Oligonucleotide, oligonucleotide conjugate, composition, and use

Abstract

A single-stranded oligonucleotide, having a length of 16-30 nucleotides, the composition of the single-stranded oligonucleotide enabling the single-stranded oligonucleotide to inhibit the expression of NTCP mRNA by means of an RNAi mechanism. Each nucleotide in the single-stranded oligonucleotide is independently a modified or unmodified nucleotide. In the single-stranded oligonucleotide, at least one nucleotide is nucleotide X, and at least one nucleotide is a fluoro-modified nucleotide. In the direction from the 5' end to the 3' end, the 13th nucleotide of the single-stranded oligonucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X, and the 15th nucleotide and all the following nucleotides of the single-stranded oligonucleotide are each independently a modified nucleotide. Also provided are a double-stranded oligonucleotide including 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 Na+-taurocholate cotransporting polypeptide (NTCP) is a transport protein expressed on the basolateral membrane of hepatocytes. Structurally, mature NTCP is a glycoprotein with a molecular weight of approximately 55 kDa, while unglycosylated NTCP contains 349 amino acid residues, has 9 transmembrane domains, and a molecular weight of approximately 37 kDa. The main function of NTCP is as an important member of the solute carrier 10 (SLC10) family, carrying out sodium-dependent uptake of conjugated bile acids from plasma into hepatocytes, playing a crucial role in the enterohepatic circulation of bile acids. In addition, certain steroid hormones, thyroid hormones, drugs, and drug-bile acid conjugates are also substrates for NTCP uptake. Recent studies have found that NTCP acts as a common receptor for HBV and HDV, playing a key role in viral entry into hepatocytes. In the drug development of oligonucleotides, including single-chain and double-chain oligonucleotides, the improvement of oligonucleotide modifications has never ceased. In single-chain oligonucleotides, such as ASO and ssRNAi, and in double-chain oligonucleotides, such as the antisense strand of siRNA, the type, location, and amount of modification can significantly affect key properties such as pharmacodynamic activity, stability, and long-lasting effect. Although numerous oligonucleotide modification schemes have been disclosed in the prior art, how to improve the modification of oligonucleotides, especially the antisense strands of single-chain and double-chain oligonucleotides, to obtain oligonucleotides with higher activity, higher stability, and / or longer-lasting effect remains a research direction in this field. Summary of the Invention The present invention provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present invention as the antisense strand, and an oligonucleotide conjugate, all of which exhibit good pharmaceutical activity and stability when targeting NTCP mRNA. In one aspect, this disclosure provides a single-chain oligonucleotide of 16-30 nucleotides in length, the composition of which enables it to inhibit the expression of NTCP mRNA via an RNAi mechanism; each nucleotide in the single-chain oligonucleotide is independently modified or unmodified, wherein at least one nucleotide in the single-chain oligonucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide; furthermore, the 13th nucleotide of the single-chain oligonucleotide is a substituted alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; the 14th nucleotide of the single-chain oligonucleotide is nucleotide X; and each of the 15th nucleotide and all subsequent nucleotides of the single-chain oligonucleotide is independently modified; each nucleotide X is independently deoxyribonucleotide or unmodified nucleotide. In another aspect, this disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described in this disclosure. In another aspect, this disclosure provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand and the antisense strand being independently modified or unmodified, the sense strand and the antisense strand being at least partially anticomplementary to form a double-stranded region, wherein the unmodified equivalent sequences of the sense strand and the antisense strand are identical to the unmodified equivalent sequences of the sense strand and the antisense strand of any one of the siNTCP1-M1-siNTCP15-M1 listed in Table 1B by at least 15, at least 16, at least 17, at least 18 or 19 consecutive nucleotides, and wherein there are no more than 3 base differences, no more than 1 base difference, or no base differences. In another aspect, this disclosure also provides an oligonucleotide conjugate containing an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being independently formed by removing one or more atoms or groups of atoms from a single-stranded or double-stranded oligonucleotide 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 one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and pharmaceutically acceptable salts described in this disclosure, and pharmaceutically acceptable excipients. In another aspect, this disclosure also provides the use of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with NTCP mRNA levels. In another aspect, this disclosure also provides a method for treating and / or preventing diseases or symptoms associated with NTCP mRNA levels, the method comprising administering to a subject in need an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. In another aspect, this disclosure also provides a method for regulating the expression level of the NTCP 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 another aspect, this disclosure also provides one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure for use as pharmaceuticals. In another aspect, this disclosure also provides a cell expressing NTCP mRNA, the cell comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. In addition, this disclosure also provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure. 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. Beneficial effects One or more of the following, including single-stranded oligonucleotides as the antisense strand, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, as described in this disclosure, have high activity in regulating NTCP mRNA, for example, good stability and NTCP mRNA inhibitory activity in cells and / or in the body of a subject, and therefore have good application prospects. On the one hand, in in vitro experiments, the double-stranded oligonucleotides (e.g., siRNA) containing the single-stranded oligonucleotides of this disclosure as the antisense strand, the conjugates of this disclosure, and / or pharmaceutical compositions exhibit excellent NTCP mRNA inhibitory effects. For example, in the in vitro psiCHECK assay, the conjugates of this disclosure have high inhibitory activity against the target sequence, with inhibition rates exceeding 76% at a low concentration of 0.1 nM, and even reaching 91.59%. As another example, the conjugates provided by this disclosure exhibit an inhibition rate of at least 75.3% against NTCP mRNA in HepG2 cells, and can reach over 86%. Furthermore, the conjugates of this disclosure have high inhibitory activity against NTCP mRNA expression in primary human liver cells. In some embodiments, the conjugates provided by this disclosure show high NTCP mRNA inhibitory activity in primary human liver cells at concentrations of 5 nM and 50 nM, especially at 0.5 nM, with inhibition rates exceeding 75%, and even reaching 91%, significantly higher than the reference conjugates. In other embodiments, the conjugates provided in this disclosure exhibit high NTCP mRNA inhibitory activity in primary human liver cells, with an inhibition rate of at least 79.7% and even reaching 92.1% at 50 nM; and an inhibition rate of at least 83.2% and even reaching 90.0% at 0.5 nM. In other embodiments, the IC50 of the conjugates provided in this disclosure in primary human liver cells... 50 The concentration can reach 16.88 nM, and even 7.245 nM. For example, in primary monkey liver cells, the conjugate provided in this disclosure shows a good inhibitory effect on NTCP mRNA expression. At a concentration of 5 nM (based on siRNA), the inhibition rate of NTCP mRNA in primary monkey liver cells remains above 95%, even reaching 98.3%; at a concentration of 0.5 nM (based on siRNA), the inhibition rate of NTCP mRNA in primary monkey liver cells remains above 94%, even reaching 96.4%. On the other hand, double-stranded oligonucleotides (e.g., siRNA) containing the single-stranded oligonucleotides of this disclosure as the antisense strand, conjugates of this disclosure, and / or pharmaceutical compositions exhibit excellent NTCP mRNA inhibitory effects. For example, in AAV-induced humanized mice, the conjugates provided by this disclosure showed significant inhibitory effects on NTCP mRNA at a single dose of 3 mg / kg, especially on day 22, with inhibition rates exceeding 47% and even reaching 78%. These results indicate that the conjugates of this disclosure have good NTCP mRNA inhibitory effects and show significant pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to NTCP mRNA expression, demonstrating excellent development prospects. 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, NTCP mRNA refers to NTCP mRNA expressed in mammalian cells. Specifically, NTCP mRNA refers to the mRNA with the sequence shown in GenBank accession number NM_003049.4. Further, unless otherwise specified, the term "NTCP gene" as used in this disclosure refers to the gene that transcribes the aforementioned NTCP mRNA. definition In the preceding and following text, "fluorinated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with fluorine, and "non-fluorinated nucleotides" refers to nucleotides or nucleotide analogs formed by replacing the 2'-hydroxyl group of the ribosome with a non-fluorinated group. "Nucleotide analogs" refer to groups that can replace nucleotides in nucleic acids but whose structure differs from adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, or thymine deoxynucleotides. Examples include isonucleotides, bridged nucleic acids (BNAs), or acyclic nucleotides. "Methoxylated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with a methoxy group. In the context of this document, the terms "complementary" and "reverse complementary" are used interchangeably and have the meaning known to those skilled in the art: in a double-stranded nucleic acid 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: between a single-stranded oligonucleotide and NTCP mRNA, between a single-stranded oligonucleotide and nucleotide sequence m, between the sense and antisense strands of a double-stranded oligonucleotide (such as siRNA), and between the antisense strand of a double-stranded oligonucleotide and NTCP mRNA. Unless otherwise specified, "at least partially anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 50% base mismatches between the two nucleotide sequences capable of forming a double-stranded region; "substantially anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 3 base mismatches between the two nucleotide sequences capable of forming a double-stranded region; "truly anti-complementary" means that within a hypothetical or actual double-stranded region, there are no more than 1 base mismatch between the two nucleotide sequences capable of forming a double-stranded region; and "completely anti-complementary" means that within a hypothetical or actual double-stranded region, there are no base mismatches between the two nucleotide sequences capable of forming a double-stranded region. When the two nucleotide sequences are “at least partially reverse complementary,” “substantially reverse complementary,” “truly reverse complementary,” or “completely reverse complementary,” they can form a double-stranded hybrid consisting of Watson-Crick base pairs after annealing. Unless otherwise stated, when referring to a shorter nucleotide sequence as "completely anticomplementary" to a longer nucleotide sequence, it means that the two nucleotide sequences are completely anticomplementary along the entire length of the shorter nucleotide sequence. For example, the complete anticomplementary relationship between a single-stranded oligonucleotide and NTCP mRNA described in this disclosure means that the single-stranded oligonucleotide is completely anticomplementary along its entire length; in other words, each nucleotide in the single-stranded oligonucleotide forms a Watson-Crick base pair with a corresponding nucleotide on the NTCP mRNA to form a double-stranded hybrid. In the context of this disclosure, a "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences comprising all base pairs on each single strand of a hypothetical or actual double-stranded nucleic acid structure. Therefore, a double-stranded region consists of all base pairs in the double-stranded nucleic acid structure and all base mismatches between those base pairs. In some embodiments, the double-stranded nucleic acid structure includes a double-stranded region and one or more overhanging ends, said overhanging ends consisting of all nucleotides outside the double-stranded region in one or both single strands of the double-stranded nucleic acid structure that do not form base pairs. In some embodiments, the double-stranded nucleic acid structure includes only a double-stranded region. The two nucleotide sequences that can form a double-stranded region can be of the same or different lengths. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region, in which case the two nucleotide sequences forming the double-stranded nucleic acid structure are of the same length. "At least partially anticomplementary" means that there is no more than 50% base mismatch between the two nucleotide sequences; "substantially anticomplementary" means that there is no more than 3 base mismatches between the two nucleotide sequences; "substantially anticomplementary" means that there is no more than 1 base mismatch between the two nucleotide sequences; and "completely anticomplementary" means that there is no base mismatch between the two nucleotide sequences. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of the same length, the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of the longer nucleotide sequence. In some embodiments, the two nucleotide sequences forming the double-stranded nucleic acid structure are of different lengths, the double-stranded nucleic acid structure includes a double-stranded region and one or both overhanging ends of the longer nucleotide sequence. For example, in some embodiments, the sense and antisense strands of a double-stranded oligonucleotide are of different lengths. For example, the double-stranded oligonucleotide is siRNA, in which case the sense strand is usually shorter and is a shorter nucleotide sequence, while the antisense strand is longer and is the longer nucleotide sequence. The double-stranded nucleic acid structure includes a double-stranded region and a dangling end in the antisense strand. In the preceding and following text, "nucleotide sequence A and nucleotide sequence B are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary across a length of X nucleotides" means that there exists a continuous nucleotide sequence A' of length X in nucleotide sequence A, which is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence B' of length X in nucleotide sequence B. In the foregoing and hereinafter, particularly in the description of methods for preparing 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 single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate to be prepared. 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, GREEN's Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons Inc., New Jersey, 2014, each of which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is stable under basic conditions but can be removed under acidic conditions. In some embodiments, non-exclusive examples of hydroxyl protecting groups that may be used herein include dimethoxytriphenylmethyl (DMT), monomethoxytriphenylmethyl, 9-phenyloxanthracene-9-yl (Pixyl), and 9-(p-methoxyphenyl)oxanthracene-9-yl (Mox). In some embodiments, non-exclusive examples of hydroxyl protecting groups that may be used herein include Tr (triphenylmethyl), MMTr (4-methoxytriphenylmethyl), DMTr (4,4'-dimethoxytriphenylmethyl), and TMTr (4,4',4”-trimethoxytriphenylmethyl). The term “subject” as used herein refers to any animal, such as a mammal or marsupial. Subjects in this disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, rabbits, sheep, rats, and any kind of poultry. In some embodiments, “subject” refers to a mammal, such as a rodent or primate. In some embodiments, “subject” refers to a mouse, rat, or non-human primate. In some embodiments, “subject” refers to a human subject. As used herein, “treatment” refers to a method of achieving a beneficial or desired outcome, including but not limited to treatment benefits. A “treatment benefit” means the eradication or improvement of the underlying disorder being treated. Furthermore, a treatment benefit is achieved by eradicating or improving one or more physical symptoms associated with the underlying disorder, thereby observing improvement in the subject, even though the subject may still be suffering from the underlying disorder. As used herein, “prevention” refers to methods for obtaining a beneficial or desired outcome, including but not limited to preventative benefits. To obtain a “preventative benefit,” the single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of this disclosure may be given to a subject at risk of developing a disease associated with NTCP mRNA, or to a subject reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease may not have been made. In some embodiments, “prevention” includes, before the risk of disease associated with NTCP mRNA progresses to a defined disease course, intervening in the levels of NTCP mRNA or NTCP protein to reduce or eliminate the risk of disease. Unless otherwise specified, in the context of any reference to an oligonucleotide and / or oligonucleotide conjugate described in the application or method provided in this disclosure, including but not limited to any oligonucleotide and / or oligonucleotide conjugate represented by a structural formula described in the application or method provided in this disclosure, the reference also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or oligonucleotide conjugate, depending on the context. The single-stranded oligonucleotides disclosed herein In one aspect, this disclosure provides a single-chain oligonucleotide of 16-30 nucleotides in length, the composition of which enables it to inhibit the expression of NTCP mRNA via an RNAi mechanism; each nucleotide in the single-chain oligonucleotide is independently modified or unmodified, wherein at least one nucleotide in the single-chain oligonucleotide is nucleotide X, and at least one nucleotide is a fluorinated nucleotide; furthermore, the 13th nucleotide of the single-chain oligonucleotide is a substituted alkoxy-modified nucleotide in the direction from the 5' end to the 3' end; the 14th nucleotide of the single-chain oligonucleotide is nucleotide X; and each of the 15th nucleotide and all subsequent nucleotides of the single-chain oligonucleotide is independently modified; each nucleotide X is independently deoxyribonucleotide or unmodified nucleotide. In this disclosure, by regulating the expression level of NTCP mRNA and / or altering the NTCP protein level, it is possible to treat or prevent diseases related to the expression level of NTCP mRNA and / or the NTCP protein level. The inventors unexpectedly discovered that the single-chain oligonucleotides described in this disclosure, double-chain oligonucleotides containing the single-chain oligonucleotides described in this disclosure as antisense strands, and oligonucleotide conjugates have good stability and NTCP mRNA inhibitory activity in cells and / or in subjects, and therefore have good application prospects. To achieve RNAi activity, the single-stranded oligonucleotides described in this disclosure are 16-30 nucleotides in length. In some embodiments, the single-stranded oligonucleotides described in this disclosure are 17-28, 19-27, or 20-25 nucleotides in length. In some embodiments, the single-stranded oligonucleotides described in this disclosure are 19, 21, or 23 nucleotides in length. In these cases, the single-stranded oligonucleotides described in this disclosure, the double-stranded oligonucleotides containing the single-stranded oligonucleotide as the antisense strand, and the oligonucleotide conjugates exhibit a better balance between stability and RNAi activity. In the single-stranded oligonucleotides of this disclosure, at least one nucleotide is nucleotide X, at least one nucleotide is a fluorinated nucleotide, and, in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X, the 13th nucleotide of the single-stranded oligonucleotide is a substituted alkoxy-modified nucleotide, and each of the 15th nucleotide and all subsequent nucleotides of the single-stranded oligonucleotide is independently modified nucleotide. The inventors have particularly discovered that the single-stranded oligonucleotides of this disclosure, by comprising the aforementioned fluorinated nucleotide, substituted alkoxy-modified nucleotide, and nucleotide X, can effectively maintain the high inhibitory activity of single-stranded oligonucleotides, double-stranded oligonucleotides, and oligonucleotide conjugates against NTCP mRNA while maintaining stability. In some embodiments, the number of nucleotides X in the single-stranded oligonucleotide is 1-3, for example, 1, 2, or 3. In some embodiments, the 12th and 14th nucleotides in the single-stranded oligonucleotide are each independently nucleotide X in the 5' to 3' direction. In some embodiments, only the 14th nucleotide in the single-stranded oligonucleotide is nucleotide X in the 5' to 3' direction. Each nucleotide X is independently selected from deoxyribonucleotides or unmodified nucleotides. In this context, "unmodified nucleotide" refers to a ribonucleotide (RNA) with both the base and ribose unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the 2' position of the ribose is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide with modified bases, a nucleotide in which the hydroxyl group at the 2' position of the ribose is replaced by another atom or group, or a nucleotide analog. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide are deoxyribonucleotides in the 5' to 3' direction, and each of the other nucleotides X is independently unmodified nucleotide. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide is a deoxyribonucleotide in the 5' to 3' direction, and each of the other nucleotides is independently modified nucleotide. In some embodiments, the number of modified nucleotides accounts for more than 50%, 70%, or 85% of the total number of nucleotides in the single-stranded oligonucleotide of this disclosure. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide of this disclosure does not exceed 5 or 4. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide of this disclosure does not exceed 3, 2, or 1. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, each of the nucleotides in the single-stranded oligonucleotide is independently modified. As previously described, in addition to nucleotide X and substituted alkoxy-modified nucleotides, the single-chain oligonucleotides of this disclosure also include fluorinated nucleotides. In some embodiments, the number of fluorinated nucleotides is 2-7. In some embodiments, fluorinated nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to 1 or 2 of the 2nd and 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to the 2nd and 6th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, fluorinated nucleotides refer to the 2nd, 6th, and 16th nucleotides of the single-chain oligonucleotide, in the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 5th, 7th, 12th, and 16th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 7th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, the fluorinated nucleotides refer to the 2nd, 6th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide, with the direction from the 5' end to the 3' end. In some embodiments, each modified nucleotide, except for the 13th and 14th nucleotides and fluorinated nucleotides, is independently selected from alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, alkyl-modified nucleotides, substituted alkyl-modified nucleotides, amine-modified nucleotides, heat-labile nucleotides, and BNA, along the 5'-to-3' direction. In some embodiments, each modified nucleotide, except for the 13th and 14th nucleotides and fluorinated nucleotides, is independently selected from alkoxy-modified nucleotides, substituted alkoxy-modified nucleotides, or heat-labile nucleotides, along the 5'-to-3' direction. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed three. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide does not exceed two. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is one. In some embodiments, the single-stranded oligonucleotide does not contain heat-labile nucleotides. In some embodiments, the number of heat-labile nucleotides does not exceed two. In some embodiments, the number of heat-labile nucleotides is one or two. In some embodiments, each modified nucleotide other than the substituted alkoxy-modified nucleotide, nucleotide X, fluorinated nucleotide, and heat-labile nucleotide is independently an alkoxy-modified nucleotide. In this context, "thermally unstable nucleotide" refers to a nucleotide with a thermally unstable modification, wherein the thermally unstable modification is a modification that lowers the thermal dissociation temperature of the oligonucleotide duplex by at least 0.5 °C compared to an oligonucleotide duplex with an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification in PCT Publication WO2018 / 098328A1.

