribose 2'-substituted alkoxy-modified nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy-modified nucleotide; or, In the 5'-3' direction, nucleotides 2, 5, 7, 12, 14, 16, and 19 are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a ribose 2'-alkoxy modified nucleotide.

30. The single-chain oligonucleotide according to any one of claims 16-29, wherein, Each ribose 2'-alkoxy modified nucleotide is a ribose 2'-methoxy modified nucleotide; and / or, each ribose 2'-substituted alkoxy modified nucleotide is a ribose 2'-O-methoxyethyl modified nucleotide.

31. The single-chain oligonucleotide according to any one of claims 1-30, wherein, At least two of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide are phosphate groups with modifying groups.

32. The single-chain oligonucleotide of claim 31, wherein, One to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the single-stranded oligonucleotide, and / or one to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end, are phosphate ester groups with modifying groups.

33. The single-stranded oligonucleotide of claim 31 or 32, 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.

34. The single-stranded oligonucleotide according to any one of claims 31-33, wherein, The phosphate ester group with the modifying group is a thiophosphate ester group having the structure shown in formula (28):

35. The single-chain oligonucleotide according to any one of claims 1-34, 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.

36. The single-chain oligonucleotide of claim 35, wherein, The single-stranded oligonucleotide is 21 nucleotides in length and has a nucleotide composition shown in any one of the following (i)-v) along the 5'-3' orientation: i) The 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides; and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; or, ii) The 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides; and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; or, iii) The 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides; and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; or, iv) The 14th nucleotide is nucleotide X and is a deoxyribonucleotide; the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides; the 13th nucleotide is a ribose 2'-O-methoxyethyl nucleotide; and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; or, v) Nucleotides 2, 5, 7, 12, 14, 16 and 19 are fluorinated nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide; Furthermore, each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the single-stranded oligonucleotide, and each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 3' end, is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate group; 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).

37. The single-stranded oligonucleotide according to any one of claims 1-36, wherein, The single-stranded oligonucleotide has at least 16, at least 17, at least 18, at least 19, at least 20 or 21 consecutive identical nucleotides with any of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base differences.

38. The single-stranded oligonucleotide of claim 37, wherein, In the 5'-3' orientation, at least the 2nd to 19th nucleotides of the single-stranded oligonucleotide have a difference of no more than one base between the 2nd to 19th nucleotides of any of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2, or no base difference at all.

39. The single-stranded oligonucleotide of claim 37 or 38, wherein, The single-chain oligonucleotide is any one of the nucleotide sequences shown in SEQ ID NO:124-SEQ ID NO:173 listed in Table 2; or, the single-chain oligonucleotide is any one of the nucleotide sequences shown in SEQ ID NO:223-SEQ ID NO:274 listed in Table 3.

40. A double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand is 15-28 nucleotides in length, each nucleotide in the sense strand is independently a modified or unmodified nucleotide, and the sense strand and 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 1-39.

41. The double-stranded oligonucleotide of claim 40, wherein, The length of the positive chain is 15-26, 17-24, or 19-23 nucleotides; or, the length of the positive chain is 19, 20, or 21 nucleotides.

42. The double-stranded oligonucleotide of claim 40 or 41, wherein, The length difference between the sense and antisense strands is 0-5 nucleotides.

43. The double-stranded oligonucleotide according to any one of claims 40-42, wherein, The length of the sense strand is no greater than the length of the antisense strand; or, the lengths of the sense strand and the antisense strand are the same, each being 19, 20, or 21 nucleotides independently.

44. The double-stranded oligonucleotide of claim 42, wherein, The length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 20-24 nucleotides. 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.

45. The double-stranded oligonucleotide according to any one of claims 40-44, wherein, The sense strand is 19 nucleotides long and the antisense strand is 21 nucleotides long; or, the sense strand is 21 nucleotides long and the antisense strand is 21 nucleotides long; or, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long.

46. ​​The double-stranded oligonucleotide according to any one of claims 40-45, wherein, The justice chain and the antisense chain are substantially opposite, substantially opposite, or completely opposite complementary.

47. The double-stranded oligonucleotide of claim 46, wherein, 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.

48. The double-stranded oligonucleotide of claim 47, wherein, 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.

49. The double-stranded oligonucleotide according to any one of claims 40-48, wherein, The unmodified equivalent sequence of the positive strand comprises 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 no bases. Nucleotide sequence m is a continuous nucleotide sequence in human PSD3 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.

