Oligonucleotide, oligonucleotide conjugate, composition and use

Abstract

Provided is a single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide and APOC3mRNA have sufficient complementarity to mediate an RNAi effect. Each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide. At least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, and at least one nucleotide is a fluoro-modified nucleotide. In the direction from the 5' end to the 3' end, at least one nucleotide X is located after the eighth nucleotide of the single-stranded oligonucleotide and spaced apart from the eighth nucleotide of the single-stranded oligonucleotide by 4-7 nucleotides. Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. Further provided are a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, and a pharmaceutical composition.

Description

Oligonucleotides, oligonucleotide conjugates, and compositions and uses TECHNICAL FIELD The present disclosure relates to a single-stranded oligonucleotide, in particular to an antisense strand of a double-stranded oligonucleotide, and further relates to a double-stranded oligonucleotide comprising the antisense strand, an oligonucleotide conjugate, a pharmaceutical composition, and uses and methods of preparation thereof. BACKGROUND Dyslipidemia, also known as hyperlipidemia, is a systemic disease caused by abnormal metabolism or transport of fat, which makes plasma lipids higher than normal values, and seriously threatens the health of patients worldwide. The existing drugs for treating dyslipidemia mainly include statins, cholesterol absorption inhibitors, resins, probucol, fibrates and niacin and its derivatives. Apolipoprotein C3 (APOC3) plays an important role in lipid metabolism. The expression of APOC3 in the blood circulation of people carrying APOC3 mutant genes is reduced by 46%, and the plasma triglyceride level is reduced by 39% compared with ordinary people. At the same time, the lower blood lipid level can reduce the risk of heart disease in APOC3 mutant gene carriers by 35.1% compared with non-carriers. Therefore, if the gene expression can be silenced at the gene level to block the generation of APOC3, it will undoubtedly be the most ideal treatment. Small interfering RNA (siRNA) can inhibit or block the expression of any interested target gene in a sequence-specific manner based on the mechanism of RNA interference (RNAi), so as to achieve the purpose of treating diseases. Stabilization modification of siRNA and its delivery system are two key technologies in the development of small RNA drugs. In the research of oligonucleotides, including single-stranded oligonucleotides and double-stranded oligonucleotides, the improvement of modification of oligonucleotides has never stopped. In single-stranded oligonucleotides such as ASO, ssRNAi, and antisense strands of double-stranded oligonucleotides such as siRNA, according to the type, position and number of modifications, it may have a significant impact on the key performance of the oligonucleotide, such as pharmacological activity, stability, long-acting, etc. Although a large number of modification schemes of oligonucleotides are disclosed in the prior art, how to improve the modification of oligonucleotides, especially single-stranded oligonucleotides and antisense strands of double-stranded oligonucleotides, to obtain oligonucleotides with higher activity, higher stability and / or long-acting is still the direction of research and development in the field. SUMMARY The present disclosure provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, and an oligonucleotide conjugate, which all exhibit good pharmaceutical activity and stability when targeting APOC3 mRNA. In one aspect, the present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having a complementarity with an APOC3 mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide being a modified or unmodified nucleotide, wherein at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, at least one nucleotide is a fluorinated modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced apart from the 8th nucleotide by 4-7 nucleotides; And, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides from the 15th nucleotide and after of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In yet another aspect, the present disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand and the antisense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse-complementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide as described in the present disclosure. In yet another aspect, the present disclosure also provides an oligonucleotide conjugate containing at least one oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or the double-stranded oligonucleotide provided in the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate as described in the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutical composition containing one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt as described in the present disclosure, and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure also provides a use of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease or a symptom associated with an APOC3 mRNA level. In yet another aspect, the present disclosure also provides a method of treating and / or preventing a disease or a symptom associated with APOC3 mRNA level, comprising administering to a subject in need thereof one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In yet another aspect, the present disclosure also provides a method of modulating APOC3 mRNA in a cell in vitro or in vivo, comprising contacting an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure with the cell in vitro or in vivo. In yet another aspect, the present disclosure also provides one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure for use as a medicament. In yet another aspect, the present disclosure also provides a cell expressing APOC3 mRNA, comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In addition, the present 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 the present disclosure. All publications, including patents, patent applications, or any other documentary publications, mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication was specifically and individually incorporated herein by reference. All publications, including patents, patent applications, or any other documentary publications, mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication was specifically and individually incorporated herein by reference. Beneficial Effects One or more of the double-stranded oligonucleotides, oligonucleotide conjugates, and pharmaceutical compositions comprising the single-stranded oligonucleotides described in the present disclosure as antisense strands have higher activity in modulating APOC3 mRNA and / or APOC3 protein, for example, good stability and inhibitory activity of APOC3 mRNA and / or APOC3 protein in vivo in a subject, thus having good application prospects. The double-stranded oligonucleotide (e.g., siRNA), oligonucleotide conjugate and / or pharmaceutical composition of the present disclosure containing the single-stranded oligonucleotide of the present disclosure as the antisense strand shows excellent inhibitory effect on APOC3 mRNA and / or APOC3 protein. For example, the conjugate provided by the present disclosure can maintain inhibitory activity on plasma APOC3 protein in vivo for a relatively long period of time. In the in vivo test of transgenic mice, the conjugate provided by the present disclosure shows a better inhibition rate on plasma APOC3 protein throughout the test period of 57 days, indicating that the conjugate provided by the present disclosure has good long-acting property. The inhibition rate of the conjugate provided by the present disclosure on plasma APOC3 protein is significantly higher than that of the reference conjugate throughout the test period. Specifically, the inhibition rate of the conjugate of the present disclosure on plasma APOC3 protein is above 87% on day 8, above 86% on day 14, above 74% on day 31, above 58% on day 43, and still maintains effective inhibition on plasma APOC3 protein on day 57, with an inhibition rate of above 13%, and even above 62%. In another aspect, the conjugate of the present disclosure can maintain inhibitory activity on plasma APOC3 protein in mice for a relatively long period of time, indicating that the conjugate provided by the present disclosure has good long-acting property. The conjugate of the present disclosure has an inhibition rate on plasma APOC3 protein in mice of above 80%, and even above 86% on day 29 at a dosing dose of 3 mg / kg; and has an inhibition rate on plasma APOC3 protein in mice of above 74%, and even above 80% on day 29 at a lower dosing dose of 1 mg / kg. Even on day 57, the conjugate of the present disclosure has an inhibition rate on plasma APOC3 protein in mice of above 56% at a dosing dose of 3 mg / kg; and has an inhibition rate on plasma APOC3 protein in mice of above 41% at a dosing dose of 1 mg / kg. Therefore, it is shown that the conjugate of the present disclosure has good APOC3 mRNA and / or APOC3 protein modulating activity, shows significant pharmaceutical activity in the preparation of a medicament for treating and / or preventing a disease or symptom associated with APOC3 mRNA expression, and has excellent development prospects. DETAILED DESCRIPTION The detailed description of the present disclosure is described in detail below. It should be understood that the detailed description described herein is only used to illustrate and explain the present disclosure, and is not used to limit the present disclosure. In the present disclosure, APOC3 mRNA refers to APOC3 mRNA expressed in a mammalian cell. In the present disclosure, APOC3 mRNA refers to mRNA of the sequence shown in Genbank Accession No. NM_174936.3. Further, the term "APOC3 gene" used in the present disclosure refers to a gene that transcribes the aforementioned APOC3 mRNA, unless otherwise specified. Definitions In the context of the present document, the expressions "complementary" or "reverse complementary" are used interchangeably and have the meaning well known to those skilled in the art, i.e. in a double-stranded nucleic acid structure, the bases of one strand each form a hydrogen bond between base pairs in a complementary manner with the bases on the other strand, effecting base pairing, forming Watson-Crick base pairs. A "base pair" refers to two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or in RNA, uracil (U)); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair comprises 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 to be complementary to each other, and the sequence of one strand can be deduced from the sequence of its complementary strand. When the bases are modified, as long as the aforementioned purine-pyrimidine pairing relationship is not affected (including but not limited to the number and strength of hydrogen bonds between bases), the modified bases are also considered to be able to form complementary pairs. Accordingly, "mismatch" or "base mismatch" in the art means that the bases at the corresponding positions between the two single-stranded nucleic acids involved do not pair in a complementary manner; when the corresponding position comprises an abasic nucleotide, it is also considered to form a mismatch with the base on the other strand. In the above and below, "nucleotide sequence A is substantially reverse complementary, substantially reverse complementary, or completely reverse complementary to nucleotide sequence B over a span of X nucleotides" means that there is a continuous nucleotide sequence A' of length X in nucleotide sequence A, which is substantially reverse complementary, substantially reverse complementary, or completely reverse complementary to a continuous nucleotide sequence B' of the same length X in nucleotide sequence B. Unless specifically stated otherwise, in the context of the present document, a reference to an oligonucleotide and / or an oligonucleotide conjugate described in the applications or methods provided by the present disclosure, including but not limited to an oligonucleotide and / or an oligonucleotide conjugate represented by any structural formula described in the applications or methods provided by the present disclosure, also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or the conjugate, depending on the context. In the foregoing and hereinafter, particularly in describing the preparation of a single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of the present disclosure, unless otherwise specified, the nucleoside monomer refers to modified or unmodified nucleoside phosphoramidite monomers (unmodified or modified RNA phosphoramidites, sometimes also referred to as Nucleoside phosphoramidites) used in the phosphoramidite solid phase synthesis according to the kind and order of nucleotides in the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate to be prepared. The phosphoramidite solid phase synthesis is a method used in RNA synthesis well known to those skilled in the art. The nucleoside monomers used in the present disclosure are all commercially available. Various