[0236] -

[0251] The thermal instability modification described in the paragraph. In some embodiments, the heat-labile nucleotide is a type of acyclic nucleotide or heteronucleotide. Acyclic nucleotides are a class of nucleotides formed by opening the sugar ring of a nucleotide. In some embodiments, acyclic nucleotides can be unblocking nucleic acids (UNA) or glycerol nucleic acids (GNA), wherein UNA is shown in formula (15) and GNA is shown in formula (16): In formulas (15) and (16) above, R is selected from H, OH or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C or T. Isonucleotides are compounds formed by altering the position of a base on the ribose ring in a nucleotide. In some embodiments, an isonucleotide can be a compound formed by moving a base from the 1'-position to the 2'-position or 3'-position on the ribose ring, as shown in formula (17) or (18). In the compounds of formulas (17)-(18) above, Base represents a nucleic acid base, such as A, U, G, C or T; R is selected from H, OH, F or non-fluorinated modifications as described above. In some embodiments, the heat-labile nucleotide is selected from one of the following: GNA as shown in formula (27A), 2'-OMe abasic nucleotide as shown in formula (27B), 3'-OMe modified nucleotide as shown in formula (27C), 5'-Me modified nucleotide as shown in formula (27D), SNA as shown in formula (27E), hGNA as shown in formula (27F), hhGNA as shown in formula (27G), mGNA as shown in formula (27H), TNA as shown in formula (27I), h'GNA as shown in formula (27J), UNA as shown in formula (27K), or a hyperspacer as shown in formula (27L). In the compounds of formulas (27A)-(27L) above, Base represents a nucleic acid base, such as A, U, G, C, or T; R 27 Selected from H, OH, F, alkoxy, alkyl, or alkoxy-substituted alkyl groups. * indicates that the carbon atom is chiral, and the compound can be an R configuration, an S configuration, or a racemic mixture of R and S configurations. In some embodiments, each thermally unstable nucleotide is independently a GNA as shown in formula (27A). In this context, BNA refers to a restricted or inaccessible nucleotide. A BNA can contain a bridging structure with a "fixed" C3'-endoglucan condensation, consisting of a five-, six-, or seven-membered ring. This bridge is typically incorporated into the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be an LNA, ENA, cET BNA, etc., where LNA is shown in formula (12), ENA in formula (13), and cET BNA in formula (14). In some embodiments, for ease of synthesis, each alkoxy-modified nucleotide is independently a 2'-methoxy-modified nucleotide (2'-OMe), as shown in formula (8). In some embodiments, the 2'-amino-modified nucleotide (2'-NH2) is shown in formula (9). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in formula (10). In equations (7) to (10) above, Base represents a nucleic acid base, such as A, U, G, C or T. In the preceding and following text, “fluorinated nucleotides,” “2’-fluorinated nucleotides,” “nucleotides in which the 2’-hydroxyl group of the ribose group is replaced by fluorine,” and “nucleotides with a 2’-fluorinated ribose group” have the same meaning, all referring to compounds in which the 2’-hydroxyl group of the nucleotide is replaced by fluorine, resulting in compounds with the structure shown in formula (7); “methoxylated nucleotides,” “2’-methoxylated nucleotides,” “nucleotides in which the 2’-hydroxyl group of the ribose group is replaced by methoxyl,” and “nucleotides with a 2’-methoxy ribose group” have the same meaning, all referring to compounds in which the 2’-hydroxyl group of the ribose group of the nucleotide is replaced by methoxyl, resulting in compounds with the structure shown in formula (8). In some embodiments, the single-stranded oligonucleotides of this disclosure are 19-23 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, one of the 5th-7th nucleotides, and the 2nd and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and when the 5th nucleotide is not a fluorinated nucleotide, it is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently an alkoxy-modified nucleotide. In some embodiments, each nucleotide X in the single-chain oligonucleotides described herein refers to a deoxynucleotide. In some embodiments, each alkoxy-modified nucleotide in the single-chain oligonucleotides described herein refers to a methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide in the single-chain oligonucleotides described herein refers to a 2'-O-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single-chain oligonucleotides described herein refers to an LNA or cET BNA. In some embodiments, each heat-labile nucleotide in the single-chain oligonucleotides described herein refers to a GNA. In some embodiments, each of at least two linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of one to four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of one to four linking groups between adjacent nucleotides in the 3'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of two linking groups or four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, each of two linking groups or four linking groups between adjacent nucleotides in the 5'-1st to 5th nucleotides is independently a phosphate group with a modifying group. In some embodiments, in the single-stranded oligonucleotides of this disclosure, if unmodified nucleotides are present, each of the two linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate ester group with a modifying group. The modified phosphate ester groups can enhance the resistance of the single-stranded oligonucleotides of this disclosure to exonuclease activity, thereby increasing the stability of the oligonucleotides in the body. In some embodiments, each of 2-6 linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of 3 or 4 linking groups between adjacent nucleotides in the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the single-stranded oligonucleotide is independently a phosphate group with a modifying group. In some embodiments, if unmodified nucleotides are present in the single-stranded oligonucleotide, each of 1 or all 2 of the 2 linking groups between each unmodified nucleotide and its adjacent nucleotide is independently a phosphate group with a modifying group. In some embodiments, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28): In some embodiments, the 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxynucleotide, a 5'-phosphate nucleotide, or a 5'-phosphate analog-modified nucleotide, wherein the 5'-hydroxynucleotide has the structure shown in formula (29); the 5'-phosphate nucleotide has the structure shown in formula (30); and the 5'-phosphate analog-modified nucleotide has a structure selected from those shown in formulas (31) to (34). R is selected from H, OH, OCH3 and F; Base represents a nucleic acid base, selected from A, U, C, G or T. In some embodiments, the 5'-phosphate nucleotide is a nucleotide containing a 5'-phosphate modification as shown in formula (30), and the 5'-phosphate analog modified nucleotide is a nucleotide containing a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modification as shown in formula (31), or a nucleotide modified with a 5'-thiophosphate as shown in formula (33). In some embodiments, the 5'-terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxy nucleotide or a nucleotide containing a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modification. In some embodiments, the 5'-terminal nucleotide being a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modified nucleotide can further increase one or more of the stability, in vivo pharmacodynamic activity, and long-lasting effect of the single-stranded oligonucleotide, double-stranded oligonucleotide containing the single-stranded oligonucleotide, and oligonucleotide conjugates described herein. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 13th nucleotide is a 2'-O-methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, and the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is independently a methoxy modified nucleotide; the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end is a thiophosphate group; the 5' terminal nucleotide is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). As previously described, the composition of the single-chain oligonucleotides described in this disclosure enables them to inhibit the expression of NTCP mRNA via an RNAi mechanism. In some embodiments, the single-chain oligonucleotides described in this disclosure have sufficient complementarity with the NTCP mRNA to produce an RNAi effect. In some embodiments, the single-chain oligonucleotides described in this disclosure are fully complementary to the NTCP mRNA. In the context of this disclosure, "fully complementary" means that the complementarity between the single-chain oligonucleotides described in this disclosure and the NTCP mRNA is sufficient to reduce or eliminate the production of the protein encoded by the NTCP mRNA through RNAi. In some embodiments, "fully complementary" means that the single-chain oligonucleotides described in this disclosure and the NTCP mRNA are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary across at least 16 nucleotides, for example, across 16-25 nucleotides, across 18-23 nucleotides, or across 19-21 nucleotides. In some embodiments, the single-chain oligonucleotides described in this disclosure are completely anticomplementary to the NTCP mRNA. In some embodiments, the two "fully complementary" nucleotide sequences may include completely anticomplementary internal regions (e.g., completely anticomplementary across a length of at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotides of this disclosure are completely anticomplementary to NTCP mRNA at least within a seed region. The "seed region" refers to the region of nucleotides 2-8 of the single-stranded oligonucleotide of this disclosure, where the single-stranded oligonucleotide of this disclosure can better mediate RNAi and suppress NTCP mRNA levels. In some embodiments, the single-stranded oligonucleotide is substantially anticomplementary or completely anticomplementary to AGT mRNA across at least 16 nucleotides. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide from position 2 to 19 is completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide other than position 1 at the 5' end is completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, all nucleotides of the single-stranded oligonucleotide are completely anticomplementary to the NTCP mRNA. In some embodiments, the single-stranded oligonucleotide is substantially anticomplementary, substantially anticomplementary, or completely anticomplementary to a continuous nucleotide sequence m in the NTCP mRNA; the length of the nucleotide sequence m is not greater than the length of the single-stranded oligonucleotide, and the length of the nucleotide sequence m is the same as the length of the single-stranded oligonucleotide, or differs by no more than 8 nucleotides, or differs by 1-5 nucleotides. In some embodiments, the length of the nucleotide sequence m is at least 16 nucleotides, or 16-25 nucleotides, or 18-23 nucleotides, or 19-21 nucleotides; or, the length of the nucleotide sequence m is 19, 21, or 23 nucleotides. In some embodiments, the single-stranded oligonucleotide has the same length as the nucleotide sequence m, and at least the nucleotide sequence other than the terminal nucleotide of the single-stranded oligonucleotide is completely anticomplementary to the nucleotide sequence m. Thus, double-stranded oligonucleotides or oligonucleotide conjugates containing the single-stranded oligonucleotide as the antisense strand of this disclosure can further improve the inhibitory effect on NTCP mRNA. In some embodiments, the nucleotide sequence other than position 1 of the single-stranded oligonucleotide is completely anticomplementary to the nucleotide sequence m in the 5'-3' direction. In some embodiments, all nucleotides of the single-stranded oligonucleotide are completely anticomplementary to the nucleotide sequence m. In some embodiments, the single-chain oligonucleotide of this disclosure may be one of the following first, second, third, fourth or fifth single-chain oligonucleotides, each of which will be described below. The first type of single-stranded oligonucleotide In some embodiments, this disclosure provides a first single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:2 and differs from it by no more than 3 bases. 5'-Z2GUAGCAAAUUCUAAGUUG-3'(SEQ ID NO:2), Wherein, Z2 is A or U, and nucleotide sequence II contains nucleotide Z'2 at a position corresponding to Z2, Z'2 being the first nucleotide at the 5' end of the single-stranded oligonucleotide. In the preceding and following text of this disclosure, "positional correspondence" means that the nucleotides are located at the same position in the nucleotide sequence, starting from the same end of the nucleotide sequence. For example, the first nucleotide at the 5' end of nucleotide sequence II is the nucleotide that corresponds to the first nucleotide of SEQ ID NO:2. In some embodiments, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 may include a difference at the Z'2 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 may include a base difference at the Z'2 position and / or a base difference at a nucleotide position adjacent to Z'2. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 includes a difference at the Z'2 position, where Z'2 is selected from G or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 is a difference at the Z'2 position, where Z'2 is selected from C or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to NTCP mRNA. Each of the non-fluorinated nucleotides is independently selected from 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides with 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat-labile nucleotides. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has a base of G; or, the nucleotide sequence IV is 2 nucleotides in length and has a base composition of GG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has a base composition of GGG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has a base composition of GGGA in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, and the length of the nucleotide sequence V is 1 to 3 nucleotides, attached to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to NTCP mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GG or UU, following the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2 and nucleotide sequence V has a base composition of GG. The second type of single-stranded oligonucleotide In some embodiments, this disclosure provides a second single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:4 and differs from it by no more than 3 bases. 5'-Z4GUCUUGAAUUUCUCAUAG-3'(SEQ ID NO:4), Wherein, Z4 is A or U, and nucleotide sequence II contains nucleotide Z'4 at a position corresponding to Z4, Z'4 being the first nucleotide at the 5' end of the single-stranded oligonucleotide. In some embodiments, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 may include a difference at the Z'4 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 may include a base difference at the Z'4 position and / or a base difference at a nucleotide position adjacent to Z'4. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 includes a difference at the Z'4 position, where Z'4 is selected from G or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 is a difference at the Z'4 position, where Z'4 is selected from C or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to NTCP mRNA. Each of the non-fluorinated nucleotides is independently selected from 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides with 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat-labile nucleotides. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has a base of C; or, the nucleotide sequence IV is 2 nucleotides in length and has a base composition of CA in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has a base composition of CAC in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has a base composition of CACC in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, and the length of the nucleotide sequence V is 1 to 3 nucleotides, attached to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to NTCP mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from CA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:4 and nucleotide sequence V has a base composition of UU. The third type of single-stranded oligonucleotide In some embodiments, this disclosure provides a third single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:6 and differs from it by no more than 3 bases. 5'-Z6UGAUGAUUCUGAUAGAUG-3'(SEQ ID NO:6), Wherein, Z6 is A or U, and nucleotide sequence II contains nucleotide Z'6 at a position corresponding to Z6, Z'6 being the first nucleotide at the 5' end of the single-stranded oligonucleotide. In some embodiments, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6 may include a difference at the Z'6 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6 may include a base difference at the Z'6 position and / or a base difference at a nucleotide position adjacent to Z'6. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6 includes a difference at the Z'6 position, where Z'6 is selected from G or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6 is a difference at the Z'6 position, where Z'6 is selected from C or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to NTCP mRNA. Each of the non-fluorinated nucleotides is independently selected from 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides with 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat-labile nucleotides. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has the base U; or, the nucleotide sequence IV is 2 nucleotides in length and has the base composition UA ​​in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has the base composition UAC in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has the base composition UACU in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, and the length of the nucleotide sequence V is 1 to 3 nucleotides, attached to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to NTCP mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from UA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:6 and nucleotide sequence V has a base composition of UA. The fourth type of single-stranded oligonucleotide In some embodiments, this disclosure provides a fourth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:8 and differs from it by no more than 3 bases. 5'-Z8AAGUAGCAAAUUCUAAGU-3'(SEQ ID NO:8), Wherein, Z8 is A or U, and nucleotide sequence II contains nucleotide Z'8 at a position corresponding to Z8, Z'8 being the first nucleotide at the 5' end of the single-stranded oligonucleotide. In some embodiments, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 may include a difference at the Z'8 position and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 may include a base difference at the Z'8 position and / or a base difference at a nucleotide position adjacent to Z'8. In some embodiments, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 includes a difference at the Z'8 position, where Z'8 is selected from G or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 is a difference at the Z'8 position, where Z'8 is selected from C or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in nucleotide sequence IV is independently one of a non-fluorinated nucleotide. Nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to NTCP mRNA. Each of the non-fluorinated nucleotides is independently selected from 2'-methoxy-modified nucleotides, 2'-alkyl-modified nucleotides with 1-3 carbon atoms, 2'-amino-modified nucleotides, 2'-substituted amino-modified nucleotides, and heat-labile nucleotides. In some embodiments, the length of nucleotide sequence IV is 2 nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has the base U; or, the nucleotide sequence IV is 2 nucleotides in length and has the base composition UG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has the base composition UGGG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has the base composition UGGG in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, and the length of the nucleotide sequence V is 1 to 3 nucleotides, attached to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; after the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to NTCP mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from UG or UU, following the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:8 and nucleotide sequence V has a base composition of UG. The fifth type of single-stranded oligonucleotide In some embodiments, this disclosure provides a fifth single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains nucleotide sequence II, which is of the same length as the nucleotide sequence shown in SEQ ID NO:10 and differs from it by no more than 3 bases. 5'-Z 10 CUUUCAGAAUUGCUUUGG-3' (SEQ ID NO:10), Among them, Z 10 For G or C, the position in nucleotide sequence II corresponds to Z. 10 nucleotide Z' 10 Z' 10 It is the first nucleotide at the 5' end of the antisense strand. In some embodiments, nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:10 by no more than one base. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 may include Z'. 10 Differences at positions and / or base differences at any other nucleotide position in nucleotide sequence II. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 may include Z'. 10 Location and / or with Z' 10 Base differences at adjacent nucleotide positions. In some embodiments, there are no base differences between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 includes Z' 10 The difference in position, and Z' 10 Selected from A or U. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 is Z'. 10 The difference in position, and Z' 10 Choose from A or U. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is attached to the 3' end of the nucleotide sequence II and has a length of 1, 2, 3, or 4 nucleotides. Each nucleotide in the nucleotide sequence IV is independently one of the non-fluorinated modified nucleotides. The nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to the NTCP mRNA. Each of the non-fluorinated modified nucleotides is independently selected from one of the following: 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with 1-3 carbon atoms, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides, and thermally unstable modified nucleotides. In some embodiments, the nucleotide sequence IV is 1 nucleotide in length and has a base of G; or, the nucleotide sequence IV is 2 nucleotides in length and has a base composition of GA in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 3 nucleotides in length and has a base composition of GAC in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV is 4 nucleotides in length and has a base composition of GACC in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to NTCP mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:10 and nucleotide sequence V has a base composition of GA. In some embodiments, nucleotide sequence II is identical to any one of the nucleotide sequences shown in SEQ ID NO:21-SEQ ID NO:30 in Table 1A for at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 consecutive nucleotides. In some embodiments, nucleotide sequence II has no more than one base difference or no base difference between the first to 19th nucleotides of any one of the nucleotide sequences shown in SEQ ID NO:21-SEQ ID NO:30 in Table 1A; or, nucleotide sequence II is any one of SEQ ID NO:21-SEQ ID NO:30 listed in Table 1A. Table 1A Unmodified double-stranded oligonucleotide sequences In some embodiments, the single-chain oligonucleotide is the antisense strand of any one of siNTCP1-M1-siNTCP15-M1 shown in Table 1B. In some embodiments, the single-chain oligonucleotide is the antisense strand of any one of conjugates 1-20 shown in Table 2. 