50. The double-stranded oligonucleotide of claim 49, wherein, The unmodified equivalent sequence of the positive strand is identical to any one of the sequences shown in SEQ ID NO:1-SEQ ID NO:38 listed in Table 1 for at least 15, at least 16, at least 17, at least 18 or 19 consecutive nucleotides, and the consecutive identical nucleotides have no more than 3 base differences, no more than 1 base difference, or no base differences.

51. The double-stranded oligonucleotide of claim 50, wherein, In the 5'-3' orientation, at least the first 18 nucleotides of the unmodified equivalent sequence of the stated positive strand include no more than one base difference or no base difference between the first 18 nucleotides of the nucleotide sequences shown in any one of SEQ ID NO:1-SEQ ID NO:38 listed in Table 1; or, The unmodified equivalent sequence of the positive strand is equal in length to the nucleotide sequence shown in any one of SEQ ID NO:1-SEQ ID NO:38 listed in Table 1, and has no more than one base difference or no base difference; or, The unmodified equivalent sequence of the positive strand is any one of the nucleotide sequences shown in Table 1, from SEQ ID NO:1 to SEQ ID NO:

38.

52. The double-stranded oligonucleotide according to any one of claims 40-51, wherein, The unmodified equivalent sequence of the double-stranded nucleotides is compared with any one of the unmodified siRNAs listed in Table 1. The unmodified equivalent sequence of the sense strand of the double-stranded oligonucleotide has at least 15, 16, 17, 18, or 19 consecutive identical nucleotides with the sense strand of any one of the siRNAs in Table 1 (siRNA1-siRNA38), and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference; the unmodified equivalent sequence of the antisense strand of the double-stranded oligonucleotide has at least 17, 18, 19, 20, or 21 consecutive identical nucleotides with the antisense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base difference.

53. The double-stranded oligonucleotide as described in any one of claims 52, wherein, In the 5'-3' orientation, at least the first 1-18 nucleotides of the unmodified equivalent sequence of the sense strand of the double-stranded oligonucleotide include no more than one base difference or no base difference between the first 1-18 nucleotides of the sense strand of any one of the siRNAs in Table 1 (siRNA1-siRNA38); at least the second 19 nucleotides of the unmodified equivalent sequence of the antisense strand of the double-stranded oligonucleotide include no more than one base difference or no base difference between the second 19 nucleotides of the antisense strand of the siRNA.

54. The double-stranded oligonucleotide as described in any one of claims 53, wherein, The unmodified equivalent sequences of the double-stranded oligonucleotides have sense and antisense strands of equal length to the sense and antisense strands of any one of the siRNAs shown in Table 1 (siRNA1-siRNA38), and there is either one base difference or no base difference between the sense and antisense strands of the siRNA and the siRNA; or, The unmodified equivalent sequence of the double-stranded oligonucleotide is any one of the siRNAs shown in Table 1, from siRNA1 to siRNA38.

55. The double-stranded oligonucleotide according to any one of claims 40-54, wherein, In the 3'-5' direction, 2-3 of the 11th-13th nucleotides of the positive strand are fluorinated nucleotides, the first and / or the last nucleotide is a ribose 2'-alkoxy-modified nucleotide or a reverse debased deoxynucleotide, and each of the remaining nucleotides in the positive strand is independently a non-fluorinated nucleotide, and each non-fluorinated nucleotide is independently selected from one of ribose 2'-alkoxy-modified nucleotides, alkyl-modified nucleotides, amine-modified nucleotides, and heat-labile nucleotides.

56. The double-stranded oligonucleotide of claim 55, wherein, In the 3'-5' direction, the 11th and 13th nucleotides, or the 11th-13th nucleotides, of the positive strand are fluorinated nucleotides, the 1st and / or the last nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides in the positive strand is independently a ribose 2'-alkoxy modified nucleotide.

57. The double-stranded oligonucleotide of claim 55 or 56, wherein, Each of the ribose 2'-alkoxy modified nucleotides is independently a ribose 2'-methoxy modified nucleotide.

58. The double-stranded oligonucleotide according to any one of claims 40-57, wherein, In the positive strand, at least one of the linking groups between adjacent nucleotides is a phosphate group with a modifying group, and the phosphate group with the modifying group is present at least once between adjacent nucleotides in the first to fifth nucleotides at the 5' end and between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand.