protecting groups, such as hydroxyl protecting groups or amino protecting groups, can be used in the present disclosure. In the foregoing and hereinafter, a protecting group renders a chemical functional group insensitive to particular reaction conditions, and can be added to and removed from that functional group in a molecule without substantially damaging the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Peter G. M. Wuts, GREEN’s Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons Inc., New Jersey, 2014, each of which is incorporated by reference herein 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 can be used herein include dimethoxytrityl (DMT), monomethoxytrityl, 9-phenylxanthyl (Pixyl), and 9-(p-methoxyphenyl)xanthyl (Mox). In some embodiments, non-exclusive examples of hydroxyl protecting groups that can be used herein include Tr (trityl), MMTr (4-methoxytrityl), DMTr (4,4'-dimethoxytrityl), and TMTr (4,4',4"-trimethoxytrityl). The term “subject,” as used herein, refers to any animal, such as a mammal or a marsupial. Subjects of the present disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus or other types of macaques), mice, pigs, horses, donkeys, cows, rabbits, sheep, rats, and any species of poultry. As used herein, "treatment" refers to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the observation of improvement in a subject, even though the subject can still be afflicted with the underlying disorder, by eradicating or ameliorating one or more of the signs or symptoms of the underlying disorder. As used herein, "prevention" refers to an approach for obtaining beneficial or desired results, including but not limited to prophylactic benefit. To obtain "prophylactic benefit", a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate of the present disclosure can be administered to a subject at risk of developing a disease associated with APOC3 mRNA, or to a subject reporting one or more physiological symptoms of a disease associated with APOC3 mRNA, even though the diagnosis of the disease can not have been made. In some embodiments, "prevention" includes reducing or eliminating a specific disease risk by administering a single-stranded oligonucleotide, a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate to a subject at risk of developing the specific disease, intervening in the level of APOC3 mRNA or APOC3 protein before the specific disease risk progresses to an explicit disease process. Single-stranded oligonucleotide of the present disclosure The present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having a complementarity with APOC3 mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, and at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and the 8th nucleotide is spaced 4-7 nucleotides apart; And, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides from the 15th nucleotide and after of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA; Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In the present disclosure, by modulating the expression level of APOC3 mRNA and / or changing the protein level, diseases associated with the expression level and / or protein level of APOC3 mRNA can be treated or prevented. The inventors surprisingly found that the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as the antisense strand and the oligonucleotide conjugate of the present disclosure have good stability and APOC3 mRNA inhibitory activity in cells and / or in vivo in a subject, and thus have good application prospects. To exert the RNAi effect, the single-stranded oligonucleotide of the present disclosure has a length of 16-30 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 17-28, 19-26, or 20-24 nucleotides. In some embodiments, the single-stranded oligonucleotide of the present disclosure has a length of 19, 21 or 23 nucleotides. In this case, the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as the antisense strand and the oligonucleotide conjugate of the present disclosure have a better balance of synthesis cost, stability and RNAi activity. In the single-stranded oligonucleotide of the present disclosure, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 4-7 nucleotides, and is located after the 8th nucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA. The inventors have particularly found that the single-stranded oligonucleotide conjugate of the present disclosure can effectively maintain the high inhibitory activity of the single-stranded oligonucleotide, the double-stranded oligonucleotide and the oligonucleotide conjugate on APOC3 mRNA while maintaining stability by comprising a fluorine-modified nucleotide and a nucleotide X. 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, in the single-stranded oligonucleotide, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide in the direction from the 5' end to the 3' end; and each nucleotide X is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 3, 5, 7 or 10 nucleotides in the direction from the 5' end to the 3' end. In some embodiments, in the single-stranded oligonucleotide, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and one of the nucleotides X is spaced apart from the 8th nucleotide by 5 nucleotides, i.e., in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X. In some embodiments, there is only one nucleotide X in the single-stranded oligonucleotide, which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, there are 2 nucleotides X in the single-stranded oligonucleotide, in which 1 nucleotide X is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction, and the other nucleotide X is spaced 3, 7, or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the 12th and 14th nucleotides, or the 14th and 16th nucleotides, or the 14th and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are nucleotides X. Each nucleotide X is independently selected from a deoxynucleotide or an unmodified nucleotide. In the present context, "unmodified nucleotide" refers to a ribonucleotide (RNA) in which both the base and the ribose are unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the 2' position of the nucleotide ribose is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide in which the base is modified, a nucleotide in which the hydroxyl group at the 2' position of the nucleotide 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 in the 5' end to 3' end direction are deoxynucleotides, and the other nucleotide X is an unmodified nucleotide. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction is a deoxynucleotide, and the other nucleotides are modified nucleotides. In some embodiments, the number of modified nucleotides is more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide of the present disclosure; or, the number of unmodified nucleotides in the single-stranded oligonucleotide is no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is 2 or 1. In some embodiments, each of the total number of nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide. As previously described, the single-stranded oligonucleotide described in the present disclosure includes fluorine-modified nucleotides in addition to nucleotide X. In some embodiments, the number of fluorine-modified nucleotides is 2-7. In some embodiments, the fluorine-modified nucleotides refer to 1 or 2 of the 2nd, 11th and 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 11th, 12th, 16th, 18th and 19th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th and 16th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 5th, 7th, 12th and 16th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 5th, 7th, 11th and 16th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 7th, 12th, 16th and 19th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, 12th, 16th and 19th nucleotides in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, each modified nucleotide in the single-stranded oligonucleotide, except for nucleotide X and the fluorine-modified nucleotide, is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 3. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is no more than 2. In some embodiments, the number of substituted alkoxy-modified nucleotides in the single-stranded oligonucleotide is 1. In some embodiments, there is no substituted alkoxy-modified nucleotide in the single-stranded oligonucleotide. In some embodiments, each modified nucleotide in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide, is selected from an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, or a thermally unstable nucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 0-2. In some embodiments, there is no thermally unstable nucleotide in the single stranded oligonucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is no more than 2. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 1 or 2. In some embodiments, the single stranded oligonucleotide contains only 1 thermally unstable nucleotide. In some embodiments, each modified nucleotide in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide and the thermally unstable nucleotide, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide. In the present context, a “thermally unstable nucleotide” refers to a nucleotide having a thermally unstable modification, which is a modification that results in a decrease in the thermal dissociation temperature of a duplex of an oligonucleotide having the modification at the corresponding position by at least 0.5 °C as compared to a duplex of an oligonucleotide having an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification of PCT publication WO2018 / 098328A1

[0236] -

[0251] The thermally unstable modification described in the paragraph. In some embodiments, the thermally unstable modification nucleotide is one of an acyclic nucleotide or an iso-nucleotide. An acyclic nucleotide is a class of nucleotides in which the sugar ring of the nucleotide is opened. In some embodiments, the acyclic nucleotide can be an unlocked nucleic acid (UNA) or a glycerol nucleic acid (GNA), wherein the UNA is shown in formula (15) and the GNA is shown in formula (16): In the above formula (15) and formula (16), 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. An iso-nucleotide refers to a compound in which the position of the base on the ribose ring is changed. In some embodiments, the iso-nucleotide can be a compound in which the base is moved from the 1'-position to the 2'-position or the 3'-position on the ribose ring, as shown in formula (17) or (18). In the above formula (17)-(18) compounds, Base represents a nucleic acid base, such as A, U, G, C, or T; and R is selected from H, OH, F, or a non-fluorine group as described above. In some embodiments, the thermally unstable modified nucleotide is selected from one of 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), and Hyp-spacer as shown in formula (27L): In the above compounds of formula (27A)-(27L), Base represents a nucleic acid base, such as A, U, G, C, or T; R 27 is selected from H, OH, F, alkoxy, alkyl, or alkoxy-substituted alkyl. The * indicates that the carbon atom has chirality at that carbon atom, and the compound can be in the R configuration, the S configuration, or a racemic mixture of the R and S configurations. In some embodiments, each thermally unstable modified nucleotide is independently a GNA as shown in formula (27A). In the above context, BNA refers to a constrained or inaccessible nucleotide. A BNA can contain a five-, six-, or seven-membered ring bridged structure with a "fixed" C3'-endo sugar conformation. The bridge is typically incorporated at the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be a LNA, an ENA, a cET BNA, etc., where the LNA is shown in formula (12), the ENA is shown in formula (13), and the cET BNA is shown in formula (14): In some embodiments, for ease of synthesis, each alkoxyl-modified nucleotide is independently a 2'-methoxyl-modified nucleotide (2'-OMe), which is 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 the above compounds of formula (7)-(10) and formula (12)-(14), Base represents a nucleic acid base, such as A, U, G, C, or T. In the foregoing and hereinafter, "fluoro-modified nucleotide", "2'-fluoro-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by fluorine" and "nucleotide having a 2'-fluoro-ribosyl group" have the same meaning and refer to a nucleotide whose 2'-hydroxyl is replaced by fluorine to form a compound having a structure as shown in Formula (7); "methoxy-modified nucleotide", "2'-methoxy-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy" and "nucleotide having a 2'-methoxy-ribosyl group" have the same meaning and refer to a nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy to form a compound having a structure as shown in Formula (8). In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide if it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide if it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 12th and 14th nucleotides are nucleotide X, the 2nd, 7th and 16th nucleotides are fluorine-modified 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 an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th and 16th nucleotides are nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; in the 3' end to 5' end direction, 