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, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially anticomplementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described above in this disclosure. In the double-stranded oligonucleotides of this disclosure, the length of the sense strand and the antisense strand is each 19-26 nucleotides. In some embodiments, the length difference between the sense strand and the antisense strand is 0-5 nucleotides. In some embodiments, the length of the sense strand is not greater than the length of the antisense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Therefore, the length ratio of the sense strand to the antisense strand in the double-stranded oligonucleotides of this disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, the length of the sense strand is 15-26 or 17-24 nucleotides. In some embodiments, the length of the sense strand is 19-21 nucleotides. In some embodiments, for ease of synthesis, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 19-23 nucleotides. In some embodiments, the lengths of the sense strand and antisense strand are the same, both being 19, 20, or 21 nucleotides. In some embodiments, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 20-24 nucleotides, with the antisense strand being 1-3 nucleotides longer than the sense strand. In some embodiments, the length of the antisense strand is 2 nucleotides longer than the sense strand. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides. In some embodiments, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long. In some embodiments, in the positive strand of the double-stranded oligonucleotide of this disclosure, 2-3 of the 11th-13th nucleotides of the positive strand, in the direction from the 3' end to the 5' end, are fluorinated nucleotides, and the first and / or last nucleotide of the positive strand is an alkoxylated nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having the structure shown in formula (35)). In some embodiments, in the direction from the 3' end to the 5' end, the first nucleotide of the positive strand is an alkoxylated nucleotide or an inverted abasic deoxyribonucleotide. In some embodiments, apart from the fluorinated and inverted abasic deoxyribonucleotides described above, the nucleotides at the remaining positions in the positive strand are each independently non-fluorinated nucleotides, and each non-fluorinated nucleotide is independently selected from one of alkoxylated nucleotides, alkylated nucleotides, amine-modified nucleotides, and thermally unstable nucleotides. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the penultimate nucleotide of the positive strand. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the 3' terminal nucleotide of the positive strand, and the oxygen atom attached to the ribose ring via a methylene group as shown in formula (35) may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand, and the oxygen atom of formula (35) directly attached to the ribose ring may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, the 11th and 13th nucleotides, or nucleotides 11-13, of the positive strand are fluorinated nucleotides, and the first and / or last nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, with the remaining nucleotides in the positive strand being alkoxylated nucleotides. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or nucleotides 11-13, of the sense strand are fluorinated nucleotides, arranged from the 3' end to the 5' end; the first and / or last nucleotide of the sense strand is an alkoxylated nucleotide or a reverse debased deoxynucleotide; and the remaining nucleotides are each independently alkoxylated nucleotides. In this case, through the positional coordination of the modified nucleotides of the sense and antisense strands, the double-stranded oligonucleotides of this disclosure exhibit better stability and / or RISC complex formation activity, thereby displaying stable and efficient NTCP mRNA repressive activity. In some embodiments, each alkoxylated nucleotide is independently methoxylated nucleotide. In some embodiments, in the positive strand, at least one of the linking groups connecting two adjacent nucleotides is independently a phosphate group with a modifying group, and the phosphate group with the modifying group is present at least once between two adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand and between two adjacent nucleotides in the first to fifth nucleotides at the 3' end. In this case, the double-stranded oligonucleotide of this disclosure has a good balance between resistance to exonucleases and NTCP mRNA, thereby improving stability while also exhibiting highly efficient NTCP mRNA inhibitory activity. In some embodiments, each of 1-4 linking groups between any two adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand, and / or each of 1-4 linking groups between any two adjacent nucleotides in the first to fifth nucleotides at the 3' end of the positive strand, is independently a phosphate group with a modifying group. In some embodiments, each of all four linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the positive strand is independently a phosphate group with a modifying group. In some embodiments, each of the four linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the sense strand is independently a phosphate group with a modifying group. In some embodiments, the linking group connecting two adjacent nucleotides in the first to third, first to fourth, or first to fifth nucleotides at the 5' end and / or the 3' end of the sense strand is a phosphate group with a modifying group. In some embodiments, the linking group between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the sense strand is a phosphate group with a modifying group. The definition and selection range of the phosphate group with a modifying group are the same as those described above for the antisense strand of this disclosure. In some embodiments, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28). In some embodiments, the positive strand is the positive strand of any one of siRNA1-siRNA3 shown in Table 1B; in some embodiments, the positive strand is the positive strand of any one of conjugate 1-conjugate 20 shown in Table 2. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides, are fluorinated nucleotides in the direction from the 3' end to the 5' end; the first and / or last nucleotide of the sense strand is an alkoxylated nucleotide or a reverse debased deoxynucleotide; and the nucleotides at the remaining positions are each independently alkoxylated nucleotides; and each of 1-4 linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand, is independently a phosphate ester group with a modifying group. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, from the 3' end to the 5' end, the 11th-13th nucleotides are fluorinated nucleotides, the 1st nucleotide is an alkoxylated nucleotide or a reverse debased deoxynucleotide, and the remaining nucleotides are each independently alkoxylated nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand, are each independently phosphate groups with a modifying group; in the antisense strand, from the 5' end... In the direction from the 5' end to the 3' end, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 14th nucleotide is nucleotide X, and the 2nd, 6th and 16th nucleotides are fluorinated nucleotides. Each of the remaining nucleotides in the antisense strand is independently an alkoxy-modified nucleotide. The linking group between any two adjacent nucleotides in the 5' end of the first to third nucleotides and between any two adjacent nucleotides in the 3' end of the first to third nucleotides are independently phosphate groups with modifying groups. The 5' end nucleotide of the antisense strand is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate-modified nucleotide of formula (31). In some embodiments, the linking group between every two adjacent nucleotides in the 1-2, 1-3, 1-4, or 1-5 nucleotides at the 5' and / or 3' ends of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the linking group between every two adjacent nucleotides in the 1-3, 1-4, or 1-5 nucleotides at the 5' end of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the linking group between two adjacent nucleotides in the 1-2, 1-3, 1-4, or 1-5 nucleotides at the 3' end of the positive strand is a phosphate ester group with a modifying group, and the linking group between the remaining adjacent nucleotides in the positive strand is a phosphate ester group. In some embodiments, the phosphate ester group with the modifying group is a thiophosphate ester group with the structure shown in formula (28), and the alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises 19 nucleotides in the sense strand and 21 nucleotides in the antisense strand; in the sense strand, from the 3' end to the 5' end, the 11th to 13th nucleotides are fluorinated nucleotides, the first nucleotide is a reverse debased deoxynucleotide, and the remaining nucleotides are each independently methoxylated nucleotides; the linking group between adjacent nucleotides in the 1st to 5th nucleotides at the 5' end of the sense strand is a thiophosphate group. In some embodiments, in the double-stranded oligonucleotide of this disclosure, the sense strand comprises 19 nucleotides and the antisense strand comprises 21 nucleotides; in the sense strand, nucleotides 11-13 are fluorinated nucleotides in the direction from the 3' end to the 5' end, the first nucleotide is a reverse debased deoxynucleotide, and the remaining nucleotides are each independently methoxylated nucleotides; in the sense strand, each of the 1-4 linking groups between adjacent nucleotides in the 5' end of the first-5 nucleotides is independently a phosphate thioate group; in the antisense strand, nucleotide 13 is a 2'-O The antisense chain is a methoxyethyl modified nucleotide, the 14th nucleotide is a deoxynucleotide, and the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides. Each of the remaining nucleotides in the antisense chain is independently a methoxy modified nucleotide. In the antisense chain, the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides in the 1st to 3rd nucleotides at the 3' end are thiophosphate groups. The 5' terminal nucleotide of the antisense chain is a 5'-hydroxy nucleotide of formula (29) or a 5'-vinyl phosphate modified nucleotide of formula (31). The double-stranded oligonucleotides disclosed herein, through the aforementioned modification scheme, achieve a good balance between NTCP mRNA regulatory activity and in vivo stability. In the context of this disclosure, "modification scheme" refers to a combination of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications of different numbers, positions, and types that are unrelated to or weakly related to a specific sequence. In some embodiments, the double-stranded oligonucleotides of this disclosure, through the aforementioned modification scheme, can maintain excellent stability without significantly reducing the original 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 oligonucleotides of this disclosure are siRNAs. The double-stranded oligonucleotides of this disclosure, through the aforementioned modification scheme, can maintain excellent stability without significantly reducing the original RNAi activity of the siRNA, thereby achieving a good balance between NTCP mRNA regulatory activity and in vivo stability. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises a substantially anticomplementary or completely anticomplementary double-stranded region, and one or two dangling ends of the sense strand and / or one or two dangling ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide of this disclosure comprises a substantially anticomplementary or completely anticomplementary double-stranded region and one dangling end of the antisense strand. In some embodiments, the double-stranded region formed by the sense and antisense strands contains at least 16 base pairs. In some embodiments, the double-stranded region formed by the sense and antisense strands contains 16-23 base pairs. In some embodiments, the double-stranded region formed by the sense and antisense strands contains 18, 19, 20, or 21 base pairs. In the context of this disclosure, a "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences comprising all base pairs on each of the single strands of a double-stranded nucleic acid structure. Therefore, a double-stranded region consists of all base pairs in the double-stranded nucleic acid structure and all base mismatches between those base pairs. In some embodiments, the number of base mismatches does not exceed 20%, 15%, 10%, or 5% of the total number of base pairs forming the double-stranded region. In some embodiments, the number of base mismatches in the double-stranded region does not exceed 3, 2, or 1. In some embodiments, the double-stranded nucleic acid structure includes a double-stranded region and one or more overhanging ends consisting of nucleotides that have not formed base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only a double-stranded region. In some embodiments, the sense and antisense strands form a double-stranded region spanning at least 16 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains at least 16 base pairs. In the context of this disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense and antisense strands form a double-stranded region spanning 16-23 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains 16-23 base pairs. In some embodiments, the sense and antisense strands form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the double-stranded region formed by the sense and antisense strands contains 18, 19, 20, or 21 base pairs. In some embodiments, the sense and antisense strands are substantially anticomplementary or completely anticomplementary within the double-stranded region. In some embodiments, the sense and antisense strands of the double-stranded oligonucleotides of this disclosure are substantially anticomplementary or completely anticomplementary over their entire nucleotide length. In some embodiments, the sense strand and the antisense strand are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary. In some embodiments, the sense strand and the antisense strand are substantially anticomplementary or completely anticomplementary within the double-stranded region. In some embodiments, along the 5'-3' direction, at least the nucleotide sequence of the sense strand other than the first and last positions is substantially anticomplementary or completely anticomplementary to the antisense strand. In some embodiments, along the 5'-3' direction, the nucleotide sequence of the sense strand other than the last position is completely anticomplementary to the antisense strand; or all nucleotides of the sense strand are completely anticomplementary to the antisense strand. In some embodiments, the double-stranded oligonucleotides described in this disclosure include an unmodified equivalent sequence of the positive strand comprising a nucleotide sequence of the same length as nucleotide sequence m, and having a difference of no more than 3 bases, no more than 1 base, or no base difference, wherein the definition and selection of nucleotide sequence m are as described above. In the preceding and following text, "unmodified equivalent sequence" refers to an oligonucleotide sequence that does not contain any ribose ring modifications, base modifications, or phosphate backbone modifications compared to the original sequence used as the basis for alignment. For example, the unmodified equivalent sequence of VPAmsCfsdTGmsUmia is ACUGUN, where N is A, C, G, or U. In the preceding and following text, a "base difference" between two nucleotide sequences refers to a change in the type of bases at the same position of the nucleotides compared to the latter. For example, if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, then a base difference exists between the two nucleotide sequences at that position. When bases are modified, as long as the purine-pyrimidine pairing relationship for forming the aforementioned double-stranded nucleic acid structure is not affected, it is also considered that there is no base difference between the modified base and the original base. In some embodiments, it is considered that there is no base difference between U and T. In some embodiments, it is considered that there is no base difference between C and 5-methylcytosine (5mC). In some embodiments, it is also considered that a base difference has occurred at that position when a baseless nucleotide or its equivalent is replaced with a nucleotide at the original position. When comparing two nucleotide sequences to determine the number of base differences, alignment is performed in the manner with the fewest base differences among all alignment methods, and the base differences are determined based on this alignment method. In this context, "identical positions" refers to the corresponding positions between two nucleotide sequences in that alignment. For example, when nucleotide sequences A (positions 1-5) are aligned with nucleotide sequences B (positions 2-6) in the same direction, the number of base differences is minimized compared to other alignment methods. In this case, "identical positions" means that position 1 of nucleotide sequence A is aligned with position 2 of nucleotide sequence B, position 2 of nucleotide sequence A is aligned with position 3 of nucleotide sequence B, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths refers to the number of base differences calculated from the first nucleotide without a base difference to the last nucleotide without a base difference in the alignment with the minimum number of base differences. In some embodiments, the number of base differences between two nucleotide sequences of the same length refers to the total number of base differences between the first to last nucleotides of one nucleotide sequence and the first to last nucleotides of the other nucleotide sequence, in the same direction. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths means that, in the same direction, there are no base differences between the first to last nucleotides of the shorter nucleotide sequence and each nucleotide at the same position in the other nucleotide sequence. In some embodiments, the absence of base differences between two nucleotide sequences of the same length means that, in the same direction, there are no base differences between the first to last nucleotides of one nucleotide sequence and the first to last nucleotides of the other nucleotide sequence. The double-stranded oligonucleotide disclosed herein can be any double-stranded oligonucleotide that regulates the expression level of NTCP mRNA. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or downregulates the expression level of NTCP mRNA, such as siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or upregulates the expression of NTCP mRNA, for example, saRNA. In some embodiments, the double-stranded oligonucleotide is siRNA. In some embodiments, the double-stranded oligonucleotide of this disclosure may be any one of the first to fifth types of double-stranded oligonucleotides, each of which is described below. The first type of double-stranded oligonucleotide In some embodiments, this disclosure provides a first double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO:1 and differs by no more than 3 bases; and the antisense strand comprises nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO:2 and differs by no more than 3 bases. 5'-CAACUUAGAAUUUGCUACZ1-3' (SEQ ID NO:1); 5'-Z2GUAGCAAAUUCUAAGUUG-3'(SEQ ID NO:2), Wherein, Z1 is U, A or ia, ia represents reverse debased deoxynucleotide, Z2 is A or U, nucleotide sequence I contains nucleotide Z'1 corresponding to Z1, nucleotide sequence II contains nucleotide Z'2 corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, there is no more than one base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1, and / or no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2. The base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 may include a difference at the Z'1 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base differences between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 may include base differences at the Z'1 position and / or at positions of nucleotides adjacent to Z'1. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:1 is the base difference at position Z'1, preferably, Z'1 is a reverse debased deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 includes a difference at the Z'2 position, where Z'2 is selected from C or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 is a difference at the Z'2 position, where Z'2 is selected from C or G. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I; or, a base mismatch exists between the second nucleotide of nucleotide sequence II and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high NTCP mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide in length, oriented from 5' to 3', with C as the base of sequence III and G as the base of sequence IV; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides in length, with CC as the base composition of sequence III and GG as the base composition of sequence IV, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being CCC and the base composition of nucleotide sequence IV being GGG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being UCCC and the base composition of nucleotide sequence IV being GGGA, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being CC and the base composition of nucleotide sequence IV being GG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GG or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2, nucleotide sequence I consists of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is GG in the direction from the 5' end to the 3' end. The second type of double-stranded oligonucleotide In some embodiments, this disclosure provides a second double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO:3 and differs by no more than 3 bases; and the antisense strand comprises nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO:4 and differs by no more than 3 bases. 