59. The double-stranded oligonucleotide of claim 58, wherein, One to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand; and / or, one to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end are phosphate ester groups with modifying groups; or, Each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3rd nucleotides at the 5' end of the positive strand, and / or each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3rd nucleotides at the 3' end of the positive strand, is independently a phosphate group with a modifying group; or, Each phosphate group with a modifying group is a thiophosphate group having the structure shown in formula (28).

60. The double-stranded oligonucleotide according to any one of claims 40-59, 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 3'-5' direction, the 1st and / or the last nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide. One to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand, and / or one to four of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand, are thiophosphate groups.

61. The double-stranded oligonucleotide according to any one of claims 40-59, wherein, The sense strand contains 19-21 nucleotides, and the antisense strand contains 21-23 nucleotides; In the positive strand, along the 3'-5' direction, the 11th and 13th nucleotides, or the 11th-13th nucleotides, are fluorinated nucleotides, the 1st and / or the last nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy modified nucleotide; each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3th nucleotides at the 5' end of the positive strand, and / or each of the linking groups between adjacent nucleotides in the 1st-5th or 1st-3th nucleotides at the 3' end of the positive strand, is independently a phosphate ester group with a modifying group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate ester group; In the antisense strand, in the 5'-3' direction, the 14th nucleotide is nucleotide X; two of the 5th-7th and 19th nucleotides, as well as the 2nd, 12th, and 16th nucleotides, are fluorinated nucleotides; the 3rd nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide; and the 5th nucleotide, if not fluorinated, is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide; each of the remaining nucleotides is independent. The nucleotide is a ribose 2'-alkoxy modified nucleotide; or, in the 5'-3' orientation, the 14th nucleotide is nucleotide X, the 2nd, 6th, and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-substituted alkoxy modified nucleotide or BNA, the 3rd or 5th nucleotide is a ribose 2'-alkoxy modified nucleotide or a ribose 2'-substituted alkoxy modified nucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy modified nucleotide; or, in the 5'-3' orientation... The second and fourteenth nucleotides are fluorinated nucleotides, the fifth nucleotide is a fluorinated nucleotide, one of the sixth-eighth nucleotides is a fluorinated nucleotide, one of the eleventh-thirteenth nucleotides is a fluorinated nucleotide, one of the fifteenth-seventh nucleotides is a fluorinated nucleotide, the eighteenth or nineteenth nucleotide is a fluorinated nucleotide, the third nucleotide is a ribose 2'-alkoxy-modified nucleotide or a ribose 2'-substituted alkoxy-modified nucleotide, and each of the remaining nucleotides is independently a ribose 2'-alkoxy-modified nucleotide; each of the linking groups between adjacent nucleotides in the first-third nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the first-third nucleotides at the 3' end, is independently a phosphate ester group with a modifying group, and each of the linking groups between adjacent nucleotides in the remaining nucleotides is independently a phosphate ester group; and the 5'-terminal nucleotide of the antisense strand is a nucleotide modified with a 5'-hydroxy nucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analogue.

62. The double-stranded oligonucleotide of claim 61, wherein, The sense strand contains 19 nucleotides, and the antisense strand contains 21 nucleotides; In the positive chain, the 11th and 13th nucleotides are fluorinated nucleotides in the 3'-5' direction, the 1st nucleotide is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide. Each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the positive strand is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate group. In the antisense strand, along the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; or, in the antisense strand, along the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxyribonucleotide, the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide. The antisense strand may contain nucleotides that are fluorinated; or, in the antisense strand, the 14th nucleotide is nucleotide X and is a deoxynucleotide in the 5'-3' direction, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide; or, in the antisense strand, the 2nd, 5th, 7th, 12th, 14th, 16th and 19th nucleotides are fluorinated nucleotides in the 5'-3' direction, and each of the remaining nucleotides is independently a ribose 2'-methoxy nucleotide. Each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 3' end, is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate group. Furthermore, the 5' terminal nucleotide of the antisense strand is a 5'-hydroxy nucleotide as shown in formula (29) or a nucleotide modified with 5'-vinyl phosphate as shown in formula (31).