1 of the 1st-2nd nucleotides is a thermally unstable nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide.In some embodiments, the single stranded oligonucleotide described in the present disclosure has a length of 19-23 nucleotides, and in the direction from the 5' end to the 3' end, 1 of the 16th-19th nucleotides and the 14th nucleotide is a nucleotide X, the 2nd and 6th nucleotides are fluorinated modified nucleotides, the 16th nucleotide is a fluorinated modified nucleotide when the 16th nucleotide is not a nucleotide X, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 20th nucleotide is an alkoxy modified nucleotide or a thermally unstable nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide is 21 nucleotides in length, wherein the 16th or 19th nucleotide and the 14th nucleotide are nucleotide X, and wherein the 14th nucleotide is a deoxy nucleotide or an unmodified nucleotide and the 16th or 19th nucleotide is an unmodified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluoro-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 11th, and 16th nucleotides are fluoro-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 12th and 14th nucleotides are deoxy nucleotides, the 2nd, 7th, and 16th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 21 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluoro-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide of the single stranded oligonucleotide is a thermally unstable nucleotide in the 3' end to 5' end direction, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy-modified nucleotide.In some embodiments, the single stranded oligonucleotide described herein has a length of 21 nucleotides, and in a 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 19thnucleotide is an unmodified nucleotide, the 2nd, 6thand 16thnucleotides are fluoro-modified nucleotides, the 13thnucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, each nucleotide X in the single stranded oligonucleotide described herein is a deoxy nucleotide. In some embodiments, each alkoxy-modified nucleotide in the single stranded oligonucleotide described herein is a methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide in the single stranded oligonucleotide described herein is a 2'-0-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single stranded oligonucleotide described herein is a LNA, ENA or cET BNA. In some embodiments, each heat unstable nucleotide in the single stranded oligonucleotide described herein is a GNA. In some embodiments, each of at least 2 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide described herein is independently a phosphorothioate group with a modification group. In some embodiments, each of 1-4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 5' end in the single stranded oligonucleotide described herein is independently a phosphorothioate group with a modification group. In some embodiments, each of 1-4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 3' end in the single stranded oligonucleotide described herein is independently a phosphorothioate group with a modification group. In some embodiments, each of 2 of the linking groups between adjacent nucleotides in the 1st-3rdnucleotides at the 5' end or 4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 5' end in the single stranded oligonucleotide described herein is independently a phosphorothioate group with a modification group. In some embodiments, each of 2 of the linking groups between adjacent nucleotides in the 1st-3rdnucleotides at the 3' end or 4 of the linking groups between adjacent nucleotides in the 1st-5thnucleotides at the 3' end in the single stranded oligonucleotide described herein is independently a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide described herein, each of 1 or 2 of the 2 linking groups between the unmodified nucleotide and the adjacent nucleotides is independently a phosphorothioate group with a modification group. The modified phosphorothioate group can make the single stranded oligonucleotide described herein better resistant to exonuclease, and enhance the stability of the oligonucleotide in a subject. In some embodiments, at least 2, or each of 2-6, of the linking groups between adjacent nucleotides in the single stranded oligonucleotide of the present disclosure are independently phosphodiester groups with a modification group. In some embodiments, each of 2-6 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide are independently phosphodiester groups with a modification group. In some embodiments, each of 3 or 4 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide are independently phosphodiester groups with a modification group. In some embodiments, each of the linking groups between adjacent nucleotides in the first 1-3 nucleotides at the 5' end, and the first 1-3 nucleotides at the 3' end of the single stranded oligonucleotide are independently phosphodiester groups with a modification group. In some embodiments, if there is an unmodified nucleotide in the single stranded oligonucleotide, each of the 1 or 2 of the 2 linking groups between the unmodified nucleotide and the adjacent nucleotides are independently phosphodiester groups with a modification group. In some embodiments, the phosphodiester group with a modification group is a phosphorothioate group with a structure as shown in formula (28): In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide with a structure as shown in formula (29), a 5'-phosphate nucleotide with a structure as shown in formula (30), or a 5'-phosphate analog modified nucleotide with a structure selected from one of formula (31) - formula (34): wherein R is selected from one of 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 5'-phosphate modified nucleotide as shown in formula (30), the 5'-phosphate analog modified nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide as shown in formula (31), or a 5'-phosphorothioate modified nucleotide as shown in formula (33). In some embodiments, the 5' terminal nucleotide of the single stranded oligonucleotide is a 5'-hydroxyl nucleotide or a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide. In some embodiments, the 5' terminal nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide, which can further increase one or more of the stability, the pharmacodynamic activity in a subject, and the long-acting property of the single stranded oligonucleotide, the double stranded oligonucleotide comprising the single stranded oligonucleotide, and the oligonucleotide conjugate of the present disclosure. In some embodiments, the single-stranded oligonucleotide is 21 nucleotides in length, and in the 5' end to 3' end direction, the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; or the 14th nucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 11th, and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; the linking group between any two adjacent nucleotides of the 1st-3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides of the 1st-3rd nucleotides at the 3' end are phosphorothioate groups; the 5' terminal nucleotide is a 5'-hydroxyl nucleotide of Formula (29) or a 5'-vinylphosphonate-modified nucleotide of Formula (31). As previously described, the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to an APOC3 mRNA to mediate an RNAi effect. In some embodiments, the single-stranded oligonucleotides of the present disclosure are sufficiently complementary to an APOC3 mRNA. In the context of the present disclosure, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to an APOC3 mRNA such that the single-stranded oligonucleotide reduces or eliminates the production of a protein encoded by the APOC3 mRNA through an RNAi effect. In some embodiments, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure are substantially reverse complementary, substantially reverse complementary, or completely reverse complementary to an APOC3 mRNA over a length of at least 16 nucleotides, for example, over a length of 16-25 nucleotides, over a length of 18-23 nucleotides, or over a length of 19-21 nucleotides. In some embodiments, the single-stranded oligonucleotides of the present disclosure are completely reverse complementary to an APOC3 mRNA. In the preceding and following text, "at least partially anticomplementary," "substantially anticomplementary," "truly anticomplementary," and "completely anticomplementary" can refer to the base pairing between two single-stranded nucleotide sequences: between a single-stranded oligonucleotide and APOC3 mRNA, 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 APOC3 mRNA. Unless otherwise specified, "at least partially anticomplementary" means that within a given length of nucleotide sequence, there are no more than 50% base mismatches between the two nucleotide sequences; "substantially anticomplementary" means that within a given length of nucleotide sequence, there are no more than 3 base mismatches between the two nucleotide sequences; "truly anticomplementary" means that within a given length of nucleotide sequence, there are 1 base mismatch between the two nucleotide sequences; and "completely anticomplementary" means that within a given length of nucleotide sequence, there are no base mismatches between the two nucleotide sequences. When two nucleotide sequences are completely anticomplementary within a given length of nucleotide sequence, they can anneal to form a double-stranded hybrid uniquely composed of Watson-Crick base pairs within the given length of nucleotide sequence. 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 over the entire length of the shorter nucleotide sequence. For example, the complete anticomplementary relationship between the single-stranded oligonucleotide and APOC3 mRNA described in this disclosure means complete anticomplementary relationship over the entire length of the single-stranded oligonucleotide described in this disclosure; in other words, the single-stranded oligonucleotide can form a double-stranded hybrid by each nucleotide uniquely forming a Watson-Crick base pair with a nucleotide on APOC3 mRNA. In some embodiments, the two "fully complementary" nucleotide sequences may include completely anticomplementary internal regions (e.g., completely anticomplementary over a length spanning at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotide and APOC3 mRNA are completely anticomplementary at least within the seed region. The “seed region” refers to the region of nucleotides 2-8 of the single-stranded oligonucleotide described in this disclosure. In this region, the single-stranded oligonucleotide described in this disclosure can better mediate RNAi and inhibit the level of APOC3 mRNA. In some embodiments, the single-stranded oligonucleotide is substantially or completely complementary to the APOC3 mRNA over a stretch of at least 16 nucleotides. In some embodiments, the nucleotide sequence of positions 2-19 of the single-stranded oligonucleotide is completely complementary to the APOC3 mRNA in the 5' to 3' direction. In some embodiments, the nucleotide sequence of positions other than position 1 of the single-stranded oligonucleotide is completely complementary to the APOC3 mRNA in the 5' to 3' direction. In some embodiments, all of the nucleotides of the single-stranded oligonucleotide are completely complementary to the APOC3 mRNA. In some embodiments, the single-stranded oligonucleotide of the present disclosure can be the first, second, or third single-stranded oligonucleotide described below, each of which is described below. The first single-stranded oligonucleotide In some embodiments, the present disclosure provides the first single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises a nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2GAAUACUGUCCCUUUUAA-3' (SEQ ID NO: 2), wherein Z2 is A or U, and the nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, which is the first nucleotide at the 5' end of the single-stranded oligonucleotide. In the foregoing and hereinafter of the present disclosure, "corresponding to" means being at the same position in a nucleotide sequence, counting from the same end of the nucleotide sequence, for example, the first nucleotide at the 5' end of the nucleotide sequence II is the nucleotide corresponding to the first nucleotide of SEQ ID NO: 2. In some embodiments, each U in the nucleotide sequence of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate of the present disclosure can be optionally replaced by T. These base differences do not significantly reduce the APOC3 mRNA inhibition ability of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate or increase its off-target effect. These single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates comprising base differences are also within the scope of protection of the present disclosure. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 can include a difference at position Z'2 and / or a base difference at any other nucleotide position in nucleotide sequence II. In some embodiments, wherein the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 can include a base difference at position Z'2 and / or at a nucleotide position adjacent to Z'2. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a difference at position Z'2, and Z'2 is selected from U, G, or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a difference at position Z'2, and Z'2 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, the nucleotide sequence IV is linked to the 3' end of nucleotide sequence II, has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides; the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOC3 mRNA, each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide having an alkyl group of carbon number 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is G; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is GC in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is GCA in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is GCAA 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 in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II; the nucleotide sequence V forms a 3' overhang end of the antisense strand of the double-stranded oligonucleotide after the single-stranded oligonucleotide forms the double-stranded oligonucleotide with the sense strand. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the 5' end to 3' end direction, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is selected from GC or UU. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, and the base composition of the nucleotide sequence V is GC. A second single-stranded oligonucleotide In some embodiments, the disclosure provides a second single-stranded oligonucleotide, wherein the single-stranded oligonucleotide contains a nucleotide sequence II that is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4 and differs by no more than 3 bases: 5'-Z4UCUUGUCCAGCUUUAUUG-3' (SEQ ID NO: 4), wherein Z4 is A or U, and the nucleotide sequence II contains a nucleotide Z'4 at the position corresponding to Z4, Z'4 being the first nucleotide at the 5' end of the single-stranded oligonucleotide. In some embodiments, the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 can include a difference at the Z'4 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 can include a difference at the Z'4 position and / or a difference at a nucleotide position adjacent to Z'4. In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 includes a difference at the Z'4 position, and Z'4 is selected from U, G, or C. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a difference at the Z'4 position, and Z'4 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, the nucleotide sequence IV is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3 or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides; the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to the APOC3 mRNA, each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is G; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is GG in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is GGA in the direction from the 5' end to the 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is GGAG 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 in the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1-3 nucleotides, and is linked 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 positive strand, the nucleotide sequence V constitutes the 3' overhanging end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, 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 fully reverse-complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from GG or UU. In some embodiments, the single-stranded oligonucleotide only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 4, and the base composition of the nucleotide sequence V is GG. The third single-stranded oligonucleotide In some embodiments, the present disclosure provides a third single-stranded oligonucleotide, wherein the single-stranded oligonucleotide comprises a nucleotide sequence II, the nucleotide sequence II has a length equal to the nucleotide sequence shown in SEQ ID NO: 6, and no more than 3 base differences: 5'-Z6GCACUGAGAAUACUGUCC-3' (SEQ ID NO: 6), wherein Z6 is A or U, and nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the single-stranded oligonucleotide. In some embodiments, there is no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 can 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 set forth in SEQ ID NO: 6 can include a 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 the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 includes a difference at the Z'6 position, and Z'6 is selected from U, G, or C. In some embodiments, the base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a difference at the Z'6 position, and Z'6 is selected from C, U, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, the nucleotide sequence IV is linked to the 3' end of nucleotide sequence II, the length of the nucleotide sequence IV is 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of the non-fluoro-modified nucleotides; the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the APOC3 mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the length of the nucleotide sequence IV is 2 nucleotides. In some embodiments, the length of the nucleotide sequence IV is 1 nucleotide, and the base is C; or, the length of the nucleotide sequence IV is 2 nucleotides, and the base composition is CU from 5' end to 3' end; or, the length of the nucleotide sequence IV is 3 nucleotides, and the base composition is CUU from 5' end to 3' end; or, the length of the nucleotide sequence IV is 4 nucleotides, and the base composition is CUUU from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked 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 a 3' overhang end of the antisense strand of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or fully reverse complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from CU or UU. In some embodiments, the single-stranded oligonucleotide only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 6, and the base composition of the nucleotide sequence V is CU. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1-siRNA6 shown in Table 1. Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of conjugate 1-conjugate 7 shown in Table 2. In some embodiments, the single-stranded oligonucleotide of the present disclosure can independently exert a pharmacodynamic activity. In some embodiments, the single-stranded oligonucleotide of the present disclosure is an antisense oligonucleotide (ASO). In some embodiments, the single-stranded oligonucleotide of the present disclosure is a single-stranded RNAi (ssRNAi) compound. In some embodiments, the single-stranded oligonucleotide of the present disclosure exerts a pharmacodynamic activity as a single strand (e.g., an antisense strand) of a double-stranded oligonucleotide. The double-stranded oligonucleotide of the present disclosure The present disclosure also provides a double-stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand is a modified or unmodified nucleotide, and the sense strand and the antisense strand are at least partially reverse complementary to form a double-stranded region, wherein the antisense strand is a single-stranded oligonucleotide as described in the present disclosure. In the double-stranded oligonucleotide of the present disclosure, the length of the sense strand and the antisense strand is each 19-26 nucleotides. In some embodiments, the length of the antisense strand is not less than the length of the sense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Thus, the ratio of the length of the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 19 / 23, 19 / 24, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 20 / 24, 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, for the convenience 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 length of the sense strand and the antisense strand is the same, and each is 19, 20, or 21 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 20-24 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides, and the length of the antisense strand is 21-24 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 22-24 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 length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides. In some embodiments, in the sense strand of the double-stranded oligonucleotide of the present disclosure, 2-3 of the 11th-13th nucleotides of the sense strand in the direction from the 3' end to the 5' end are fluorine-modified nucleotides, and the 1st nucleotide and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having a structure as shown in formula (35)). In some embodiments, the 1st nucleotide of the sense strand in the direction from the 3' end to the 5' end is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide. In some embodiments, in addition to the above-mentioned fluorine-modified and inverted abasic deoxyribonucleotide, the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide; In some embodiments, the oxygen atom shown in formula (35) that is directly connected to the ribose ring can be connected to the 3' phosphate group of the 2nd last nucleotide from the 3' end of the sense strand. In some embodiments, the oxygen atom shown in formula (35) that is directly connected to the ribose ring can be connected to the 3' phosphate group of the terminal 3' nucleotide of the sense strand, and the oxygen atom shown in formula (35) that is methylene-linked to the ribose ring can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the oxygen atom shown in formula (35) that is methylene-linked to the ribose ring can be connected to the 5' phosphate group of the 2nd last nucleotide from the 5' end of the sense strand. In some embodiments, the oxygen atom shown in formula (35) that is methylene-linked to the ribose ring is connected to the 5' phosphate group of the 2nd last nucleotide from the 5' end of the sense strand, and the oxygen atom shown in formula (35) that is directly connected to the ribose ring can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the 11th and 13th nucleotides, or the 11th to 13th nucleotides, of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are alkoxy-modified nucleotides, in the direction from the 3' end to the 5' end. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or the 11th to 13th nucleotides, of the sense strand are fluorine-modified nucleotides, the 1st nucleotide and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are alkoxy-modified nucleotides, in the direction from the 3' end to the 5' end. At this time, the double-stranded oligonucleotide of the present disclosure has better stability and / or activity of forming a RISC complex by the position cooperation of the modified nucleotides of the sense strand and the antisense strand, thereby showing stable and efficient APOC3 mRNA inhibitory activity. In some embodiments, each of the alkoxy-modified nucleotides is a methoxy-modified nucleotide. In some embodiments, in the sense strand, at least one of the linking groups linking adjacent two nucleotides is a phosphate group with a modification group, which is present between adjacent nucleotides in the first to fifth nucleotides at the 5' terminal end and between adjacent nucleotides in the first to fifth nucleotides at the 3' terminal end of the sense strand. At this time, the double-stranded oligonucleotide of the present disclosure has the ability to resist nucleic acid exonuclease and good balance of APOC3 mRNA, thereby having high efficient APOC3 mRNA inhibitory activity while improving stability. In some embodiments, 1 to 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the sense strand, and / or 1 to 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 5' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides in the first to fifth nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, the linking group linking adjacent nucleotides in the first to third, first to fourth, or first to fifth nucleotides at the 5' and / or 3' terminal end of the sense strand is a phosphate group with a modification group. In some embodiments, the linking group between adjacent nucleotides in the first to third nucleotides at the 5' end of the sense strand is a phosphate group with a modification group. The definition and selection range of the phosphate group with a modification group are the same as described above for the phosphate group with a modification group in the antisense strand of the present disclosure. In some embodiments, each phosphate group with a modification group is a phosphorothioate group having a structure as shown in formula (28). In some embodiments, the sense strand is the sense strand possessed by any one of siRNA1 - siRNA6 shown in Table 1; in some embodiments, the sense strand is the sense strand possessed by any one of conjugate 1 - conjugate 7 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, from the 3' end to the 5' end are fluoro-modified nucleotides, the 1st and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides from the 3' end of the sense strand, are independently phosphates with a modification group. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2, 1-3, 1-4, or 1-5 nucleotides from the 5' end and / or the 3' end of the sense strand is a phosphate with a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand is a phosphate. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-3, 1-4, or 1-5 nucleotides from the 5' end of the sense strand is a phosphate with a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand is a phosphate. In some embodiments, the linking group between every two adjacent nucleotides in the 1st-2, 1-3, 1-4, or 1-5 nucleotides from the 3' end of the sense strand is a phosphate with a modification group, and the linking group between the remaining adjacent nucleotides in the sense strand is a phosphate. In some embodiments, all adjacent nucleotides in the sense strand are linked by a phosphate. In some embodiments, the phosphate with a modification group is a phosphorothioate group with the structure shown in formula (28), and the alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. In some embodiments, in the double-stranded oligonucleotide of the present disclosure, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end of the sense strand and / or the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 3' end of the sense strand are phosphate groups with a modification group; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end of the antisense strand is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide.the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end of the antisense strand and the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 3' end of the antisense strand are phosphodiester groups with a modification group, and if there are unmodified nucleotides, 1-2 of the 2 linking groups between each unmodified nucleotide and the adjacent nucleotide are phosphodiester groups with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate modified nucleotide represented by formula (31). In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides. in the sense strand, the 11th to 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an alkoxy-modified nucleotide or an inverted deoxy nucleotide, and the nucleotides at the remaining positions are each independently alkoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end of the sense strand and / or the linking groups between adjacent nucleotides in the 1st to 3rd nucleotides from the 3' end of the sense strand are phosphodiester groups with a modification group; In the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides are deoxynucleotides, the 2nd, 5th, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide of the antisense strand is a thermally unstable nucleotide in the direction from the 3' end to the 5' end, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In the antisense strand, the linkage groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and the 1st-3rd nucleotides at the 3' end of the antisense strand are both phosphate groups with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31). In some embodiments, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides. In the sense strand, the 11th and 13th nucleotides are fluorine-modified nucleotides, the 1st nucleotide is an inverted de-alkylated deoxynucleotide, and the remaining nucleotides are methoxy-modified nucleotides, from the 3' end to the 5' end; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; In the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, and the remaining nucleotides in the antisense strand are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31); In the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, and the remaining nucleotides in the antisense strand are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31). The double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between APOC3 mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme. In the context of the present disclosure, the "modification scheme" refers to a combination of different numbers, positions, and types of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications that are not or weakly related to a specific sequence. In some embodiments, the double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between APOC3 mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original pharmaceutical activity of the double-stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide of the present disclosure is an siRNA. The double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between APOC3 mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original RNAi activity of the siRNA. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse complementary or completely reverse complementary, and one or two overhanging ends of the sense strand and / or one or two overhanging ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse complementary or completely reverse complementary, and one overhanging end of the antisense strand. In the context of the present disclosure, the "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences including all base pairs and all base mismatches located between the base pairs on each single strand in a double-stranded nucleic acid structure. Thus, the double-stranded region consists of all base pairs and all base mismatches located between the base pairs in a double-stranded nucleic acid structure. In some embodiments, the number of base mismatches is not more than 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 is not more than 3, not more than 2, or not more than 1. In some embodiments, the double-stranded nucleic acid structure includes the double-stranded region and one or more overhanging ends composed of nucleotides that do not form base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning at least 16 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising at least 16 base pairs. In the context of the present disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 16-23 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 16-23 base pairs. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 18, 19, 20, or 21 base pairs. In some embodiments, the sense strand and the antisense strand are substantially reverse complementary or completely reverse complementary within the double-stranded region. In some embodiments, the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure are substantially reverse complementary or completely reverse complementary over the entire nucleotide length. In some embodiments, the number of base differences between the sense strand and the APOC3 mRNA is no more than 3, no more than 2, or no more than 1. In some embodiments, there is no base difference between the sense strand and the APOC3 mRNA. In the foregoing and hereinafter, a nucleotide sequence and another nucleotide sequence have a "base difference" if the base type of a nucleotide at a same position in the former is different from that in the latter, e.g., 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, it is recognized that there is a base difference between the two nucleotide sequences at the position. When a base is modified, as long as the modification does not affect the purine-pyrimidine pairing relationship when forming the double-stranded nucleic acid structure described above, it is also recognized that there is no base difference between the modified base and the original base. In some embodiments, it is recognized that there is no base difference between U and T. In some embodiments, it is recognized that there is no base difference between C and 5-methylcytosine (5mC). In some embodiments, when a nucleotide at a position is replaced with an abasic nucleotide or an equivalent thereof, it is also recognized that a base difference is generated at the position. When aligning two nucleotide sequences to determine the number of base differences, the alignment is performed in a manner that has the least number of base differences among all possible alignments, and the base differences are determined based on the alignment. At this time, the "same position" refers to the corresponding position between the two nucleotide sequences in the alignment. For example, when nucleotide sequence A positions 1-5 are aligned with nucleotide sequence B positions 2-6 in the same direction, and the number of base differences is the least compared to other alignments, the "same position" refers to the alignment of nucleotide sequence A position 1 with nucleotide sequence B position 2, nucleotide sequence A position 2 with nucleotide sequence B position 3, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths is the total number of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the number of base differences between two nucleotide sequences of the same length is the total number of base differences between the first nucleotide to the last nucleotide of either nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths is the absence of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of the same length is the absence of base differences between the first nucleotide to the last nucleotide of one nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. The double-stranded oligonucleotide of the present disclosure can be various double-stranded oligonucleotides that modulate the expression of APOC3 mRNA. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or down-regulates the expression of APOC3 mRNA, such as an siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or up-regulates the expression of APOC3 mRNA, such as a saRNA. In some embodiments, the double-stranded oligonucleotide is an siRNA. In some embodiments, the double-stranded oligonucleotide of the present disclosure can be one of the following first-third double-stranded oligonucleotides, each of which is described below. First double-stranded oligonucleotide In some embodiments, the present disclosure provides a first double-stranded oligonucleotide, which contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 1, and has no more than 3 base differences; the antisense strand contains a nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-UUAAAAGGGACAGUAUUCZ1-3' (SEQ ID NO: 1); 5'-Z2GAAUACUGUCCCUUUUAA-3' (SEQ ID NO: 2), wherein Z1 is U, A or an inverted abasic deoxy nucleotide (ia), Z2 is A or U, nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only nucleotide sequence I, and the antisense strand comprises only nucleotide sequence II. In some embodiments, there is no more than 1 base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1, and / or no more than 1 base difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a difference at Z'1 position and / or a base difference at any other nucleotide position in nucleotide sequence I. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a base difference at Z'1 position and / or a base difference at a nucleotide position adjacent to Z'1. In some embodiments, the base difference between nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 is a base difference at Z'1 position, and preferably Z'1 is an inverted abasic deoxy nucleotide. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a difference at Z'2 position, and Z'2 is selected from C, U or G. In some embodiments, the difference between nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a difference at Z'2 position, and Z'2 is selected from C, U or G. In some embodiments, the 2nd-19th nucleotide of nucleotide sequence II is fully reverse complementary to APOC3 mRNA in a 5' end to 3' end direction. In some embodiments, nucleotide sequence II is fully reverse complementary to nucleotide sequence I. In some embodiments, the 2nd nucleotide in nucleotide sequence II in a 5' end to 3' end direction is base mismatched with the 2nd nucleotide in nucleotide sequence I in a 3' end to 5' end direction. By including the base mismatch, higher APOC3 mRNA inhibitory activity can be achieved while maintaining low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of C, and the nucleotide sequence IV has a base of G, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of GC, and the nucleotide sequence IV has a base composition of GC, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of UGC, and the nucleotide sequence IV has a base composition of GCA, in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of UUGC, and the nucleotide sequence IV has a base composition of GCAA, in the direction from the 5' end to the 3' end. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides, two consecutive uracil ribonucleotides, or fully reverse complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from GC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, the nucleotide sequence I consists of SEQ ID NO: 1, and the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is GC. The second double-stranded oligonucleotide In some embodiments, the present disclosure provides a second double-stranded oligonucleotide comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I, the nucleotide sequence I being equal in length to the nucleotide sequence set forth in SEQ ID NO: 3 and having no more than 3 base differences; the antisense strand comprising a nucleotide sequence II, the nucleotide sequence II being equal in length to the nucleotide sequence set forth in SEQ ID NO: 4 and having no more than 3 base differences: 5'-CAAUAAAGCUGGACAAGAZ3-3'(SEQ ID NO: 3); 5'-Z4UCUUGUCCAGCUUUAUUG-3'(SEQ ID NO: 4), wherein Z3 is U, A or inverted abasic deoxynucleotide (ia), Z4 is A or U, the nucleotide sequence I comprises a nucleotide Z'3 at a position corresponding to Z3, the nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, and Z'4 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4. The base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 can include a difference at the position of Z'3 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 can include a base difference at the position of Z'3 and / or at a nucleotide position adjacent to Z'3. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 3 is a base difference at the position of Z'3, and preferably, Z'3 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 comprises a difference at position Z'4, and Z'4 is selected from C, U, or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 4 is a difference at position Z'4, and Z'4 is selected from C, U, or G. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. In some embodiments, the 2nd nucleotide in the nucleotide sequence II is base- mismatched with the 2nd nucleotide in the nucleotide sequence I in the direction from 5' end to 3' end. By including this base-mismatch, one can have higher APOC3 mRNA inhibitory activity while maintaining low off-target effects. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse-complementary or fully reverse-complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide in the direction from 5' end to 3' end, the nucleotide sequence III has a base of C, and the nucleotide sequence IV has a base of G; in this case, the length ratio of the sense strand and the antisense strand is 20 / 20. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of CC in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of GG; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of UCC in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of GGA; in this case, the length ratio of the sense strand and the antisense strand is 22 / 22. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of CUCC in the direction from 5' end to 3' end, and the nucleotide sequence IV has a base composition of GGAG; in this case, the length ratio of the sense strand and the antisense strand is 23 / 23. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the formation of the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, 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 fully reverse complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is selected from GG or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 4, the nucleotide sequence I consists of SEQ ID NO: 3, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from the 5' end to the 3' end, the base composition of the nucleotide sequence V is GG. A third double-stranded oligonucleotide In some embodiments, the present disclosure provides a third double-stranded oligonucleotide comprising a sense strand and an antisense strand, the sense strand comprising a nucleotide sequence I, the nucleotide sequence I being equal in length to the nucleotide sequence set forth in SEQ ID NO: 5 and having no more than 3 base differences; the antisense strand comprising a nucleotide sequence II, the nucleotide sequence II being equal in length to the nucleotide sequence set forth in SEQ ID NO: 6 and having no more than 3 base differences: 5'-GGACAGUAUUCUCAGUGCZ5-3' (SEQ ID NO: 5); 5'-Z6 GCACUGAGAAUACUGUCC-3' (SEQ ID NO: 6), wherein Z5 is U, A or an inverted abasic deoxynucleotide (ia), Z6 is A or U, the nucleotide sequence I comprises a nucleotide Z'5 at a position corresponding to Z5, the nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a difference at position Z'5 and / or a base difference at any other nucleotide position in the nucleotide sequence I. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 can include a difference at position Z'5 and / or a base difference at a nucleotide position adjacent to Z'5. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 5 is a base difference at position Z'5, preferably, Z'5 is an inverted abasic deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 includes a difference at position Z'6, and Z'6 is selected from C, U or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 6 is a difference at position Z'6, and Z'6 is selected from C, U or G. In some embodiments, the 2nd-19th nucleotides of the nucleotide sequence II are fully reverse complementary to the APOC3 mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. In some embodiments, there is a base mismatch between the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end and the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, a higher APOC3 mRNA inhibitory activity can be achieved while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3 or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 1 nucleotide, the base of the nucleotide sequence III is G, and the base of the nucleotide sequence IV is C, in the direction from the 5' end to the 3' end; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is AG, and the base composition of the nucleotide sequence IV is CU, in the direction 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 length of each of the nucleotide sequence III and the nucleotide sequence IV is 3 nucleotides, the base composition of the nucleotide sequence III is AAG, and the base composition of the nucleotide sequence IV is CUU, in the direction 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. In some embodiments, the length of each of the nucleotide sequence III and the nucleotide sequence IV is 4 nucleotides, the base composition of the nucleotide sequence III is AAAG, and the base composition of the nucleotide sequence IV is CUUU, in the direction 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, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is, in the direction from the 5' end to the 3' end, 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the APOC3 mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is selected from CU or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 6, the nucleotide sequence I consists of SEQ ID NO: 5, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is CU. In some embodiments, the double-stranded oligonucleotide is one of siRNA1-siRNA6 shown in Table 1 below: Table 1 siRNA sequences of the disclosure wherein the capital letters C, G, U, A and T represent the base composition of the nucleotides; the lower case letter o represents that the nucleotide adjacent to the left of the letter o is an alkoxy-modified nucleotide; the lower case letter f represents that the nucleotide adjacent to the left of the letter f is a fluoro-modified nucleotide; each N is independently U or T; the lower case letter s represents that the linkage between the two nucleotides adjacent to the left and right of the letter s is a phosphorothioate linkage; the lower case letter d represents that the nucleotide adjacent to the right of the letter is a deoxy nucleotide; ia represents an inverted abasic deoxy nucleotide; P1represents that the nucleotide adjacent to the right of the letter is a 5'-phosphate nucleotide, a 5'-hydroxyl nucleotide, a 5'-phosphorothioate modified nucleotide (Ps) or a 5'-vinylphosphonate (VP) modified nucleotide. In some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide; each P1is independently a 5'-hydroxyl nucleotide or a 5'-vinylphosphonate (E-VP) modified nucleotide. The single-stranded oligonucleotides and / or double-stranded oligonucleotides provided by the present disclosure can be obtained by conventional oligonucleotide preparation methods in the art, such as solid phase synthesis and liquid phase synthesis methods. Among them, the solid phase synthesis has been commercialized and customized services. The methods for preparing nucleoside monomers with corresponding modifications and introducing modified nucleotide groups into the single-stranded oligonucleotides and / or double-stranded oligonucleotides described by the present disclosure by using nucleoside monomers with corresponding modifications are also well known to those skilled in the art. All modified nucleoside monomers can be commercially available or prepared by known methods. The single-stranded oligonucleotides, double-stranded oligonucleotides provided by the present disclosure can be used alone, or form a pharmaceutical composition with a pharmaceutically acceptable carrier, or form an oligonucleotide conjugate with a delivery group, or in any other suitable form. An effective amount of the single-stranded oligonucleotides, the double-stranded oligonucleotides, the pharmaceutical composition or the oligonucleotide conjugate is contacted with cells to regulate the expression of the target gene, or an effective amount of the single-stranded oligonucleotides, the double-stranded oligonucleotides, the oligonucleotide conjugate or the pharmaceutical composition is administered to a subject to regulate the expression of the target gene, so as to treat the pathological conditions or diseases related to the expression level of the target gene. Oligonucleotide conjugate In another aspect, the present disclosure provides an oligonucleotide conjugate containing an oligonucleotide group, and a delivery group conjugated to the oligonucleotide group, wherein the oligonucleotide group is independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or the double-stranded oligonucleotide provided by the present disclosure. In the context of the present disclosure, "conjugated" means that two or more chemical moieties, each having a specific function, are connected to each other in a covalent linkage, unless otherwise indicated; correspondingly, "conjugate" means a compound formed by the covalent linkage between the respective chemical moieties. Further, "oligonucleotide conjugate" means a compound formed by the covalent linkage of one or more chemical moieties having a specific function to an oligonucleotide. Oligonucleotide conjugate should be understood in the context of the present disclosure as a general term for a plurality of oligonucleotide conjugates or an oligonucleotide conjugate represented by a certain chemical formula. In the context of the present disclosure, "conjugated molecule" should be understood as a specific compound that can be conjugated to an oligonucleotide by a reaction to ultimately form an oligonucleotide conjugate of the present disclosure. The delivery group is a group for delivering the single-stranded oligonucleotide group or the double-stranded oligonucleotide group into a cell expressing APOC3 mRNA. In some embodiments, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the single-stranded oligonucleotide group or the double-stranded oligonucleotide group, the linker group, and the targeting group are covalently or non-covalently connected in sequence, each of the targeting groups is independently selected from a ligand group capable of binding to a cell surface receptor or a group capable of increasing compatibility with a tissue. In some embodiments, each of the targeting groups is independently targeted to one or more of the central nervous system, the liver, the kidney, the lung, the muscle, and the eye. In some embodiments, the targeting group is targeted to the liver. In some embodiments, at least one or each targeting group is independently selected from a ligand capable of binding to a mammalian hepatocyte surface asialoglycoprotein receptor. In some embodiments, the targeting group is 1-6. In one embodiment, the targeting group is 2-4. The oligonucleotide group can be non-covalently or covalently conjugated to the delivery group, for example, can be covalently conjugated to the delivery group. In some embodiments, the oligonucleotide group is a single-stranded oligonucleotide group, and the conjugation site of the single-stranded oligonucleotide group to the delivery group can be at the 3' end or 5' end of the single-stranded oligonucleotide, or in the internal sequence of the single-stranded oligonucleotide. 