5'-CUAUGAGAAAUUCAAGACZ3-3' (SEQ ID NO: 3); 5'-Z4GUCUUGAAUUUCUCAUAG-3'(SEQ ID NO:4), Wherein, Z3 is U, A or ia, Z4 is A or U, nucleotide sequence I contains nucleotide Z'3 corresponding to Z3, nucleotide sequence II contains nucleotide Z'4 corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, there is no more than one base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:3, and / or no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4. The base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:3 may include a difference at the Z'3 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base differences between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:3 may include base differences at the Z'3 position and / or at the positions of nucleotides adjacent to Z'3. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:3 is the base difference at position Z'3, preferably, Z'3 is a reverse debased deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 includes a difference at the Z'4 position, where Z'4 is selected from C or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4 is a difference at the Z'4 position, where Z'4 is selected from C or G. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I. Alternatively, a base mismatch exists between the second nucleotide of nucleotide sequence II in the 5' to 3' direction and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high NTCP mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide in length, oriented from 5' to 3', with G as the base of sequence III and C as the base of sequence IV; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides in length, with UG as the base composition of sequence III and CA as the base composition of sequence IV, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being GUG and the base composition of nucleotide sequence IV being CAC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being GGUG and the base composition of nucleotide sequence IV being CACC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being UG and the base composition of nucleotide sequence IV being CA, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from CA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2, nucleotide sequence I consists of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is UU in the direction from the 5' end to the 3' end. The third type of double-stranded oligonucleotide In some embodiments, this disclosure provides a third double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO:5 and differs by no more than 3 bases; and the antisense strand comprises nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO:6 and differs by no more than 3 bases. 5'-CAUCUAUCAGAAUCAUCAZ5-3' (SEQ ID NO: 5); 5'-Z6UGAUGAUUCUGAUAGAUG-3'(SEQ ID NO:6), Wherein, Z5 is U, A or ia, Z6 is A or U, nucleotide sequence I contains nucleotide Z'5 corresponding to Z5, nucleotide sequence II contains nucleotide Z'6 corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, there is no more than one base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:5, and / or no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6. The base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:5 may include a difference at the Z'5 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base differences between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:5 may include base differences at the Z'5 position and / or at the positions of nucleotides adjacent to Z'5. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:5 is the base difference at position Z'5, preferably, Z'5 is a reverse debased deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6 includes a difference at the Z'6 position, where Z'6 is selected from C or G. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I. Alternatively, a base mismatch exists between the second nucleotide of nucleotide sequence II in the 5' to 3' direction and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high NTCP mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide long along the 5'-3' direction, with nucleotide sequence III having a base of A and nucleotide sequence IV having a base of U; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides long, with nucleotide sequences III having a base composition of UA along the 5'-3' direction; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being GUA and the base composition of nucleotide sequence IV being UAC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being AGUA and the base composition of nucleotide sequence IV being UACU, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being UA and the base composition of nucleotide sequence IV being UA, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from UA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2, nucleotide sequence I consists of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is UA in the direction from the 5' end to the 3' end. The fourth type of double-stranded oligonucleotide In some embodiments, this disclosure provides a fourth double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO:7 and differs by no more than 3 bases; and the antisense strand comprises nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO:8 and differs by no more than 3 bases. 5'-ACUUAGAAUUUGCUACUUZ7-3' (SEQ ID NO:7); 5'-Z8AAGUAGCAAAUUCUAAGU-3'(SEQ ID NO:8), Wherein, Z7 is U, A or ia, Z8 is A or U, nucleotide sequence I contains nucleotide Z'7 corresponding to Z7, nucleotide sequence II contains nucleotide Z'8 corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, there is no more than one base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:7, and / or no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8. The base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:7 may include a difference at the Z'7 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base differences between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:7 may include base differences at the Z'7 position and / or at the positions of nucleotides adjacent to Z'7. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:7 is the base difference at position Z'7, preferably, Z'7 is a reverse debased deoxynucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 includes a difference at the Z'8 position, where Z'8 is selected from C or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8 is a difference at the Z'8 position, where Z'8 is selected from C or G. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I. Alternatively, a base mismatch exists between the second nucleotide of nucleotide sequence II in the 5' to 3' direction and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high NTCP mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide in length, oriented from 5' to 3', with nucleotide sequence III having a base of A and nucleotide sequence IV having a base of U; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides in length, with nucleotide sequence III having a base composition of CA and nucleotide sequence IV having a base composition of UG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being CCA and that of nucleotide sequence IV being UGG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being CCCA and that of nucleotide sequence IV being UGGG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being CA and that of nucleotide sequence IV being UG, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from UG or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II consists of SEQ ID NO:2, nucleotide sequence I consists of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is UG in the direction from the 5' end to the 3' end. The fifth type of double-stranded oligonucleotide In some embodiments, this disclosure provides a fifth double-stranded oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises nucleotide sequence I, which is equal in length to the nucleotide sequence shown in SEQ ID NO:9 and differs by no more than 3 bases; and the antisense strand comprises nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO:10 and differs by no more than 3 bases. 5'-CCAAAGCAAUUCUGAAAGZ9-3' (SEQ ID NO:9); 5'-Z 10 CUUUCAGAAUUGCUUUGG-3' (SEQ ID NO:10), Wherein, Z9 is C, G, or ia, Z 10 For G or C, nucleotide sequence I contains nucleotide Z'9 at position Z9, and nucleotide sequence II contains nucleotide Z at position Z. 10 nucleotide Z' 10 Z' 10 It is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, there is no more than one base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:9, and / or no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10. The base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:9 may include a difference at the Z'9 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base differences between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:9 may include base differences at the Z'9 position and / or at positions of nucleotides adjacent to Z'9. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence shown in SEQ ID NO:9 is the base difference at position Z'9, preferably, Z'9 is a reverse debased deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 includes Z' 10 The difference in position, and Z' 10 Selected from A or U. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10 is Z'. 10 The difference in position, and Z' 10 Choose from A or U. In some embodiments, nucleotides 2-19 of nucleotide sequence II are completely anticomplementary to NTCP mRNA in the 5' to 3' direction. In some embodiments, nucleotide sequence II is completely anticomplementary to nucleotide sequence I. Alternatively, a base mismatch exists between the second nucleotide of nucleotide sequence II in the 5' to 3' direction and the second nucleotide of nucleotide sequence I in the 3' to 5' direction. By including this base mismatch, high NTCP mRNA inhibitory activity can be achieved while maintaining low off-target effects. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein the length of nucleotide sequence III is 1, 2, 3, or 4 nucleotides, the length of nucleotide sequence IV and nucleotide sequence III are equal, and the nucleotide sequence IV and nucleotide sequence III are substantially anticomplementary or completely anticomplementary, wherein nucleotide sequence III is attached to the 5' end of nucleotide sequence I. In some embodiments, nucleotide sequences III and IV are each independently one nucleotide in length, oriented from 5' to 3', with C as the base of sequence III and G as the base of sequence IV; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or, nucleotide sequences III and IV are each independently two nucleotides in length, with UC as the base composition of sequence III and GA as the base composition of sequence IV, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or In some embodiments, nucleotide sequences III and IV are each 3 nucleotides in length, with the base composition of nucleotide sequence III being GUC and that of nucleotide sequence IV being GAC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are each 4 nucleotides in length, with the base composition of nucleotide sequence III being GGUC and that of nucleotide sequence IV being GACC, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, nucleotide sequences III and IV are 2 nucleotides in length, with the base composition of nucleotide sequence III being UC and that of nucleotide sequence IV being GA, oriented from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand further contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II, forming the 3' overhang of the antisense strand after the formation of a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or is completely reverse complementary to AGT mRNA. In some embodiments, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GA or UU, following the direction from the 5' end to the 3' end. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II and nucleotide sequence V, wherein nucleotide sequence II is composed of SEQ ID NO:2, nucleotide sequence I is composed of SEQ ID NO:1, nucleotide sequence V is attached to the 3' end of nucleotide sequence II, and the base composition of nucleotide sequence V is selected from GA in the direction from the 5' end to the 3' end. In some embodiments, nucleotide sequence I is identical to any one of the sense strands of siRNA6-siRNA15 in Table 1A by at least 15 consecutive nucleotides, and there are no more than 3 base differences therein; nucleotide sequence II is identical to any one of the antisense strands of siRNA6-siRNA15 in Table 1A by at least 15 consecutive nucleotides, and there are no more than 3 base differences therein. In some embodiments, the nucleotide sequence I is identical to the sense strand of any one of siRNA6-siRNA15 listed in Table 1A for at least 15, at least 16, at least 17, at least 18, or 19 consecutive nucleotides, respectively, with no more than 3 base differences, no more than 1 base difference, or no base differences; the nucleotide sequence II is identical to the antisense strand of any one of siRNA6-siRNA15 listed in Table 1A for at least 15, at least 16, at least 17, at least 18, or 19 consecutive nucleotides, respectively, with no more than 3 base differences, no more than 1 base difference, or no base differences. In some embodiments, the nucleotide sequence I is of equal length to the sense strand of any one of siRNA6-siRNA15 listed in Table 1A, with at least one base difference between positions 1-18, or no base difference at all, in the 5'-3' direction; the nucleotide sequence II is of equal length to the antisense strand of the siRNA, with at least one base difference between positions 2-21, or no base difference at all. In some embodiments, the nucleotide sequence I differs from any of the nucleotide sequences shown in SEQ ID NO:11-SEQ ID NO:20 in Table 1A by no more than one base, or there is no base difference, and the nucleotide sequence II differs from the first to the 19th bases shown in any of the nucleotide sequences shown in SEQ ID NO:21-SEQ ID NO:30 in Table 1A by no more than one base, or there is no base difference. In some embodiments, the sense and antisense strands of the double-stranded oligonucleotide are of equal length to the sense and antisense strands of one of siNTCP1-M1-siNTCP15-M1 shown in Table 1 below, and the number of base differences is no more than 3, no more than 1, or there are no base differences. In some embodiments, the double-stranded oligonucleotide is one of siNTCP1-M1-siNTCP15-M1 shown in Table 1B below: Table 1B: Disclosed siRNA sequences In this diagram, uppercase letters C, G, U, A, and T represent the base composition of a nucleotide; lowercase letter o indicates that the uppercase letter to the left of o represents an alkoxy-modified nucleotide; lowercase letter f indicates that the uppercase letter to the left of f represents a fluorinated nucleotide; lowercase letter e indicates that the uppercase letter to the left of e represents a substituted alkoxy-modified nucleotide; lowercase letter d indicates that the uppercase letter to the right of d represents a deoxynucleotide; and lowercase letter s indicates the base composition of a nucleotide. Two adjacent uppercase letters represent nucleotides linked by a phosphate thioester group; a lowercase letter 'x' indicates that the two adjacent uppercase letters on either side of that letter are linked by a phosphate thioester group or a phosphate thioester group; the letter combination 'P1' indicates that the uppercase letter to the right of that letter combination represents a 5'-hydroxy nucleotide or a 5'-VP modified nucleotide; 'ia' represents a reverse debased deoxynucleotide; and each 'U' in the above sequence can be replaced by a 'T', and / or each 'C' can be replaced by 5mC, which substitutions do not significantly reduce the NTCP mRNA expression regulatory activity and / or off-target effect inhibition ability of the double-stranded oligonucleotide. In some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide is a 2'-O-methoxyethyl modified nucleotide represented by 'moe'. In some embodiments, each lowercase letter 'x' independently represents a phosphate thioester group linked between the two uppercase letters on either side of that letter. The antisense and / or double-stranded oligonucleotides provided in this disclosure can be obtained using conventional oligonucleotide preparation methods in the art (e.g., solid-phase synthesis and liquid-phase synthesis). Solid-phase synthesis is already available as a commercially available custom service. Modified nucleotide groups can be introduced into the antisense and / or double-stranded oligonucleotides described in this disclosure using appropriately modified nucleoside monomers. Methods for preparing appropriately modified nucleoside monomers and for introducing modified nucleotide groups into antisense and / or double-stranded oligonucleotides are also well known to those skilled in the art. All modified nucleoside monomers are commercially available or prepared using known methods. The single-chain oligonucleotides and double-chain oligonucleotides provided in this disclosure can be used alone, or in combination with a pharmaceutically acceptable carrier to form a pharmaceutical composition, or in combination with a delivery group to form an oligonucleotide conjugate, or in any other suitable form. Contacting cells with an effective amount of the single-chain oligonucleotide, double-chain oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate can regulate NTCP mRNA, or administering an effective amount of the single-chain oligonucleotide, double-chain oligonucleotide, oligonucleotide conjugate, or pharmaceutical composition to a subject can regulate NTCP mRNA to achieve therapeutic effects on pathological conditions or diseases associated with NTCP mRNA levels. Oligonucleotide conjugates 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, such as an siRNA group, refers to a chemical portion formed by removing one or more atoms or groups of atoms from a single-stranded or double-stranded oligonucleotide (e.g., siRNA) molecule. Those skilled in the art will understand that the RNAi activity of the oligonucleotide group formed by this removal is at least the same as or equivalent to the RNAi activity of the single-stranded or double-stranded oligonucleotide itself. In some embodiments, the removal of one or more atoms or groups of atoms does not impair the inhibitory activity or stability of the oligonucleotide (e.g., siRNA) against the target mRNA. In some embodiments, the oligonucleotide group is formed by removing one atom or group of atoms (e.g., a hydrogen atom, a hydroxyl group, or a phosphate ester group) from a single-stranded or double-stranded oligonucleotide provided in this disclosure. For example, the siRNA group can be a chemical part formed by removing hydrogen atoms from the phosphate ester bond of siRNA, or a chemical part formed by removing hydrogen atoms from the 5' hydroxyl group of the 5' terminal nucleotide of the sense or antisense strand of siRNA, or a chemical part formed by removing hydrogen atoms from the 3' hydroxyl group of the 3' terminal nucleotide of the sense or antisense strand of siRNA. In the context of this disclosure, unless otherwise stated, "conjugation" means the covalent connection between two or more chemical parts, each having a specific function (however, without theoretical limitation, the individual components within the functional chemical part—such as a double-stranded oligonucleotide or a metal ion-ligand chelate—may not necessarily be covalently connected); correspondingly, "conjugation" refers to a compound formed by the covalent connection of the individual chemical parts. Further, "oligonucleotide conjugation" refers to a compound formed by the covalent attachment of one or more functional chemical parts to an oligonucleotide. Oligonucleotide conjugation should be understood, depending on the context, as a collective term for multiple oligonucleotide conjugations or an oligonucleotide conjugation represented by a particular chemical formula. In the context of this disclosure, "conjugated molecule" should be understood as a specific compound that can be reactively conjugated to an oligonucleotide to ultimately form the oligonucleotide conjugation of this disclosure. The delivery group is a group used to deliver a single-stranded or double-stranded oligonucleotide group into a cell expressing NTCP mRNA. In some embodiments, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the single-stranded or double-stranded oligonucleotide group, the linker group, and the targeting group are covalently or non-covalently linked in sequence, each of the targeting groups being selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes or groups capable of increasing tissue compatibility. In some embodiments, the targeting group targets the liver. In some embodiments, at least one or each targeting group is independently selected from ligands capable of binding to desialylate glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, there are 1-6 targeting groups. In one embodiment, there are 2-4 targeting 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. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the conjugation site of the double-stranded oligonucleotide group to 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 of the double-stranded oligonucleotide group to the delivery group is at the 3' end of the sense strand of the double-stranded oligonucleotide. In some embodiments, the delivery group can be attached to any position on the nucleotide, such as a phosphate group, a 2', 3', or 5'-hydroxyl group of the ribose, or a base. When the delivery group is attached to the 3' or 5' end of the positive strand of a single-stranded or double-stranded oligonucleotide, the delivery group is typically attached to the oxygen atom formed by removing a hydrogen atom from the 3' or 5'-hydroxyl group of the nucleotide; when the delivery group is attached to the inner sequence of a single-stranded or double-stranded oligonucleotide, the delivery group is typically attached to a phosphate group, a ribose ring, or a base. In some embodiments, the delivery group can be attached to the 3'-hydroxyl group of an inner sequence nucleotide of a single-stranded or double-stranded oligonucleotide, in which case the nucleotides are linked by a 2'-5' phosphodiester bond. Various connection methods can be found in the following non-patent literature: Muthiah Manoharan et al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5): 1181-7. The entire contents of this article are incorporated herein by reference. In some embodiments, the oligonucleotide and the delivery group are linked by acid-labile or reducible chemical bonds that can degrade in the acidic environment of the endosome, thereby converting the oligonucleotide group into a free oligonucleotide. For non-degradable conjugations, the delivery group can be attached to the positive and negative strands of a single-stranded or double-stranded oligonucleotide group to minimize the impact of the conjugation on the activity of the single-stranded or double-stranded oligonucleotide group. The targeting group can be linked to the oligonucleotide group via a suitable linker. Those skilled in the art can select a suitable linker based on the specific type of the targeting group. For example, when the targeting group is a group that targets receptors on the surface of hepatocytes, the types of these linkers, the types of targeting groups, and the way they are linked to the oligonucleotide can be found in the disclosure of WO2015006740A2, the entire disclosure of which is incorporated herein by reference. In some embodiments, the targeting group may be a ligand commonly used in the field of double-stranded oligonucleotide drug delivery, such as the various ligands described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of the target groups is selected from ligands capable of binding to cell surface receptors expressing NTCP mRNA. In some embodiments, at least one or each of the target groups is selected from small molecule ligand groups capable of affinity for desialylate glycoprotein receptors on the surface of hepatocytes. In some embodiments, at least one or each of the target groups is selected from any ligand capable of binding to cell surface receptors of cells expressing NTCP mRNA. In some embodiments, each of the target groups is independently a ligand with affinity for desialyl glycoprotein receptors on the surface of mammalian hepatocytes. In some embodiments, each of the target groups is independently a desialyl glycoprotein or a sugar. In some embodiments, each of the target groups is independently selected from D-mannose, L-mannose, D-arabinose, D-xylfuranose, L-xylfuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannose, β-D-mannose, α-D-mannose, β-D-mannose, α-D-glucose, β-D-glucose, α-D-glucose, β-D-glucose. α-D-Furfural, β-D-Furfural, α-D-Fructose, α-D-Galactopyranose, α-D-Galactopyranose, β-D-Galactopyranose, α-D-Galactopyranose, β-D-Galactopyranose, Glucosamine, Sialic acid, Galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-butyrylgalactosamine, N-isobutyrylgalactosamine, 2 -Amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfonamido-D-glucopyranose, N-ethanolyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4 One of the following: tri-O-acetyl-1-thio-6-O-triphenylmethyl-α-D-glucopyranoside methyl ester, 4-thio-β-D-galactopyranose, 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucopyranoside ethyl ester, 2,5-dehydrated-D-alosulfonyl, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose. In some embodiments, at least one or each of the target groups is galactose or N-acetylgalactosamine. In some embodiments, at least one or each of the target groups is galactose or N-acetylgalactosamine. In some embodiments, the double-stranded oligonucleotide group is capable of regulating the expression level of NTCP mRNA in hepatocytes. The delivery group in the oligonucleotide conjugates disclosed herein can be any of the various delivery groups known to those skilled in the art of oligonucleotide pharmaceuticals. In some embodiments, the linker group in the oligonucleotide conjugate of this disclosure has a structure as shown in formula (301): Where k is an integer from 1 to 5, Indicates the site of covalent linkage of groups; all L A Connect to L C The same atom in; or, each L A Independently connected to L C Different atoms in it. In some implementations, L C It has -NH-C(H) n301 (CH2O-) k The structure shown is such that k is an integer from 1 to 3, and n301 = 3 - k; L B The length is 5-20 atoms. In some implementations, each L A Independently, it is a straight-chain alkylene group with a length of 5-20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, 1,2,3-triazole subunit, succinimide subunit. In some implementations, L A Having a structure containing amide bonds as shown in formula (302), L B It has a structure as shown in equation (303): Where, n 302 q 302 and p 302 Each is an independent integer from 2 to 6; optionally, n 302 q 302 and p 302 Each can be 2 or 3 independently; n 303 n is an integer between 4 and 16, optionally n 303 For integers between 8 and 12, This indicates the site where the group is covalently linked. In some embodiments, the linking group has a structure as shown in formula (304) or formula (305): In the linking group, each L A Each of the target groups is connected via an ether bond and via L C The oxygen atom of the hydroxyl group in some of the middle groups is related to L. C Partially linked by ether bonds; LB 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 (305A): Wherein, Nu represents an oligonucleotide group formed from single-stranded or double-stranded oligonucleotides provided in this disclosure. In some embodiments, the linker group in the oligonucleotide conjugate of this disclosure has the structure shown in formula (306): Where, n 306 For each p, the integer is between 0 and 3. 306 Independently, integers from 1 to 6. The site indicates a covalently linked group; the linking group is connected to the target group by an ether bond formed by an oxygen atom marked with *; the linking group is connected to the double-stranded oligonucleotide by at least one of the oxygen atoms marked with # forming a phosphate ester bond or a thiophosphate ester bond, and the remaining oxygen atoms marked with # are connected to hydrogen atoms to form hydroxyl groups, or connected to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugates of this disclosure have a structure as shown in formula (307): Wherein, Nu represents an oligonucleotide group formed from single-stranded or double-stranded oligonucleotides provided in this disclosure. In some embodiments, the oligonucleotide conjugates of this disclosure have the structure shown in formula (308): in, n 308 The integers are selected from 2 to 4; Each m 308 Independently selected as an integer from 2 to 5; Each R 308 Independently, it can be a hydrogen atom, a methyl group, or an ethyl group, or two R atoms attached to the same carbon atom. 308 Together with this carbon atom, they form a carbonyl group; One of the groups represented independently by A0 is an oligonucleotide group, which is a group formed by removing an atom or group of atoms from a single-stranded or double-stranded oligonucleotide as described in this disclosure; the remaining A0 is an independent targeting group, and each targeting 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 1-70 atoms; This indicates the site where the group is covalently linked. In some embodiments, each L1 is independently a straight-chain alkylene group with a length of 1-70 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenyl, C2-C 10 Ethyne group, C6-C 10 Aromatic, C3-C 18 Heterocyclic groups and C5-C 10 Heteroaryl; and the linear alkylene group may optionally have substituents of any one or more of the group consisting of: C1-C 10 Alkyl, C6-C 10 Aryl, C5-C 10 heteroaryl, C1-C 10 Halogenated alkyl, -OC1-C 10 Alkyl, OC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-OH, -OC1-C 10 Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10 Alkyl) (C1-C 10 alkyl), -NH(C1-C 10 Alkyl), N(C1-C) 10 Alkyl) (C1-C 10 alkylphenyl), NH(C1-C 10 Alkylphenyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 Alkyl), -CON (C1-C) 10 Alkyl) (C1-C 10 Alkyl), -CONH (C1-C) 10 Alkyl groups, -CONH2, -NHC(O) (C1-C) 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 Alkyl)C(O)(C1-C10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (Halogenated alkyl groups). As used herein, “alkyl” refers to a straight-chain or branched alkyl group having a specified number of carbon atoms, typically from 1 to 20 carbon atoms, such as from 1 to 10 carbon atoms, or from 1 to 8 or 1 to 6 carbon atoms. For example, C1-C6 alkyl groups comprise straight-chain and branched alkyl groups with 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. Alkylenes are subsets of alkyl groups, referring to residues that are identical to alkyl groups but have two connection sites. 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: aziridine, heptatrienyl, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzene benzo[a]furanyl, benzo[a]oxazolyl, benzo[a]dioxolyl, benzo[a]dioxinyl, benzo[a]pyranyl, benzo[a]pyranoneyl, benzo[a]furanyl, benzo[a]furanoneyl, benzo[a]thiophenyl, benzo[a]thiophene[3,2-d]pyrimidinyl, benzo[a]triazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cinnolinyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentano[4,5] Thiophene[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8 9,10-Hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indole, isoyindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl (5,8-methano-5,6,7,8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridano[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-c]pyridinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl / thienyl. , 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 10Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10 Alkyl) (C1-C 10 alkyl), -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl) (C1-C 10 alkylphenyl), -NH(C1-C 10 Alkylphenyl), -CN, -NO2, -CO2H, -C(O)O(C1-C 10 Alkyl), -CON (C1-C) 10 Alkyl) (C1-C 10 Alkyl), -CONH (C1-C) 10 Alkyl group), -CONH2, -NHC(O) (C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 Alkyl)C(O)(C1-C 10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), -C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, -C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (Halogenated alkyl). In some embodiments, the substituent is one of -C1-C3 alkyl, -C6-C8 aryl, -O-C1-C3 alkyl, -O-(C1-C3 alkyl)phenyl, halogen, -OH, -NH2, -CN or -NO2. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable. 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 an oligonucleotide group, is to covalently link the oligonucleotide group to the target group. This allows the oligonucleotide conjugate containing the oligonucleotide group to enter hepatocytes through the targeting effect of the target group, without affecting the regulatory function of the oligonucleotide group on NTCP mRNA levels after entering the hepatocytes. Therefore, in some embodiments, the length of L1 covalently linked to A0 representing a double-stranded oligonucleotide group is 3-20 atoms, 4-15 atoms, or 5-12 atoms. In some embodiments, L1 covalently linked to A0 representing an oligonucleotide group is selected from one or more of A1, A2, A4, A5, A10, A16, A18, and A19, combined with phosphate ester groups or modified phosphate ester groups. Where j1 is an integer between 2 and 10; This indicates the site where the group is covalently linked. In some embodiments, R2 is selected from at least two of A1, A2, A4, A10 and A16 connected with a phosphate ester group or a modified phosphate ester group; in some embodiments, R2 is selected from at least two of A1, A2, A10 connected with a phosphate ester group or a modified phosphate ester group. In some embodiments, L1, covalently linked to A0 representing an oligonucleotide group, has a structure as shown in formulas (B1), (B2), (B3), or (B4): in, L represents the site where groups are covalently linked. B1 and L B2 Whether identical or different, independently selected from one of the following groups or any combination thereof: -(CH2)q1 -、-CH(OH)-、-CH(CH2OH)-、-NH-、-O-、-S-、1,4-cyclohexanediyl、1,4-piperidinidyl、1,4-phenylene、1,4-piperazinidyl、pyrrolidinediyl、where q1 is an integer from 1 to 6, L B1 and L B2 The length of each is independently 1-20 atoms. In some embodiments, L B1 and L B2 The length of each is independently 1-10 atoms. In some embodiments, L B1 and L B2 The length of each atom is 1-6 atoms. L B3 A group selected from phosphate ester groups, thiophosphate ester groups, and dithiophosphate ester groups is covalently linked to the 5' hydroxyl group at the 5' position of the ribose of the sense or antisense strand of the double-stranded oligonucleotide group, or the oxygen atom remaining after removing one hydrogen atom from the 3' hydroxyl group at the 3' position of the ribose of the 3' terminal nucleotide. In some embodiments, L B3 It is a phosphate ester group, covalently linked to the 5' hydroxyl group of the ribose at the 5' end of the positive strand of the double-stranded oligonucleotide group, or the oxygen atom remaining after removing one hydrogen atom from the 3' hydroxyl group of the ribose at the 3' end of the positive strand of the double-stranded oligonucleotide group. In some embodiments, when the oligonucleotide conjugates of this disclosure are prepared by a solid-phase synthesis process, L1, covalently linked to A0 representing an oligonucleotide group, needs to simultaneously contain a linking site for N-linking on a nitrogen-containing backbone, a linking site for linking to an oligonucleotide group, and a functional group capable of linking to a solid-phase support. In some embodiments, the N-linking site on the nitrogen-containing backbone in L1, covalently linked to A0 representing an oligonucleotide group, forms an amide bond with N, is covalently linked to the oligonucleotide group via a phosphate ester bond, and the functional group capable of linking to the solid-phase support is a hydroxyl or amino group. In some embodiments, R2 is B5, B6, B5', or B6'. in, This indicates the site where a group is covalently bonded. The value of q2 can be an integer from 1 to 10. In some implementations, q2 is an integer from 1 to 5. The function of L1 covalently linked to A0, representing the target group, is to position the target group in a suitable spatial location, thereby better binding to receptors on the surface of mammalian hepatocytes, and thus specifically targeting and entering the hepatocytes. Therefore, any L1 covalently linked to A0, representing the target group, can be used in this disclosure as long as it has an appropriate length and its chemical properties do not significantly affect delivery. In some embodiments, each L1 covalently linked to A0, representing the target group, is independently a divalent linker with a length of 3-25 atoms. In some embodiments, each L1 covalently linked to A0, representing the target group, has a length of 4-15 atoms. In some embodiments, each L1 covalently linked to A0, representing the target group, has a length of 5-10 atoms. In some embodiments, the length of each L1 covalently linked to A0, representing the target group, is the same. In some embodiments, each L1 covalently linked to A0 representing a target group may be the same or different, and is independently selected from the group consisting of the groups represented by formulas (L3)-(L18) and any combination thereof: Where each j1 is an integer from 2 to 10; each R' is independently a hydrogen atom or a C1-C3 alkyl group. This indicates the site where the group is covalently linked. For ease of synthesis and / or chemical stability, in some embodiments, each L1 covalently linked to A0 representing a target group is independently a combination of at least two linking units, each linking unit independently having a structure shown in any one of formulas (L3)-(L7). In some embodiments, each linking unit independently has a structure shown in any one of formulas (L3), (L4), and (L7). For ease of synthesis, in some embodiments, each L1 covalently linked to A0 representing a target group includes a carbonyl group bonded to a nitrogen atom shown in formula (308). In some embodiments, each L1 covalently linked to A0 representing a target group independently has the structure shown in formula (L20) or (L21): Where j2 is an integer from 4 to 9, and j3 is 1 or 2. In some embodiments, j2 is 5, 6, or 7, and j3 is 1. In some embodiments, each L1 covalently linked to A0 representing the target group is identical. In the conjugates disclosed herein, the number of targeting groups and the spacing between them are the number and spacing that provide a suitable spatial configuration of multiple targeting groups. For this purpose, n308 and each m308 are independently integers selected from 2 to 4. In some embodiments, n308 is 3 or 4, so that the number of targeting groups in the conjugates of this disclosure is 3 or 4, which enables better binding to hepatocyte surface receptors. In some embodiments, n308 is 3, and each m308 is independently 3 or 4. Those skilled in the art will understand that each R 308 When the individual atoms are hydrogen atoms, methyl groups, or ethyl groups, the delivery effect of the oligonucleotide conjugate is not affected, and the objectives of this disclosure can still be achieved. In some embodiments, for ease of synthesis, each R... 308 Each is an independent hydrogen atom. In some embodiments, the oligonucleotide conjugates of this disclosure have the structures shown in formulas (403), (404), (405), (406), (407), (408), (409), (410), (411), (412), (413), (414), (415), (416), (417), (418), (419), (420), (421), or (422): Wherein, Nu represents an oligonucleotide group, such as a single-stranded oligonucleotide group or a double-stranded oligonucleotide group formed from a single-stranded oligonucleotide or a double-stranded oligonucleotide provided in this disclosure. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom shown in the above structural formula is covalently linked to the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group. In some embodiments, the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group is a reverse debased deoxynucleotide, and the P atom shown in the above structural formula is covalently linked to the double-stranded oligonucleotide group by substituting a hydrogen atom in the hydroxyl group of the 3' terminal reverse debased deoxynucleotide of the positive strand of the double-stranded oligonucleotide group represented by Nu, which is connected to the ribose ring via a methylene group. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom remaining after removing one hydrogen atom from the 3' position hydroxyl group of the ribose ring of the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group represented by Nu. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom of the reverse debased deoxynucleotide ia (as shown in formula (35)) at the 3' end of the positive strand of the siRNA represented by Nu, thereby covalently linking it to the positive strand of the siRNA. In some embodiments, the oligonucleotide conjugate of this disclosure has the structure shown in formula (403). In some embodiments, the double-stranded oligonucleotide groups contained in the oligonucleotide conjugates of this disclosure may be siRNA groups formed by removing an atom or group of atoms from siRNA; in this case, the oligonucleotide conjugates of this disclosure are also referred to as siRNA conjugates. In some embodiments, the double-stranded oligonucleotide groups contained in the oligonucleotide conjugates of this disclosure may be siRNA groups formed from, for example, the siRNAs listed in Table 1A or Table 1B. siRNA conjugates containing these siRNA groups exhibit excellent stability and high NTCP mRNA inhibitory activity. In this context, an siRNA group refers to a chemical portion formed by removing one or more atoms or groups of atoms from an siRNA molecule. Those skilled in the art will understand that the RNAi activity of the siRNA group formed by this removal is at least the same as or equivalent to that of the siRNA itself. In some embodiments, the removal of one or more atoms or groups of atoms does not impair the inhibitory activity or stability of the siRNA against the target mRNA. In some embodiments, the siRNA group is a group formed by removing one atom or group of atoms (e.g., a hydrogen atom, a hydroxyl group, or a phosphate ester group) from the siRNA provided in this disclosure. For example, the siRNA group may be a chemical portion formed by removing a hydrogen atom from a phosphate ester bond in the siRNA, or a chemical portion formed by removing a hydrogen atom from the 5' hydroxyl group of the 5' terminal nucleotide of the sense or antisense strand in the siRNA, or a chemical portion formed by removing a hydrogen atom from the 3' hydroxyl group of the 3' terminal nucleotide of the sense or antisense strand in the siRNA. This disclosure relates to the preparation of oligonucleotide conjugates. Those skilled in the art can prepare the oligonucleotide conjugates described herein using various suitable methods. For example, 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 using a solid-phase synthesis method, a delivery group can be introduced using methods already described in detail in the prior art to synthesize the oligonucleotide conjugates described herein. For example, WO2015006740A2 describes in detail various methods for preparing oligonucleotide conjugates. When the double-stranded oligonucleotide is siRNA, the oligonucleotide conjugates of this disclosure can also be obtained using methods well known to those skilled in the art. For example, WO2014025805A1 describes a method for preparing the structure shown in formula (305A), and Rajeev et al. describe a method for preparing the structure shown in formula (307) in ChemBioChem 2015, 16, 903-908. Chinese patent application CN110959011A also discloses in detail a method for preparing the oligonucleotide conjugate shown in formula (308). The contents of the above-mentioned documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts In another aspect, this disclosure also provides pharmaceutically acceptable salts of the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described herein. Pharmaceutically acceptable salts are known to those skilled in the art. By forming salts, the pharmaceutically acceptable salts of the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described herein may exhibit better solubility, bioavailability, or stability than the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates themselves. In some embodiments, in the single-stranded oligonucleotides, double-stranded oligonucleotides, or oligonucleotide conjugates described in this disclosure, each adjacent nucleotide is linked by a phosphodiester bond or a phosphothiodiester bond. The non-bridging oxygen or sulfur atom in the phosphodiester bond or phosphothiodiester bond carries a negative charge and can exist in the form of a hydroxyl or mercapto group. The hydrogen ion in the hydroxyl or mercapto group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, ammonium ion (NH4+). + The delivery group may contain one of the organic ammonium cations. Further, the delivery group may also contain a salt-forming group, such as a phosphate group. For the purpose of improving solubility and / or bioavailability, in some embodiments, the pharmaceutically acceptable salt is a partial or complete water-soluble salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the water-soluble salt may be one or more of an amine salt, an alkali metal salt, or an alkaline earth metal salt. In some embodiments, the amine salt is selected from one or more of ammonium salts, methylamine salts, tertiary amine salts, and quaternary ammonium salts; the alkali metal salt is selected from potassium 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 one or more of triethylamine salt, triisopropylamine salt, or N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a 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 is a mixture of methylamine and ammonium salts of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt is a salt or a portion of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate, wherein the salt is one or more of methylamine, triethylamine, or sodium salts. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate is a calcium salt or a portion of a calcium salt of the double-stranded oligonucleotide or oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt is a salt or a portion of the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate, wherein the salt is one or more of methylamine, triethylamine, sodium, or calcium salts. Pharmaceutical Composition In another aspect, this disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates and pharmaceutically acceptable salts thereof 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 double-stranded oligonucleotide, the concentration of the oligonucleotide conjugate in the injection solution can be 0.01 mg / mL-20 mg / mL, 0.1 mg / mL-10 mg / mL, or 0.5 mg / mL-5 mg / mL. The protective agent may be at least one selected from inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. Based on the total weight of the pharmaceutical composition, the content of the protective agent may be 0.01-30% by weight. The osmotic pressure regulator may be sodium chloride and / or potassium chloride. The content of the osmotic pressure regulator results in an osmotic pressure of 200-700 milliosm / kg (mOsm / kg) for the pharmaceutical composition. The content of the osmotic pressure regulator can be readily determined by those skilled in the art based on the desired osmotic pressure. In some embodiments, the dosage of the formulation made from the pharmaceutical composition may be adjusted during administration depending on the route of administration. In some embodiments, the pharmaceutical composition may be a liquid formulation, such as an injection; or it may be a lyophilized powder for injection, which is mixed with liquid excipients to form a liquid formulation for administration. The liquid formulation may be administered subcutaneously, intramuscularly, or intravenously, or may be delivered via a spray to the lungs, or via a spray to other organs (such as the liver), or orally. In some embodiments, the pharmaceutical composition is administered via subcutaneous injection. Other pharmaceutically acceptable carriers may be carriers conventionally used in the field of oligonucleotide drug delivery, such as, but not limited to, magnetic nanoparticles (e.g., Fe3O4 or Fe2O3-based nanoparticles), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&L-lactic / glycolic acid) copolymer (PLGA), and poly(2-aminoethyl ethylene) phosphate. One or more of the following: phosphate), PPEEA, and poly(2-dimethylaminoethyl methacrylate), PDMAEMA, and their derivatives. In some embodiments, there are no particular requirements for the content of oligonucleotides and pharmaceutically acceptable carriers in the pharmaceutical composition. In some embodiments, the weight ratio of oligonucleotides to pharmaceutically acceptable carriers can be 1:(1-500), and in some embodiments, the weight ratio is 1:(1-50). In some embodiments, the pharmaceutical composition may be in the form of a liposomal formulation. In some embodiments, the pharmaceutically acceptable carrier used in the liposomal formulation comprises an amine-containing transfection compound (hereinafter also referred to as an organic amine), a cofactor lipid, and / or a polyethylene glycol-modified lipid. The organic amine, cofactor lipid, and polyethylene glycol-modified lipid may be selected from one or more of the amine-containing transfection compounds or their pharmaceutically acceptable salts or derivatives, cofactor lipids, and polyethylene glycol-modified lipids described in Chinese patent application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine may be a compound of formula (201) as described in Chinese patent application CN103380113A, or a pharmaceutically acceptable salt thereof: in: X 101 and X 102 Each can be independently O, S, NA, or CA, where A is hydrogen or C1-C. 20 hydrocarbon chain; Y 101 and Z 101 Each can be independently C=O, C=S, S=O, CH-OH, or SO2; R 101 R 102 R 103 R 104 R 105 R 106 and R 107 Each is independently hydrogen, cyclic or acyclic, substituted or unsubstituted, branched or straight aliphatic group, cyclic or acyclic, substituted or unsubstituted, branched or straight heteroaliphatic group, substituted or unsubstituted, branched or straight acyl group, substituted or unsubstituted, branched or straight aryl group, substituted or unsubstituted, branched or straight heteroaryl group; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; where, if m = p = 0, then R 102 It is hydrogen; Furthermore, if at least one of n or m is 2, then R 103 The nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): In this context, g, e, and f are each an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some implementations, R 103 It is a polyamine. In other embodiments, R 103 It is a ketal. In some embodiments, R in formula (201) 101 and R 102 Each of them is independently 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)-(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 from the oligonucleotide or oligonucleotide conjugate of this disclosure and the aforementioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide or oligonucleotide conjugate (based on oligonucleotide groups) to all lipids (e.g., organic amines, auxiliary lipids, and / or polyethylene glycol-modified lipids) is from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:20, from about 1:3 to about 1:20, from about 1:4 to about 1:20, from about 1:3 ...30, from about 1:3 to about 1:30, from about 1:3 to about 1:30, from The ratio of oligonucleotides or oligonucleotide conjugates (based on oligonucleotide groups) of this disclosure to total lipids is in the range of about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10. For example, the weight ratio of the oligonucleotides or oligonucleotide conjugates (based on oligonucleotide groups) of this disclosure to total lipids is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, or 1:18. In some embodiments, the components of the pharmaceutical composition may exist independently when sold, and may be in liquid form when used. In some embodiments, the pharmaceutical composition formed by the oligonucleotide or oligonucleotide conjugate provided in this disclosure and the above-described pharmaceutically acceptable carrier can be prepared according to various known methods, 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 in the oligonucleotide or oligonucleotide conjugate does not exceed 0.6 mg / mL, for example, 0.2-0.4 mg / mL. The buffer salt is selected from one or more of soluble acetate and soluble citrate, for example, sodium acetate and / or potassium acetate. The lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate are mixed, and the resulting product is incubated at 40-60°C for at least 2 minutes, for example, 5-30 minutes, to obtain the incubated liposome formulation. The volume ratio of the lipid solution to the aqueous solution of the oligonucleotide or oligonucleotide conjugate is 1:(2-5), for example, 1:4. The incubated liposome formulation is concentrated or diluted, impurities are removed, and sterilization is performed to obtain the pharmaceutical composition provided in this disclosure. Its physicochemical parameters are: pH value of 6.5-8, encapsulation efficiency of not less than 80%, particle size of 40-200 nm, polydispersity index of not more than 0.30, and osmotic pressure of 250-400 mOsm / kg; for example, the physicochemical parameters can be: pH value of 7.2-7.6, encapsulation efficiency of not less than 90%, particle size of 60-100 nm, polydispersity index of not more than 0.20, and osmotic pressure of 300-400 mOsm / kg. Concentration or dilution can be performed before, after, or simultaneously with impurity removal. Impurity removal can be achieved using various existing methods, such as ultrafiltration at 100 kDa using a tangential flow system or hollow fiber column, with the ultrafiltration exchange solution being phosphate-buffered saline (PBS) at pH 7.4. Sterilization can be achieved using various existing methods, such as filtration sterilization through a 0.22 μm filter. The use of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions disclosed herein. This disclosure also provides the use of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure in the preparation of medicaments for treating and / or preventing diseases or symptoms associated with NTCP mRNA levels. In some embodiments, diseases or symptoms associated with NTCP mRNA levels include hepatitis B, hepatitis D, elevated bile acids, dyslipidemia, or non-alcoholic steatohepatitis, with dyslipidemia including hypercholesterolemia, hypertriglyceridemia, or atherosclerosis. This disclosure also provides a method for treating and / or preventing diseases or symptoms associated with NTCP 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. Furthermore, this disclosure also provides a method for regulating the expression level of NTCP mRNA in cells, the method comprising contacting the cells with an effective amount of one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and pharmaceutical composition of this disclosure. This disclosure also provides one or more of single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions for use as pharmaceuticals. As used herein, the term "administration" refers to the delivery of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a subject via a method or route that at least partially targets one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a desired site to produce a desired effect. Routes of administration suitable for the methods of this disclosure include local administration and systemic administration. Generally, local administration results in the delivery of more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein to a specific site compared to the subject's entire body; while systemic administration results in the delivery of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions to substantially the entire body of the subject. The medication may be administered to the subject via any suitable route known in the art, including but not limited to: oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), pulmonary administration, nasal administration, rectal administration, and local administration (including oral and sublingual administration). Administration frequency may be once or more daily, weekly, bi-weekly, bi-weekly, monthly, or annually. The dosage of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure can be conventional in the art, and the dosage can be determined based on various parameters, particularly the age, weight, and sex of the subject. Toxicity and efficacy can be determined in cell culture or laboratory animals using standard pharmaceutical procedures, such as determining the LD50 (the dose that causes 50% of the population to die) and ED50 (the dose that elicits 50% of the maximum response intensity in a quantitative response, and the dose that elicits a positive response in 50% of the subjects in a qualitative response). The range of human dosages can be derived based on data obtained from cell culture analysis and animal studies. When administering one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described herein, for example, to male or female C57BL / 6J or C3H / HeNCrlVr mice, aged 6-12 weeks and weighing 18-25 g, the amount of oligonucleotide in one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions may be: 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-mentioned dosage is preferred when administering one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions described in this disclosure. The method provided in this disclosure inhibits NTCP mRNA expression in cells. The amount of oligonucleotides used in one or more of the following: single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions 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 NTCP 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 surface of target cells. The amount required to achieve this local concentration will vary with various factors, including the delivery method, delivery site, the number of cell layers between the delivery site and the target cells or tissue, and whether the delivery is local or systemic. The concentration at the delivery site can be significantly higher than the concentration at the surface of the target cells or tissue. Reagent test kit This disclosure provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions provided in this disclosure. In some embodiments, the kits described herein may provide one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutically acceptable salts and pharmaceutical compositions of the present disclosure in a single container. In some embodiments, the kits described herein may include a container providing a pharmaceutically acceptable excipient. In some embodiments, the kits may also contain other components, such as stabilizers or preservatives. In some embodiments, the kits described herein may contain at least one other therapeutic agent in a container other than the container providing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts and pharmaceutical compositions described herein. In some embodiments, the kit may include instructions for mixing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of this disclosure with a pharmaceutically acceptable carrier and / or excipients or other ingredients (if any). In the kits disclosed herein, one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and / or pharmaceutically acceptable excipients, may be provided in any form, such as liquid, dry, or lyophilized. In some embodiments, one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and optional pharmaceutically acceptable excipients, are substantially pure and / or sterile. In some embodiments, sterile water may be provided in the kits disclosed herein. The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited thereto. Without intending to be limiting, the invention is further described in detail below in the embodiments and in exemplary embodiments relating to small interfering RNA (siRNA) in pharmaceutical compositions and / or oligonucleotide conjugates of this disclosure. In this context, the double-stranded oligonucleotides, pharmaceutical compositions, and oligonucleotide conjugates of this disclosure are siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates, respectively. In the context of this disclosure, for ease of description, the siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates in these embodiments are also referred to as the siRNA, pharmaceutical compositions, and siRNA conjugates of this disclosure. This does not mean that the double-stranded oligonucleotides of this disclosure can only be siRNA; rather, the double-stranded oligonucleotides can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA), etc. It is contemplated that, based on the detailed description of siRNA, siRNA-containing pharmaceutical compositions, and siRNA conjugates, other double-stranded oligonucleotides will similarly function when used alone or in the formation of the pharmaceutical compositions and / or oligonucleotide conjugates described in this disclosure. Example Unless otherwise specified, the reagents and culture media used in the following examples are commercially available products, and the nucleic acid electrophoresis, real-time PCR and other operations used are performed in accordance with the methods described in Molecular Cloning (Cold Spring Harbor Laboratory (1989)). Preparation Examples 1-8 and 15-20: Synthesis of the siRNA conjugates disclosed herein Following the preparation method described in Example 13 of CN110959011A, conjugates 1-8 and 15-20 as shown in Table 2 were prepared, differing only in that the sense and antisense strands of the siRNA contained in the siRNA conjugates are as shown in Table 2. For nucleic acid sequences containing the sense and antisense strand sequences of siRNAs numbered as conjugates 1-8 and 15-20 in Table 2, nucleoside phosphoramide monomers were linked one by one to synthesize the sense and antisense strands of the siRNA conjugates. After synthesis, the conjugates were purified by centrifugation and ultrafiltration using a 3K (MWCO) ultrafiltration tube. Conjugates 1-8 and 15-20 are mixtures of methylamine and ammonium salts of 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 represented by Nu, as shown in formula (35), and is covalently linked to the positive strand of the siRNA via a methylene ring. Furthermore, the siRNA contained in these siRNA conjugates has the siRNA sequences corresponding to conjugates 1-8 and 15-20 in Table 2. Each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (based on siRNA) using ultrapure water (Milli-Q ultrapure water system, resistivity 18.2 MΩ*cm (25℃)), and then the molecular weight was determined using liquid chromatography-mass spectrometry (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters, model: LCT Premier). Among them, conjugate 1: theoretical value of the positive chain is 7338.314, measured value is 7337.14, theoretical value of the negative chain is 7111.868, measured value is 7110.64; conjugate 2: theoretical value of the positive chain is 7313.304, measured value is 7312.09, theoretical value of the negative chain is 7074.799, measured value is 7073.57; conjugate 3: theoretical value of the positive chain is 7227.195, measured value is 7226.08, theoretical value of the negative chain is 7159.924, measured value is 7158.82; conjugate 4: theoretical value of the positive chain is 7340.227, measured value is... The measured value for conjugate 1 is 7338.78, with a theoretical antisense chain value of 7139.001 and a measured value of 7137.80. Conjugate 2: The theoretical positive chain value is 7424.423, with a measured value of 7423.07; the theoretical antisense chain value is 6969.735, with a measured value of 6968.39. Conjugate 3: The theoretical positive chain value is 7423.439, with a measured value of 7422.25; the theoretical antisense chain value is 7027.731, with a measured value of 7026.51. Conjugate 4: The theoretical positive chain value is 7321.331, with a measured value of 7320.23; the theoretical antisense chain value is 7050.769, with a measured value of 7137.80. The value is 7049.61; Conjugate 8: Theoretical value of the positive chain is 7316.256, measured value is 7315.12, theoretical value of the negative chain is 7056.828, measured value is 7055.72; Conjugate 15: Theoretical value of the positive chain is 7275.25, measured value is 7273.1, theoretical value of the negative chain is 7110.88, measured value is 7108.8; Conjugate 16: Theoretical value of the positive chain is 7370.36, measured value is 7368.2, theoretical value of the negative chain is 7034.77, measured value is 7032.76; Conjugate 17: Theoretical value of the positive chain is 7321.33, measured .... The measured value is 7319.2, the theoretical value of the antisense chain is 7049.78, and the measured value is 7047.7; Conjugate 18: the theoretical value of the right chain is 7274.26, and the measured value is 7272.5, the theoretical value of the antisense chain is 7088.83, and the measured value is 7087.1; Conjugate 19: the theoretical value of the right chain is 7275.25, and the measured value is 7273.2, the theoretical value of the antisense chain is 7096.85, and the measured value is 7094.9; Conjugate 20: the theoretical value of the right chain is 7297.31, and the measured value is 7295.3, the theoretical value of the antisense chain is 7102.85, and the measured value is 7100.9.The measured values ​​are consistent with the theoretical values, indicating that the synthesized conjugates 1-8 and 15-20 have the target double-stranded nucleic acid sequences. Preparation Examples 9-14: Synthesis of the siRNA conjugates disclosed herein Following the preparation method described in Example 13 of CN110959011A, conjugates 9-14 as shown in Table 2 were prepared, differing only in that the sense and antisense strands of the siRNA contained in the conjugates are as shown in Table 2. For nucleic acid sequences containing the sense and antisense strand sequences of siRNAs numbered as conjugates 9-14 in Table 2, nucleoside phosphoramide monomers were sequentially linked to synthesize the sense and antisense strands of the siRNA. After synthesis, conjugates 9-14 were first purified using a self-packed column with Source15Q strong anion exchange packing material, and then desalted using a HiPrep 26 / 10 Desalting pre-packed column. Conjugates 9-14 are sodium salts of compounds having the structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the reverse debased deoxynucleotide (ia) at the 3' end of the positive strand of the siRNA represented by Nu, as shown in formula (35), and the oxygen atom is linked to the ribose ring via a methylene group, thereby covalently linking to the positive strand of the siRNA. Furthermore, the siRNAs contained in these siRNA conjugates each have the siRNA sequences corresponding to conjugates 9-14 in Table 2. Each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (based on siRNA) using ultrapure water (Milli-Q ultrapure water system, resistivity 18.2 MΩ*cm (25℃)). Molecular weight was then determined using liquid chromatography-mass spectrometry (LC-MS, Waters Corporation, model: LCT Premier). Specifically: Conjugate 9: theoretical positive value of the sense strand 7370.05, measured value 7369; theoretical positive value of the antisense strand 7111.74, measured value 7111; Conjugate 10: theoretical positive value of the sense strand 7371.97, measured value 7369; theoretical positive value of the antisense strand 7138.85, measured value 7137; Conjugate 11: theoretical positive value of the sense strand 7455.17, measured value 7453; theoretical positive value of the antisense strand 7027.61, measured value 70. 