63. The double-stranded oligonucleotide of claim 61, wherein, The sense strand contains 19 nucleotides, and the antisense strand contains 21 nucleotides; In the positive chain, nucleotides 11-13 are fluorinated nucleotides in the 3'-5' direction, nucleotide 1 is a reverse debased deoxynucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide. Each of the linking groups between adjacent nucleotides in the first to fifth or first to third nucleotides at the 5' end of the positive strand is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate group; In the antisense strand, in the 5'-3' direction, the 14th nucleotide is nucleotide X and is a deoxynucleotide, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a ribose 2'-O-methoxyethyl modified nucleotide, and each of the remaining nucleotides is independently a ribose 2'-methoxy modified nucleotide. Each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 5' end of the antisense strand, and each of the linking groups between adjacent nucleotides in the first to third nucleotides at the 3' end, is independently a thiophosphate group, and each of the linking groups between the remaining adjacent nucleotides is independently a phosphate group. Furthermore, the 5' terminal nucleotide of the antisense strand is a 5'-hydroxy nucleotide as shown in formula (29) or a nucleotide modified with 5'-vinyl phosphate as shown in formula (31).

64. The double-stranded oligonucleotide according to any one of claims 40-63, wherein, The double-stranded oligonucleotide is siRNA; or, compared to any one of the modified siRNAs listed in Table 2, the double-stranded oligonucleotide is... There are at least 15, at least 16, at least 17, at least 18, or 19 consecutive identical nucleotides between the sense strand of the double-stranded oligonucleotide and the sense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base differences; there are at least 17, at least 18, at least 19, at least 20, or 21 consecutive identical nucleotides between the antisense strand of the double-stranded oligonucleotide and the antisense strand of the siRNA, and the consecutive identical nucleotides include no more than 3 base differences, no more than 1 base difference, or no base differences.

65. The double-stranded oligonucleotide of claim 64, wherein, In the 5'-3' orientation, at least the first 18 nucleotides of the sense strand of the double-stranded oligonucleotide have a base difference of no more than one or no base difference between the first 18 nucleotides of the sense strand of the modified siRNA listed in Table 2; at least the second 19 nucleotides of the antisense strand of the double-stranded oligonucleotide have a base difference of no more than one or no base difference between the second 19 nucleotides of the antisense strand of the modified siRNA.

66. The double-stranded oligonucleotide of claim 64 or 65, wherein, The sense and antisense strands of the double-stranded oligonucleotide are of equal length to the sense and antisense strands of any of the siRNAs shown in Table 2, and there is either a single base difference or no base difference between the sense and antisense strands of the siRNA and the siRNA; or, The double-stranded oligonucleotide is any one of the modified siRNAs listed in Table 2; or, The double-stranded oligonucleotide corresponds to any of the double-stranded oligonucleotide groups contained in any of the conjugates 1-52 listed in Table 3.

67. 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 as described in any one of claims 1-39 or a double-stranded oligonucleotide as described in any one of claims 40-66.

68. The oligonucleotide conjugate of claim 67, wherein, The delivery group comprises a linker and a pharmaceutically acceptable targeting group, and the oligonucleotide group, the linker and the targeting group are covalently or non-covalently linked in sequence, and at least one or each of the targeting groups is independently selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes.

69. The oligonucleotide conjugate of claim 68, wherein, At least one or each of the target groups is a galactose group or an N-acetylgalactosamine group; or, the oligonucleotide conjugate has the structure shown in formula (403).

70. The oligonucleotide conjugate according to any one of claims 67-69, wherein, The oligonucleotide conjugate contains a double-stranded oligonucleotide group that is an siRNA group formed from any of the modified siRNAs shown in Table 2; or, The oligonucleotide conjugate contains a double-stranded oligonucleotide group that is the siRNA group present in any one of conjugates 1-52 shown in Table 3; or, The oligonucleotide conjugate is any one of conjugate 1 to conjugate 52 shown in Table 3.

71. A pharmaceutically acceptable salt of a single-stranded oligonucleotide as described in any one of claims 1-39, a double-stranded oligonucleotide as described in any one of claims 40-66, or an oligonucleotide conjugate as described in any one of claims 67-70.

72. The pharmaceutically acceptable salt of claim 71, wherein, 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.

73. The pharmaceutically acceptable salt of claim 72, wherein, The water-soluble salt is an amine salt or an alkali metal salt.