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' end or 5' end of the sense strand of the double-stranded oligonucleotide, or at the 5' end of the antisense strand, or in 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 of the nucleotides, such as the phosphate group, the 2'-, 3'- or 5'-position hydroxyl of the ribose, or the base. When the delivery group is attached to the 3'- or 5'-terminal of the sense strand of the single-stranded oligonucleotide or the double-stranded oligonucleotide, the delivery group is usually attached to the oxygen atom formed after the removal of the hydrogen atom from the 3'- or 5'-hydroxyl of the nucleotide; when the delivery group is attached to the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, the delivery group is usually attached to the phosphate group, the ribose sugar ring, or the base. In some embodiments, the delivery group can be attached to the 3'-position hydroxyl of the nucleotide in the internal sequence of the single-stranded oligonucleotide or the double-stranded oligonucleotide, in which case the nucleotides are connected by 2'-5' phosphodiester bonds. Various attachment methods can be referred to 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 disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the oligonucleotide and the delivery group can be connected by acid-labile or reducible chemical bonds, which can be degraded in the acidic environment of the intracellular endosome, thereby converting the double-stranded oligonucleotide group into a free oligonucleotide. For non-degradable conjugation, the delivery group can be connected to the sense strand of the single-stranded oligonucleotide or the double-stranded oligonucleotide group, so as to minimize the impact of conjugation on the activity of the double-stranded oligonucleotide group. The targeting group can be connected to the oligonucleotide group via a suitable linker group, which can be selected by a person skilled in the art according to the specific type of the targeting group. For example, when the targeting group is a group targeting the surface receptor of hepatocytes, the types of these linker groups, targeting groups, and the connection methods with the oligonucleotide can be referred to in the disclosure of WO2015006740A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the targeting group can be a ligand group commonly used in the field of oligonucleotide administration, such as various ligand groups 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 targeting groups is selected from a ligand group capable of binding to a cell surface receptor that expresses APOC3 mRNA. In some embodiments, at least one or each of the targeting groups is selected from a small molecule ligand group capable of having affinity for an asialoglycoprotein receptor on the surface of hepatocytes. In some embodiments, at least one or each of the targeting groups is selected from a group capable of increasing the biocompatibility of the oligonucleotide conjugate in the central nervous system. In some embodiments, at least one or each of the targeting groups is selected from a group consisting of a ligand group capable of binding to a surface receptor of a mammalian liver parenchymal cell. In some embodiments, each of the targeting groups is independently a ligand having affinity for an asialoglycoprotein receptor on the surface of a mammalian liver cell. In some embodiments, each of the targeting groups is independently an asialoglycoprotein or a saccharide. In some embodiments, each of the targeting groups is independently selected from a group consisting of D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, a-D-mannofuranose, β-D-mannofuranose, a-D-mannopyranose, β-D-mannopyranose, a-D-glucopyranose, β-D-glucopyranose, a-D-glucoruranose, β-D-glucoruranose, a-D-fructofuranose, a-D-fructopyranose, a-D-galactopyranose, β-D-galactopyranose, a-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-0-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L- pyranoglucose, 4,6-dideoxy-4-formamido-2,3-di-0-methyl-D-mannopyranose, 2-deoxy-2- sulfonamido-D-glucopyranose, N-glycolyl-a-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4-tri-0-acetyl-1-thio-6-0-trityl-a-D-glucopyranoside methyl ester, 4-thio-β-D- galactopyranose, 3,4,6,7-tetra-0-acetyl-2-deoxy-1,5-dithio-a-D-glucopyranoside ethyl ester, 2,5- anhydro-D-allosonitrile, ribose, D-ribose, D-4-thioribose, L-ribose, L-4-thioribose, and a group formed by removing one atom or group from one of the foregoing. In some embodiments, at least one or each of the targeting groups is a galactosyl group or an N-acetylgalactosamine group. In some embodiments, each of the targeting groups is an N-acetylgalactosamine group. In some embodiments, the oligonucleotide group is capable of modulating the expression level of APOC3 mRNA in a liver parenchymal cell. The delivery group in the oligonucleotide conjugates of the present disclosure can be various delivery groups known to those skilled in the art of oligonucleotide drugs. In some embodiments, the linking group in the oligonucleotide conjugates of the present disclosure has a structure as shown in formula (301): wherein k is an integer from 1 to 5, represents the site of covalent attachment of a group; all L A attached to L C the same atom in L A each L C is independently attached to a different atom in L In some embodiments, L C has the structure of -NH-C(H) n301 (CH2O-) k as shown in the structure of formula (301), wherein k is an integer from 1 to 3, n301=3-k; L B has a length of 5-20 atoms. In some embodiments, each L A is independently a straight chain alkylene having a length of 5-20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more selected from the group consisting of C(O), NH, O, S, 1,2,3-triazolylene, butadienylene imine. In some embodiments, L A has the structure of formula (302) comprising an amide bond, L B has the structure of formula (303): wherein n 302 , q 302 and p 302 are each independently an integer from 2 to 6, optionally n 302 , q 302 and p 302 are each independently 2 or 3; n 303 is an integer from 4 to 16, optionally n 303 is an integer from 8 to 12, represents the site of covalent attachment of a group. In some embodiments, the linker group has the structure of formula (304) or formula (305): In the linker group, each L A is attached to one of the targeting groups through an ether linkage, and is attached through the oxygen atom of the hydroxyl group in the L C moiety to the L C moiety to form an ether linkage; L B is attached through the carbonyl group in formula (303) to the nitrogen atom of the amino group in the L C moiety to form an amide linkage, and is attached through the oxygen atom in formula (303) to the double stranded oligonucleotide group through an oxygen atom to form a phosphonate or thiophosphonate linkage. In some embodiments, the oligonucleotide conjugate provided herein has the structure of formula (305A): wherein, Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the linking group in the oligonucleotide conjugate of the present disclosure has a structure represented by formula (306): wherein, n 306 is an integer from 0 to 3, each p 306 is independently an integer from 1 to 6, represents a site where groups are covalently connected; the linking group is connected to the targeting group via an oxygen atom marked by * to form an ether bond; at least one of the oxygen atoms marked by # in the linking group is connected to the double-stranded oligonucleotide to form a phosphonate bond or a phosphorothioate bond, and the rest of the oxygen atoms marked by # are connected to hydrogen atoms to form hydroxyl groups or to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (307): wherein, Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (308): wherein, n 308 is an integer selected from 2 to 4; each m 308 is independently an integer selected from 2 to 5; each R 308 is independently a hydrogen atom, a methyl group or an ethyl group, or 2 R 308 on the same carbon atom together form a carbonyl group; one of the groups represented by A0, respectively, is an oligonucleotide group formed by removing one atom or group of atoms from a single-stranded oligonucleotide or a double-stranded oligonucleotide described in the present disclosure; all the remaining A0are targeting groups, each of which is the same or different, and the definition and selection range thereof are as described above. In some embodiments, each targeting group is independently selected from one of the ligands having affinity to the asialoglycoprotein receptor on the surface of mammalian liver parenchymal cells. each L1is independently a divalent linking group having a length of 1-70 or 3-25 atoms; represents a site where groups are covalently connected. In some embodiments, each L1is independently a straight-chain alkylene of 1-70 or 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more from the group consisting of C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenylene, C2-C 10 alkynylene, C6-C 10 arylene, C3-C 18 heterocyclylene, and C5-C 10 heteroarylene; and the straight-chain alkylene can optionally have substituents of any one or more from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10 haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkylphenyl, -C1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halogen substituent, -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), -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-C10 alkylphenyl, C(O)C1-C 10 haloalkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). As used herein, "alkyl" refers to straight and branched chains, typically of 1 to 20 carbon atoms, for example, 1 to 10 carbon atoms, such as 1 to 8 or 1 to 6 carbon atoms. For example, C1-C6 alkyl includes straight and branched chain alkyl groups of 1 to 6 carbon atoms. When reference is made to an alkyl group having a specific number of carbons, it is intended to encompass all possible branched and straight chain isomers of that number of carbons; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, iso-butyl, and t-butyl; "propyl" includes n-propyl and iso-propyl. Alkylene is a subset of alkyl, referring to the same groups as alkyl, but having two points of attachment. As used herein, "saturated alkyl" refers to alkyl groups in which all carbon atoms are connected by single bonds, containing no carbon-carbon double and / or triple bonds. As used herein, "alkenyl" refers to unsaturated straight or branched chain hydrocarbon groups having at least one carbon-carbon double bond obtained by the removal of a hydrogen atom from one of the carbon atoms of a parent alkyl group. The group can be in the cis- or trans- configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyl, for example, but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, and the like. In certain embodiments, alkenyl groups have 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkenylene is a subset of alkenyl, referring to the same groups as alkenyl, but having two points of attachment. 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 atoms 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, for example but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms, while in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkynylene is a subset of alkynyl, referring to the same moieties as alkynyl, but with two points of attachment. As used herein, "alkoxy" refers to an alkyl group of the specified number of carbon atoms linked via an oxygen bridge, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups typically have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms linked via an oxygen bridge. As used herein, "aryl" refers to a radical derived by removing a hydrogen atom from a carbon atom of an aromatic, monocyclic or polycyclic hydrocarbon ring system. The aromatic, monocyclic or polycyclic hydrocarbon ring system contains only carbon and hydrogen atoms, with 6 to 18 carbon atoms in the ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic, delocalized (4n+2) pi-electron system, according to Hückel theory. Aryl includes, but is not limited to, phenyl, fluorenyl, and naphthyl groups, and the like. Alkenyl is a subset of aryl, referring to the same moieties as aryl, but with two points of attachment. "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring radical, comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic system, wherein at least one ring in the ring system is fully unsaturated, i.e., comprising a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Heteroaryls include fused ring or bridged ring systems. In some embodiments, the heteroatoms in the heteroaryl are oxidized heteroatoms. In some embodiments, the heteroaryl contains one or more nitrogen atoms. In some embodiments, one or more of the nitrogen atoms in the heteroaryl are quaternized nitrogen atoms. The heteroaryl is attached to the remainder of the molecule via any ring atom. Examples of heteroaryl groups include, but are not limited to: 1,2,3-triazolyl, aziridine, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, and 1,4-benzodioxylalkyl. ioxanyl), benzonaphthylfuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophenyl, benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cinnolinyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H- Cyclopentano[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienoyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5 6,7,8,9,10-Hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indole, isoyindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl (5,8-methano-5,6,7,8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, 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-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl / thienyl. In the foregoing or hereafter, a "substituted" group, such as a substituted alkyl, substituted alkoxy, substituted amino, substituted aliphatic, substituted heteroaliphatic, substituted acyl, substituted aryl, or substituted heteroaryl. Where not otherwise specified, a "substituted" group means that one or more hydrogen atoms of the group are replaced with one or more substituents. For example, a "substituted alkoxy" means an alkoxy group in which one or more of the hydrogen atoms are replaced with a substituent. Those skilled in the art will appreciate that a wide variety of substituents can be present in the compounds useful in the present disclosure, so long as the presence of the substituent does not significantly affect the functionality of the present disclosure, and the purposes of the present disclosure are achieved. In some embodiments, the