25; Conjugate 12: Theoretical value for the sense strand is 7353.06, measured value is 7351; theoretical value for the antisense strand is 7050.65, measured value is 7049; Conjugate 13: Theoretical value for the sense strand is 7348, measured value is 7346; theoretical value for the antisense strand is 7056.7, measured value is 7054; Conjugate 14: Theoretical value for the sense strand is 7378.08, measured value is 7376; theoretical value for the antisense strand is 7020.63, measured value is 7019. The measured values ​​are consistent with the theoretical values, indicating that the synthesized conjugates 9-14 are siRNA conjugates containing the designed double-stranded nucleic acid sequence. Table 2. siRNA sequences in siRNA conjugates In this context, uppercase letters C, G, U, A, and T represent the base composition of a nucleotide; lowercase letter m indicates that the nucleotide represented by the uppercase letter to the left of m is 2'-methoxy modified; lowercase letter f indicates that the nucleotide represented by the uppercase letter to the left of f is 2'-fluoro modified; lowercase letter s indicates that the two nucleotides represented by uppercase letters to the left and right of s are linked by a phosphate thioester group; lowercase letter d indicates that the nucleotide represented by the uppercase letter to the right of d is a deoxynucleotide; ia indicates a reverse debased deoxynucleotide; and (moe) indicates that the nucleotide represented by the uppercase letter to the left is 2'-O-methoxyethyl modified. Comparative Preparation Example 1: Synthesis of Reference Conjugate 1 Following the same method as in Preparation Example 1, reference conjugate 1, as shown in Table 2, was prepared by solid-phase synthesis. The theoretical value for the sense strand of reference conjugate 1 was 7485.396, and the measured value was 7484.61; the theoretical value for the antisense strand was 7045.784, and the measured value was 7044.92. Reference conjugate 1 is a mixture of methylamine and ammonium salts of compounds having the structure shown in formula (403), wherein the conjugation group is attached to the 3' position of the ribose of the 3' terminal nucleotide of the sense strand of the siRNA represented by Nu. Furthermore, the siRNA contained in this siRNA conjugate has the siRNA sequence corresponding to reference conjugate 1 in Table 2, which is a negative control sequence not associated with NTCP mRNA. Example 1: Inhibitory activity of the conjugate against the NTCP target sequence in HEK293A cells. This experiment investigated the on-target activity of conjugates 1-8 in HEK293A cells in vitro, specifically measuring the activity of the eight conjugates in targeting perfectly matched target sequences. Following the method described in Kumico Ui-Tei et al., Functional dissection of siRNA sequence by systematic DNA substitution: modified siRNA with a DNA seed arm is a powerful tool for mammalian gene silencing with significantly reduced off-target effect. Nucleic Acids Research, 2008, 36(7), 2136-2151, a detection plasmid was constructed and co-transfected with the siRNA conjugate into HEK293A cells. The on-target activity of the siRNA conjugate was reflected by the expression level of the dual luciferase reporter gene. The specific steps are as follows: [1] Constructing detection plasmids Using psiCHECK TM -2(Promega TM The detection plasmid was constructed containing a target sequence that is fully complementary to all 21 nucleotides of the antisense strand in the siRNA conjugate to be tested and has no base differences from a portion of the NTCP mRNA. Clone the target sequence into psiCHECK TM -2 Xho I / Not I sites on the plasmid. [2] Transfection HEK293A (purchased from Nanjing Kebai Biotechnology Co., Ltd.) was cultured in H-DMEM complete medium (Hyclone) containing 10% fetal bovine serum (FBS, Hyclone) and 0.2% penicillin-streptomycin (Gibco, Invitrogen) at 37°C in an incubator containing 5% CO2 / 95% air. The HEK293A cells cultured above were then subjected to a culturing rate of 8 × 10⁻⁶ cells / mL. 3 Cells were seeded in 96-well plates. After 24 hours, when the cell growth density reached 70-80%, the H-DMEM medium in the culture wells was aspirated, and 80 μL of Opti-MEM medium (GIBCO) was added to each well for further culture for 1.5 hours. Prepare a 0.01 μM working solution of each of conjugates 1-8 using PBS. Dilute the test plasmid with DEPC-treated water to a 200 ng / μL working solution. In the culture wells of a 96-well plate containing the aforementioned cells, according to Lipofectamine TM Following the Invitrogen 2000 (Invitrogen) instructions, co-transfect the siRNA conjugate and the plasmid described above. Specifically, add the following to each well containing the cells: 1) 0.05 μL of plasmid working solution (containing 10 ng of test plasmid) diluted in 9 μL of Opti-MEM medium; 2) 1 μL of siRNA conjugate working solution; and 3) 0.2 μL of Lipofectamine. TM A solution of 2000 in 9.8 μL of Opti-MEM medium was prepared, with a final concentration of 0.1 nM for each well. The conjugates were one of the conjugates 1-8 described above. Each group had 3 replicates. [3] Detection Twenty-four hours after co-transfection, HEK293A cells were lysed using a Dual luciferase reporter gene assay kit (Promega, cat. E2940) according to the instructions, and the expression level of the dual luciferase reporter gene was detected. Each siRNA treatment group was used as a control (con.) with a specific concentration of siRNA. Ren luciferase (Ren) protein levels were normalized relative to firefly luciferase (Fir) protein levels. The results are shown in Table 3. Table 3. Inhibitory activity of siRNA conjugates against target sequences As shown in Table 3, the conjugates disclosed herein exhibit high inhibitory activity against the target sequence in the in vitro psiCHECK system. At a concentration of 0.1 nM, the inhibition rate is above 76%, and can even reach 91.59%. Experiment 2: Detection of the inhibitory efficiency of siRNA conjugate on NTCP mRNA expression in HepG2 cells. Use Lipofectamine according to the instructions provided by the supplier. TM In 2000, the test siRNA conjugates (siRNA conjugates 3-5 and reference conjugate 1) were transfected into HepG2 cells. The final concentration of each siRNA conjugate was 50 nM, and each concentration was tested in duplicate. Cells that were not treated with any siRNA conjugates served as blank controls. The expression level of NTCP mRNA in HepG2 cells transfected with each siRNA conjugate was detected by quantitative real-time PCR. The specific steps were as follows: After culturing transfected cells for 24 hours, total RNA was extracted from the cells using Trizol (Thermo Fisher Scientific) according to the standard procedure for total RNA extraction. 1 μg of total RNA was taken and reverse transcribed into cDNA using a reverse transcription kit (Promega, catalog number A3500) according to the manufacturer's instructions. The expression level of NTCP mRNA was detected using a 2×Ultra SYBR Mixture (with ROX) kit (Beijing Kangwei Century Biotechnology Co., Ltd., catalog number CW0956) with cDNA as a template, following the manufacturer's instructions. The PCR primers used for amplifying NTCP and for GAPDH as an internal control gene are shown in Table 4. Table 4 Primer Information The relative quantitative calculation of the expression level of the target gene FASN mRNA in each test group was performed using the Ct(ΔΔCt) method. The calculation method is as follows: ΔΔCt=(Ct 测试组目标基因 -Ct 测试组内参基因 )-(Ct 空白对照组目标基因 -Ct 空白对照组内参基因 ) mean Relative expression level = 2 -ΔΔCt ×100% mRNA inhibition rate = (blank control group 2) -ΔΔCt Mean - Test Group 2 -ΔΔCt ) / Blank control group 2 -ΔΔCt Mean × 100% In this study, each test group consisted of HepG2 cells treated with different concentrations of siRNA, while the control group consisted of cells not treated with siRNA. The inhibition rate of the conjugates on NTCP mRNA is shown in Table 5. Table 5. Inhibition rate of NTCP mRNA in HepG2 cells As can be seen from the results in Table 5, the conjugates provided in this disclosure all showed high NTCP mRNA inhibitory activity in HepG2 cells, with an inhibition rate of at least 75.3% and reaching over 86%. Experimental Example 3: Detection of the inhibitory efficiency of siRNA conjugates on NTCP mRNA expression in human primary liver cells. Following the supplier's instructions, the test siRNA conjugates (siRNA conjugates 1-8 and reference conjugate 1) were transfected into primary human liver cells using RNAiMAX. The final concentrations of each siRNA conjugate were 50 nM and 0.5 nM, with two replicates per concentration. Cells untreated with any siRNA conjugates served as blank controls. The expression level of NTCP mRNA in primary human liver cells transfected with each siRNA conjugate was detected by quantitative real-time PCR. The specific steps were as follows: After culturing transfected cells for 24 hours, total RNA was extracted from the cells using Trizol (Thermo Fisher Scientific) according to the standard operating procedure for total RNA extraction. 1 μg of total RNA was taken and reverse transcribed into cDNA using a reverse transcription kit (Promega, catalog number A3500) according to the manufacturer's instructions. The expression level of NTCP mRNA was detected using a 2×Ultra SYBR Mixture (with ROX) kit (Beijing Kangwei Century Biotechnology Co., Ltd., catalog number CW0956) with cDNA as a template, following the manufacturer's instructions. The PCR primers used for amplifying NTCP and for GAPDH as an internal control gene are shown in Table 4. The mRNA inhibition rate was calculated using the same method as in Experiment 2, and the results are shown in Table 6. Table 6. Inhibition rate of NTCP mRNA in primary human liver cells As shown in Table 6, the negative control reference conjugate showed almost no inhibitory effect on NTCP mRNA in human primary liver cells; in contrast, the conjugate provided in this disclosure showed high NTCP mRNA inhibitory activity in human primary liver cells, especially at 0.5 nM, with inhibition rates of over 75%, and even reaching 91%. Experiment 4: Detection of the inhibitory efficiency of siRNA conjugates on NTCP mRNA expression in human primary liver cells. The inhibitory effects of conjugates 2, 4, 6, and 9-14 on NTCP mRNA expression in primary human liver cells were tested using the same method as in Example 3, with the only difference being that the compounds used were conjugates 2, 4, 6, and 9-14, respectively. The results are shown in Table 7. Table 7. Inhibition rate of NTCP mRNA in primary human liver cells As shown in Table 7, the conjugates provided in this disclosure exhibited high NTCP mRNA inhibitory activity in human primary liver cells at different concentrations. At 50 nM, the inhibition rate was at least 79.7%, and could even reach 92.1%; at 0.5 nM, the inhibition rate was at least 83.2%, and could even reach 90.0%. Experiment 5: Detection of the inhibitory efficiency of the conjugate on NTCP mRNA expression in primary monkey liver cells. In this embodiment, conjugates 2, 3, 5, 10-13, and 14-20 prepared in the preparation example were transfected into primary monkey liver cells using RNAiMAX transfection reagent. The final concentrations of each siRNA conjugate were 5 nM and 0.5 nM (based on the amount of siRNA). Each conjugate was transfected into two wells of cells, with cells untreated as a blank control. Twenty-four hours after transfection, cellular RNA was harvested, and the expression level of the target gene NTCP mRNA in primary monkey liver cells transfected with each conjugate was detected by real-time quantitative PCR. The specific procedures are as follows: [1] Cell culture 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. [2] Transfection For each conjugate, a 20 μM stock solution (based on the amount of siRNA in the conjugate) was prepared using 1×PBS. The conjugates used were conjugates 2, 3, 5, 10⁻¹³, ​​and 14⁻²⁰. Prepare 2A solution by diluting the above conjugate stock solution with Opti-MEM medium to prepare a 6 nM working solution of the conjugate. Each 2A solution is 100 μL. Prepare 2B solutions, each containing 2 μL RNAiMAX (Thermo Fisher Scientific, catalog number: 11668-019) and 98 μL Opti-MEM medium. Mix well and incubate at room temperature for 5 min. For each conjugate to be tested, one portion of solution 2B and one portion of solution 2A were mixed and incubated at room temperature for 20 min to obtain transfection complex 2X. Two copies of each transfection complex were prepared to transfect two wells of cells. In the culture wells (all containing primary monkey liver cells and 1 mL of maintenance medium as described above, the same below), 200 μL of transfection complex 2X for each conjugate was added and mixed thoroughly to obtain a transfection mixture with a final concentration of 0.5 nM (based on the amount of siRNA), which was designated as the test group. Take 200 μL of Opti-MEM medium as the blank transfection mixture 2X'. Prepare two portions of each 2X' to add to two wells of cells. Add one portion of the blank transfection mixture 2X' to each of the other two culture wells, at a volume of 200 μL / well, to obtain the transfection mixture without the conjugate, which is designated as the blank control group. Place the 12-well plate in an incubator containing 5% CO2 / 95% air and continue culturing at 37°C for 24 hours. [3] Detection After culturing, total RNA was extracted from the cells in each culture well using Trizol (purchased from Sigma, catalog number: T9424) according to the method described in the instruction manual. For each well of cells, 0.8 μg of total RNA was collected and the reaction system was prepared using the reagents provided in the HiScript IV 1st Strand cDNA Synthesis kit (+gDNA wiper) (purchased from Nanjing Novizan Biotechnology Co., Ltd., catalog number: R412-02). The experimental procedure was followed according to the kit instructions: first, incubation at 42℃ for 2 min to remove genomic DNA; then, preparation of the first-strand cDNA synthesis reaction solution was performed, resulting in a 20 μL reverse transcription reaction system. The first-strand cDNA synthesis reaction was carried out under the following conditions: each reverse transcription reaction system was incubated at 37℃ for 15 min, followed by incubation at 85℃ for 5 s. After the reaction, 60 μL of RNase-free ddH2O was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, take 2 μL of the above solution containing cDNA as a template, and use the reagents provided by the SYBR Select Master Mix kit (purchased from Thermo, catalog number: 4472908) to prepare a 10 μL qPCR reaction system. The PCR primer sequences used to amplify the target gene monkey NTCP and the internal reference gene monkey GAPDH are shown in Table 8, and the final concentration of each primer is 0.2 μM. Table 8 Primer Information Place each qPCR reaction system in QuantStudio TM Amplification was performed using a three-step method on a 5-Real-Time PCR instrument (Thermo Fisher). 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 2W containing the amplified target gene monkey NTCP and the internal reference gene monkey GAPDH. Product 2W was then sequentially incubated at 95℃ for 15 s, 60℃ for 1 min, and then gradually increased to 95℃. During this temperature increase, fluorescence signals were collected at each new temperature point, increasing at a rate of 0.075℃ per second. After incubation at 95℃ for 15 s, the melting curves of the target gene monkey NTCP and the internal reference gene monkey GAPDH in product 2W were collected using a real-time quantitative PCR instrument, and the Ct values ​​of the target gene monkey NTCP and the internal reference gene monkey GAPDH were obtained. The mRNA inhibition rate was calculated using the same method as in Experiment Example 2. The inhibition rates of each conjugate on NTCP mRNA are shown in Table 9. Table 9. Inhibition rate of each conjugate on NTCP mRNA in primary monkey liver cells. As shown in Table 9, the conjugates provided in this disclosure exhibit good inhibitory effects on NTCP mRNA expression when using RNAiMAX transfection reagent. At a concentration of 5 nM (based on siRNA), the inhibition rate of NTCP mRNA in primary monkey liver cells remained above 95%, even reaching 98.3%; at a concentration of 0.5 nM (based on siRNA), the inhibition rate remained above 94%, even reaching 96.4%. Experimental Example 6: Activity test of conjugate 9-13 in AAV-induced humanized mice This experiment investigated the inhibitory efficiency of the conjugate 9-13 prepared in the preparation example on NTCP mRNA expression in AAV-induced humanized mice. hNTCP AAV8 adeno-associated virus-1 was prepared by Shandong Weizhen Biotechnology Co., Ltd. The adeno-associated virus vector used was pAV-TBG, and the transfected fragment was the human NTCP gene CDS region and 3' UTR sequence with a length of 1916 bp (mRNA NCBI reference: NM_003049.4). Each C57BL / 6J mouse (SPF grade, 6-8 weeks old, male; purchased from Spiford (Beijing) Biotechnology Co., Ltd.) was administered 1×10⁻⁶ mg / L via tail vein injection. 11 vg's hNTCP AAV8 adeno-associated virus-1. hNTCP AAV8 adeno-associated virus-1 at 5 × 10 11 Adenovirus model mice-1 were obtained by administering a titer of vg / mL and a volume of 200 μL per mouse. Fourteen days after modeling, the adenovirus model mice-1 were randomly divided into 5 groups of 10 mice each. The dosage was calculated based on body weight, and the mice were administered a single subcutaneous injection. Each group of mice was given conjugate 9-13 at a dose of 3 mg / kg (based on siRNA) as the test group. Each conjugate was provided in PBS aqueous solution at a concentration of 0.6 mg / mL (based on siRNA), with an administration volume of 5 mL / kg. Another group of mice was given PBS at a volume of 5 mL / kg as the blank control group. Day 1 was marked as the day of drug administration. Five mice from each group were sacrificed on day 8, and the remaining five mice were sacrificed on day 22. Subsequently, liver tissue was collected from each mouse and preserved using RNA later (Sigma Aldrich). The expression levels of NTCP mRNA in the livers of mice treated with different conjugates were detected using the detection and calculation methods described in Example 2. The inhibition rates of different conjugates on NTCP mRNA in adenovirus model mice-1 are shown in Table 11. Table 11 Inhibition rate of each conjugate on NTCP mRNA in AAV-induced humanized mice As shown in Table 11, the conjugates provided in this disclosure, at a single dose of 3 mg / kg, exhibit significant inhibitory effects on NTCP mRNA in AAV-induced humanized mice. Particularly on day 22, the inhibition rate exceeded 47%. Conjugate 11 and conjugate 12 showed inhibition rates of 68% and 78% on NTCP mRNA, respectively, demonstrating excellent NTCP mRNA inhibitory effects. Experimental Example 7: Inhibitory activity of siRNA conjugates in human primary liver cells. This experiment investigated the inhibitory activity of conjugate 11 and conjugate 12 on NTCP mRNA in primary human liver cells. Human primary liver cells (purchased from Huizhiheyuan Biotechnology (Suzhou) Co., Ltd., catalog number: 085A12.22, batch number: 24A076) were cultured in hepatocyte maintenance medium (purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd., catalog number: HCTPM-R-002) at 37°C in an incubator containing 5% CO2 / 95% air. The density of the primary human liver cells was adjusted to 1×10⁻⁶ cells / year. 5 Cell suspensions were seeded in 24-well plates. For each conjugate to be tested, a conjugate stock solution with a concentration of 10 μM (based on the amount of siRNA in the conjugate) was prepared using PBS. The conjugates used were conjugate 11 and conjugate 12. The conjugate stock solutions were then serially diluted with hepatocyte maintenance medium to 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, and 1 μM, respectively, to prepare six concentrations for use. Add 250 μL of serially diluted buffer at different concentrations to the cell culture plates, with two replicates for each concentration, to obtain mixtures with final concentrations of 0.005 nM, 0.05 nM, 0.5 nM, 5.0 nM, 50 nM, and 500 nM. The components containing conjugate 11 and conjugate 12 were designated as the test group. Add 250 μL of hepatocyte maintenance medium to the other two culture wells, designated as the blank control group. The test group and the blank control group were incubated at 37°C in an incubator containing 5% CO2 / 95% air for 72 hours. Total RNA was extracted from cells in each well using TRI Reagent (SIGMA, catalog number: T9424-200ML) according to the manufacturer's instructions. For each well, 1 μg of total RNA was taken and reverse transcribed into cDNA using the Reverse Transcription System (Promega, catalog number A3500) according to the manufacturer's instructions. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the system was incubated at 70°C for 10 min, then at 42°C for 30 min, and finally at 95°C for 5 min. After the reaction, 80 μL of DEPC water was added to the system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above-mentioned cDNA-containing solution was used as a template. A 20 μL qPCR reaction system was prepared using reagents provided by SYBR Select Master Mix (purchased from Applied Biosystems, catalog number: 4472908). The PCR primer sequences for amplifying the target gene NTCP and the internal reference gene GAPDH are shown in Table 4 above, with a final concentration of 10 μM for each primer. Each qPCR reaction system was placed on a real-time quantitative PCR instrument (purchased from Thermo, model StepOnePlus), and amplification was performed 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 W1 containing amplified target gene NTCP and internal reference gene GAPDH. Product W1 was then subjected to a gradient temperature increase to 95℃ for 15s, 60℃ for 1min, and then to 95℃ with fluorescence signals collected every 0.3℃. After 15s at 95℃, the melting curves of the target gene and the internal reference gene GAPDH in product W1 were collected by a real-time quantitative PCR instrument to obtain the Ct values ​​of the target gene NTCP and the internal reference gene GAPDH. Following the calculation method in Example 5, the expression level of the target gene NTCP mRNA in each test group was relatively quantitatively calculated to obtain the inhibition rate of NTCP mRNA in the test groups at different concentrations. Based on the activity results measured at different concentrations in the test groups, the dose-response curve was fitted using the log(inhibitor) vs. response—Variable slope function in GraphPad Prism 8.0 software. The IC50 of the test conjugate in primary human liver cells was then calculated based on the dose-response curve. 50 The value is calculated as follows: In the formula: Y represents the expression level of residual mRNA. X is the logarithm of the transfection conjugate concentration. Bot is the Y value at the bottom of the steady-state period. Top is the Y value at the peak of the steady-state period. LogIC50 is the X value when Y is halfway between the bottom and the top, while HillSlope is the slope of the curve. Based on the dose-response curve and the corresponding function, determine X when Y = 50%. 50 The IC50 values ​​of each siRNA conjugate were calculated. 50 Value = 10^X 50 (nM). Calculate the IC50 of conjugates 11 and 12 in primary human liver cells. 50 The IC50 value of conjugate 11 in primary human liver cells was obtained. 50 The value was 7.245 nM, and the IC50 of conjugate 12 in human primary liver cells was [missing value]. 50 The value is 16.88 nM, indicating that the conjugate provided in this disclosure has a strong inhibitory effect on the expression of NTCP mRNA. Some embodiments of this disclosure have been described in detail above. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure. It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately. Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.