74. The pharmaceutically acceptable salt of claim 73, wherein, 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.

75. The pharmaceutically acceptable salt of claim 74, wherein, The tertiary amine salt is triethylamine salt, triisopropylamine salt, or N,N-diisopropylethylamine salt.

76. The pharmaceutically acceptable salt according to any one of claims 71-75, wherein, 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 or partial salt is one or more of a methylamine salt, a triethylamine salt, or a sodium salt; or... 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 single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate.

77. A pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein, The active ingredient comprises one or more of the following: single-stranded oligonucleotides according to any one of claims 1-39, double-stranded oligonucleotides according to any one of claims 40-66, oligonucleotide conjugates according to any one of claims 67-70, and pharmaceutically acceptable salts according to any one of claims 71-76.

78. The pharmaceutical composition of claim 77, wherein, The pharmaceutically acceptable excipients are one or more of solvents, protective agents, osmotic pressure regulators, and other pharmaceutically acceptable carriers.

79. The pharmaceutical composition of claim 78, wherein, The solvent is one of deionized water, water for injection, pH buffer, physiological saline, ethanol, or an aqueous solution of ethanol.

80. Use of one or more of the following: a single-stranded oligonucleotide of any one of claims 1-39; a double-stranded oligonucleotide of any one of claims 40-66; an oligonucleotide conjugate of any one of claims 67-70; a pharmaceutically acceptable salt of any one of claims 71-76; and a pharmaceutical composition of any one of claims 77-79, in the preparation of a medicament for treating and / or preventing diseases or symptoms associated with PSD3 mRNA levels.

81. The use as described in claim 80, wherein, The disease or symptom associated with PSD3 mRNA levels is MASLD; or, MASLD is selected from one or more of simple steatosis, MASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma.

82. A method for treating and / or preventing diseases or symptoms associated with PSD3 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 1-39, a double-stranded oligonucleotide of any one of claims 40-66, an oligonucleotide conjugate of any one of claims 67-70, a pharmaceutically acceptable salt of any one of claims 71-76, and a pharmaceutical composition of any one of claims 77-79.

83. The method of claim 82, wherein, The disease or symptom associated with PSD3 mRNA levels is MASLD; or, MASLD is selected from one or more of simple steatosis, MASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma.

84. One or more of the following as used as a medicament: a single-stranded oligonucleotide as described in any one of claims 1-39, a double-stranded oligonucleotide as described in any one of claims 40-66, an oligonucleotide conjugate as described in any one of claims 67-70, a pharmaceutically acceptable salt as described in any one of claims 71-76, and a pharmaceutical composition as described in any one of claims 77-79.

85. One or more of the following for treating and / or preventing diseases or symptoms associated with PSD3 mRNA levels: a single-stranded oligonucleotide as described in any one of claims 1-39, a double-stranded oligonucleotide as described in any one of claims 40-66, an oligonucleotide conjugate as described in any one of claims 67-70, a pharmaceutically acceptable salt as described in any one of claims 71-76, and a pharmaceutical composition as described in any one of claims 77-79; Or, among them The disease or symptom associated with PSD3 mRNA levels is MASLD; or, MASLD is selected from one or more of simple steatosis, MASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma.

86. A method for regulating the expression level of the PSD3 gene in cells, the method comprising contacting the cells with an effective amount of one or more of the following: a single-stranded oligonucleotide of any one of claims 1-39, a double-stranded oligonucleotide of any one of claims 40-66, an oligonucleotide conjugate of any one of claims 67-70, a pharmaceutically acceptable salt of any one of claims 71-76, and a pharmaceutical composition of any one of claims 77-79.

87. A cell expressing the PSD3 gene, and the cell comprising one or more of the following: a single-stranded oligonucleotide as described in any one of claims 1-39; a double-stranded oligonucleotide as described in any one of claims 40-66; an oligonucleotide conjugate as described in any one of claims 67-70; a pharmaceutically acceptable salt as described in any one of claims 71-76; and a pharmaceutical composition as described in any one of claims 77-79.

88. A kit comprising one or more of the following: a single-stranded oligonucleotide as described in any one of claims 1-39; a double-stranded oligonucleotide as described in any one of claims 40-66; an oligonucleotide conjugate as described in any one of claims 67-70; a pharmaceutically acceptable salt as described in any one of claims 71-76; and a pharmaceutical composition as described in any one of claims 77-79.

Images