Claims

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

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

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

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

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

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

7. The single-stranded oligonucleotide according to any one of claims 1-6, wherein, Fluorinated nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides in the single-stranded oligonucleotide, following the direction from the 5' end to the 3' end.

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

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

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

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

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

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

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

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

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

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

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

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

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

21. The single-chain oligonucleotide according to any one of claims 1-20, wherein, The single-stranded oligonucleotide contains nucleotide sequence II, which is selected from one of the sequences shown in i)-v) below: i) Nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:2, and differs by no more than 3 bases: 5'-Z2GUAGCAAAUUCUAAGUUG-3'(SEQ ID NO:2), Wherein, Z2 is A or U, and nucleotide sequence II contains nucleotide Z'2 at the position corresponding to Z2, Z'2 being the first nucleotide at the 5' end of the single-stranded oligonucleotide; ii) Nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:4, and differs by no more than 3 bases: 5'-Z4GUCUUGAAUUUCUCAUAG-3'(SEQ ID NO:4), Wherein, Z4 is A or U, and nucleotide sequence II contains nucleotide Z'4 at the position corresponding to Z4, Z'4 being the first nucleotide at the 5' end of the single-stranded oligonucleotide; iii) Nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:6, and differs by no more than 3 bases: 5'-Z6UGAUGAUUCUGAUAGAUG-3' (SEQ ID NO: 6), Wherein, Z6 is A or U, and nucleotide sequence II contains nucleotide Z'6 at the position corresponding to Z6, Z'6 being the first nucleotide at the 5' end of the single-stranded oligonucleotide; iv) Nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:8, and differs by no more than 3 bases: 5'-Z8AAGUAGCAAAUUCUAAGU-3' (SEQ ID NO:8), Wherein, Z8 is A or U, and nucleotide sequence II contains nucleotide Z'8 at the position corresponding to Z8, Z'8 being the first nucleotide at the 5' end of the single-stranded oligonucleotide; v) Nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:10, and differs by no more than 3 bases: 5'-Z 10 CUUUCAGAAUUGCUUUGG-3'(SEQ ID NO:10), Among them, Z 10 For G or C, the position in nucleotide sequence II corresponds to Z. 10 nucleotide Z' 10 Z' 10 It is the first nucleotide at the 5' end of the single-stranded oligonucleotide; Alternatively, the nucleotide sequence II is identical to any one of the nucleotide sequences shown in SEQ ID NO:21-SEQ ID NO:30 in Table 1A with at least 16, at least 17, at least 18, at least 19, at least 20 or 21 consecutive nucleotides.

22. The single-chain oligonucleotide of claim 21, wherein, Nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one base; Alternatively, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4; Alternatively, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6; Alternatively, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8; Alternatively, there is no more than one base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10; Alternatively, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2; Alternatively, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:4; Alternatively, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:6; Alternatively, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:8; Alternatively, there is no base difference between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:10; Alternatively, there may be no base difference between the nucleotide sequence II and the nucleotide sequences shown in any one of SEQ ID NO:21-SEQ ID NO:30 in Table 1A, or there may be no base difference between the nucleotide sequences II and the nucleotide sequences shown in any one of SEQ ID NO:21-SEQ ID NO:30 in Table 1A.

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

24. The single-stranded oligonucleotide according to any one of claims 21-23, wherein, The single-stranded oligonucleotide also contains a nucleotide sequence V, each nucleotide of which is independently a non-fluorinated nucleotide, the length of which is 1 to 3 nucleotides, and is attached to the 3' end of either nucleotide sequence IV or nucleotide sequence II. After the single-stranded oligonucleotide forms a double-stranded oligonucleotide with the sense strand, the nucleotide sequence V constitutes the 3' overhang of the antisense strand of the double-stranded oligonucleotide. Alternatively, the nucleotide sequence V is 2 nucleotides in length and, in the direction from the 5' end to the 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or completely reverse complementary to NTCP mRNA; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of siRNA6-siRNA15 shown in Table 1A and siNTCP1-M1-siNTCP15-M1 listed in Table 1B. Alternatively, the single-chain oligonucleotide is the antisense strand of any one of the conjugates 1-20 shown in Table 2.

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

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

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

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

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

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

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

32. The double-stranded oligonucleotide of claim 31, wherein, One to four, or all four, of the linking groups connecting any two adjacent nucleotides from the first to the fifth nucleotide at the 5' end of the positive strand are independently phosphate groups with modifying groups; and / or, one to four, or all four, of the linking groups connecting any two adjacent nucleotides from the first to the fifth nucleotide at the 3' end of the positive strand are independently phosphate groups with modifying groups; Alternatively, each phosphate group with a modifying group is independently a thiophosphate group having the structure shown in formula (28); Alternatively, the antisense strand is the antisense strand of any one of siRNA6-siRNA15 shown in Table 1A and siNTCP1-M1-siNTCP15-M1 listed in Table 1B. Alternatively, the antisense chain is the antisense chain possessed by any one of the conjugates 1-20 shown in Table 2.

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

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

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

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

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

38. The double-stranded oligonucleotide according to any one of claims 25-37, wherein, The sense strand contains nucleotide sequence I, the antisense strand contains nucleotide sequence II, and the double-stranded oligonucleotide is selected from a set of sequences shown in i)-v) below: i) Nucleotide sequence I is the same length as the nucleotide sequence shown in SEQ ID NO:1, and differs by no more than 3 bases; nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:2, and differs by no more than 3 bases. 5'-CAACUUAGAAUUUGCUACZ1-3' (SEQ ID NO:1); 5'-Z2GUAGCAAAUUCUAAGUUG-3'(SEQ ID NO:2), Wherein, Z1 is U, A or ia, Z2 is A or U, ia represents reverse debase deoxynucleotide, nucleotide sequence I contains nucleotide Z'1 corresponding to Z1, nucleotide sequence II contains nucleotide Z'2 corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand; ii) Nucleotide sequence I is the same length as the nucleotide sequence shown in SEQ ID NO:3, and differs by no more than 3 bases; nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:4, and differs by no more than 3 bases. 5'-CUAUGAGAAAUUCAAGACZ3-3' (SEQ ID NO: 3); 5'-Z4GUCUUGAAUUUCUCAUAG-3'(SEQ ID NO:4), Wherein, Z3 is U, A or ia, Z4 is A or U, nucleotide sequence I contains nucleotide Z'3 corresponding to Z3, nucleotide sequence II contains nucleotide Z'4 corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the antisense strand; iii) Nucleotide sequence I is the same length as the nucleotide sequence shown in SEQ ID NO:5, and differs by no more than 3 bases; nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:6, and differs by no more than 3 bases. 5'-CAUCUAUCAGAAUCAUCAZ5-3' (SEQ ID NO: 5); 5'-Z6UGAUGAUUCUGAUAGAUG-3'(SEQ ID NO:6), Wherein, Z5 is U, A or ia, Z6 is A or U, nucleotide sequence I contains nucleotide Z'5 corresponding to Z5, nucleotide sequence II contains nucleotide Z'6 corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the antisense strand; iv) Nucleotide sequence I is the same length as the nucleotide sequence shown in SEQ ID NO:7, and differs by no more than 3 bases; nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:8, and differs by no more than 3 bases. 5'-ACUUAGAAUUUGCUACUUZ7-3' (SEQ ID NO:7); 5'-Z8AAGUAGCAAAUUCUAAGU-3'(SEQ ID NO:8), Wherein, Z7 is U, A or ia, Z8 is A or U, nucleotide sequence I contains nucleotide Z'7 corresponding to Z7, nucleotide sequence II contains nucleotide Z'8 corresponding to Z8, and Z'8 is the first nucleotide at the 5' end of the antisense strand; v) Nucleotide sequence I is the same length as the nucleotide sequence shown in SEQ ID NO:9, and differs by no more than 3 bases; nucleotide sequence II is the same length as the nucleotide sequence shown in SEQ ID NO:10, and differs by no more than 3 bases. 5'-CCAAAGCAAUUCUGAAAGZ9-3' (SEQ ID NO:9); 5'-Z 10 CUUUCAGAAUUGCUUUGG-3'(SEQ ID NO:10), Wherein, Z9 is C, G, or ia, Z 10 For G or C, nucleotide sequence I contains nucleotide Z'9 at position Z9, and nucleotide sequence II contains nucleotide Z at position Z. 10 nucleotide Z' 10 Z' 10 It is the first nucleotide at the 5' end of the antisense strand; Alternatively, the double-stranded oligonucleotide may be any one of siRNA6-siRNA15 listed in Table 1A.

39. The double-stranded oligonucleotide of claim 38, wherein, Nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO: 1, 3, 5, 7 or 9 by no more than one base, and nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO: 2, 4, 6, 8 or 10 by no more than one base. Alternatively, the nucleotide sequence I differs from any of the nucleotide sequences shown in SEQ ID NO:11-SEQ ID NO:20 in Table 1A by no more than one base, and the nucleotide sequence II differs from the first to the nineteenth bases shown in any of the nucleotide sequences shown in SEQ ID NO:21-SEQ ID NO:30 in Table 1A by no more than one base.

40. The double-stranded oligonucleotide of claim 39, wherein, The double-stranded oligonucleotide is any one of the double-stranded oligonucleotides shown in Table 1B, specifically siNTCP1-M1-siNTCP15-M1.

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

42. The oligonucleotide conjugate of claim 41, wherein, The delivery group comprises a linker group and a pharmaceutically acceptable target group, and the oligonucleotide group, the linker group, and the target group are sequentially covalently or non-covalently linked, each target group being selected from ligands capable of binding to hepatocyte surface receptors or groups capable of increasing tissue compatibility; or, Each of the target groups is selected from ligands capable of binding to the desialyl glycoprotein receptor on the surface of mammalian hepatocytes. Alternatively, the oligonucleotide conjugate may contain an oligonucleotide group that is an siRNA group formed from siRNA listed in Table 1B; Alternatively, the oligonucleotide conjugate has the structure shown in formula (403): In formula (403), Nu is an oligonucleotide group; or, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom is covalently linked to the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group; or, the 3' terminal nucleotide of the positive strand of the double-stranded oligonucleotide group is a reverse debased deoxynucleotide, and the P atom is covalently linked to the double-stranded oligonucleotide group by substituting the hydrogen atom in the hydroxyl group of the reverse debased deoxynucleotide of the positive strand of the double-stranded oligonucleotide group that is linked to the ribose ring via the methylene group. Alternatively, the oligonucleotide conjugate is one of conjugate 1 to conjugate 20 listed in Table 2.

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

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

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

46. ​​The use as described in claim 45, wherein, The diseases or symptoms associated with NTCP mRNA levels are one or more of the following: hepatitis B, hepatitis D, elevated bile acids, dyslipidemia, and non-alcoholic steatohepatitis.

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

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

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

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

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

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