substituents are selected from the group consisting of: C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, -OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C10 haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkylphenyl, -C1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halo substituent, -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), -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)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). In some embodiments, the substituent is one of -C1-C3alkyl, -C6-C8aryl, -O-C1-C3alkyl, -O-(C1-C3alkyl)phenyl, halo, -OH, -NH2, -CN, or -NO2. Those skilled in the art will appreciate that, for any group containing one or more substituents, such groups do not intend to introduce any substitution or substitution pattern that is not synthetically practical, synthetically feasible, and / or synthetically stable. A skilled artisan will appreciate that, although L1is defined for convenience as being a linker formed by the initial replacement or substitution of a linear alkylene, it can not be a linear group or an amine or alkenyl resulting from the replacement and / or substitution described above. Unless otherwise indicated, the "length" of any group in a chemical structure depicted in the disclosure refers to the number of atoms in the longest chain of atoms in the group, not counting hydrogen atoms; in the case of groups involving two atoms connected in multiple ways (e.g., two atoms belonging to the same cyclic group, such that there are at least 2 chains of atoms that include the two atoms), the length is counted as the shortest chain of atoms between the two atoms. For example, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4-phenylene, 1,4-piperazinediyl are each counted as 4 atoms in length, while 1,2-cyclopentanediyl is counted as only 2 atoms in length. The role of L1covalently linked to A0representing an oligonucleotide group is to covalently link the oligonucleotide group to the targeting group, to enable the oligonucleotide conjugate comprising the oligonucleotide group to enter a cell expressing APOC3 mRNA via the targeting of the targeting group, and not to interfere with the APOC3 mRNA level modulating effect of the oligonucleotide group after entering the cell expressing APOC3 mRNA. Thus, in some embodiments, L1covalently linked to A0representing an oligonucleotide group has a length of 3-20 atoms, or 4-15 atoms, or 5-12 atoms. In some embodiments, L1covalently linked to A0representing an oligonucleotide group is selected from one or more of the following combinations of A1, A2, A4, A5, A10, A16, A18, and A19with a phosphate group or a modified phosphate group: wherein j1is an integer from 2 to 10; denotes the site of covalent attachment of a group. In some embodiments, R2is selected from at least two of the following combinations of A1, A2, A4, A10, and A16with a phosphate group or a modified phosphate group; in some embodiments, R2is selected from at least two of the following combinations of A1, A2, A10with a phosphate group or a modified phosphate group. In some embodiments, L1covalently linked to A0representing an oligonucleotide group has a structure as shown in formula (B1), (B2), (B3), or (B4): wherein, denotes the site of covalent attachment of a group, L B1 and L B2the same or different, are independently selected from one or any combination of the following groups: -(CH2) q1 -CH(OH)-, -CH(CH2OH)-, -NH-, -O-, -S-, 1,4-cyclohexanediyl, 1,4-piperidinediyl, 1,4- phenylenediyl, 1,4-piperazinediyl, pyrrolidinediyl, wherein q1 is an integer from 1 to 6, L B1 and L B2 each independently have a length of 1 to 20 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 10 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 6 atoms. L B3 is selected from one of a phosphonate group, a thiophosphonate group, a dithiophosphonate group, and is covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the sense strand or the antisense strand of the double-stranded oligonucleotide group. In some embodiments, L B3 is a phosphonate group, and is covalently attached to the oxygen atom remaining after removal of a hydrogen atom from the ribose 5' position hydroxyl group of the 5' terminal nucleotide, or the ribose 3' position hydroxyl group of the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group. In some embodiments, in the case that the oligonucleotide conjugate of the disclosure is prepared by a process of solid phase synthesis, L1covalently attached to A0representing the oligonucleotide group needs to contain simultaneously a linking site to N on the nitrogen-containing backbone, a linking site to the oligonucleotide group and a functional group capable of linking to a solid support. In some embodiments, the site linked to N on the nitrogen-containing backbone in L1covalently attached to A0representing the oligonucleotide group forms an amide bond with N, the oligonucleotide group is covalently attached through a phosphonate bond, and the functional group capable of linking to a solid support is a hydroxyl group or an amino group. In some embodiments, R2is B5, B6, B5’ or B6’: wherein, represents the site of covalent bond linkage of the group. q2may have a value in the range of an integer from 1 to 10, and in some embodiments, q2is an integer from 1 to 5. The role of L1 covalently linked to A0 representing a targeting group is to place the targeting group in a suitable spatial position for better binding to the receptor, thus specifically targeting and entering the relevant cellular tissue. Therefore, L1 covalently linked to A0 representing a targeting group can be used in the present disclosure as long as it has a suitable length and the chemical properties do not significantly affect the delivery. In some embodiments, each L1 covalently linked to A0 representing a targeting group is independently a divalent linking group of 3-25 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is 4-15 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is 5-10 atoms in length. In some embodiments, each L1 covalently linked to A0 representing a targeting group is the same. In some embodiments, each L1 covalently linked to A0 representing a targeting group is the same or different, and is independently selected from the group consisting of the groups represented by formulae (L3)-(L18) and any combination of connections thereof: wherein each j1 is an integer from 2 to 10; each R’ is independently a hydrogen atom or a C1-C3 alkyl group, represents the site of covalent attachment of the group. For ease of synthesis and / or chemical stability, in some embodiments, each L1 covalently linked to A0 representing a targeting group is independently a combination of connections of at least 2 connection units, each connection unit independently having a structure represented by any one of formulae (L3)-(L7). In some embodiments, each connection unit independently has a structure represented by any one of formulae (L3), (L4), and (L7). For ease of synthesis, in some embodiments, each L1 covalently linked to A0 representing a targeting group includes a carbonyl group attached to the nitrogen atom represented in formula (308). In some embodiments, each L1 covalently linked to A0 representing a targeting group independently has a structure represented by formula (L20) or (L21): wherein 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 a targeting group is the same. In the conjugate of the present disclosure, the number of targeting groups and the spacing between the targeting groups are such that a proper spatial configuration of multiple targeting groups is provided. To this end, n308and each m308are independently an integer selected from 2-4. In some embodiments, n308is 3 or 4, such that the number of targeting groups in the conjugate of the present disclosure is 3 or 4, which can better bind to the surface receptors of hepatocytes. In some embodiments, n308is 3 and each m308is independently 3 or 4. As understood by one skilled in the art, each R 308 is a hydrogen atom, a methyl group or an ethyl group, without affecting the delivery effect of the oligonucleotide conjugate, and each R 308 is a hydrogen atom. In the conjugate of the present disclosure, each targeting group is the same or different, and is independently selected from a ligand group capable of binding to a cell surface receptor. In some embodiments, at least one or each targeting group is a group capable of targeting the liver. In some embodiments, at least one or each targeting group is one of the ligand groups capable of having affinity to a receptor on the surface of a mammalian hepatocyte. In some embodiments, at least one or each targeting group is one of the ligand groups capable of having affinity to an asialoglycoprotein receptor (ASGPR) on the surface of a mammalian hepatocyte. In some embodiments, each targeting group is a galactose group or an N-acetylgalactosamine group formed by removing one atom or group from a galactose group or an N-acetylgalactosamine group. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure represented by formula (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 by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present 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 sense strand of the double-stranded oligonucleotide group. In some embodiments, the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is a reversed deoxy-abasic nucleotide, and the P atom shown in the above structural formula is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group of the ribose ring of the 3' terminal reversed deoxy-abasic nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu with a methylene group. In some embodiments, the P atom shown in the above structural formula (403)-(422) is covalently linked to the oxygen atom remaining after removing one hydrogen atom from the 3' position hydroxyl group of the ribose of the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu. In some embodiments, the P atom shown in the above structural formula (403)-(422) is covalently linked to the oxygen atom of the reversed deoxy-abasic nucleotide (ia) shown in the above structural formula (35) linked to the ribose ring by a methylene group at the 3' terminal of the sense strand of the siRNA represented by Nu, thereby covalently linking to the sense strand of the siRNA. In some embodiments, the oligonucleotide group comprised in the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by removing one atom or group of atoms from an siRNA, in which case the oligonucleotide conjugate of the present disclosure is also referred to as an siRNA conjugate. In some embodiments, the oligonucleotide group comprised in the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by an siRNA listed in Table 1. The siRNA conjugate comprising these siRNA groups exhibits excellent stability and high APOC3 mRNA inhibitory activity. In some embodiments, the oligonucleotide conjugate of the present disclosure is one of Conjugate 1-Conjugate 7 listed in Table 2. Preparation of the oligonucleotide conjugate of the present disclosure The oligonucleotide conjugates described in the present disclosure can be prepared by various suitable methods by those skilled in the art. For example, the oligonucleotide conjugates described in the present disclosure can be synthesized by introducing the delivery group by methods that have been described in detail in the prior art when the nucleoside monomers are linked one by one according to the sequence and modification scheme of the single-stranded oligonucleotide or the sense strand and the antisense strand of the double-stranded oligonucleotide described in the present disclosure by the solid-phase synthesis method. For example, the preparation methods of various oligonucleotide conjugates are described in detail in WO2015006740A2. In the case of siRNA as the double-stranded oligonucleotide, the oligonucleotide conjugates of the present disclosure can also be obtained by means well known to those skilled in the art. The preparation method of the structure shown in formula (305A) is described in WO2014025805A1, and the preparation method of the structure shown in formula (307) is described in Rajeev et al., ChemBioChem 2015, 16, 903-908. The preparation method of the oligonucleotide conjugate shown in formula (308) is also disclosed in detail in Chinese patent application CN110959011A. The contents of the above documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salt In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate described in the present disclosure. The pharmaceutically acceptable salt is known to those skilled in the art. By forming a salt form, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate described in the present disclosure can show better solubility, bioavailability or stability than the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate itself. In some embodiments, in the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate described in the present disclosure, the non-bridging oxygen atom or the sulfur atom in the phosphodiester bond or the phosphorothioate bond connecting between each adjacent nucleotide carries a negative charge, which can exist in the form of a hydroxyl group or a thiol group, and the hydrogen ion in the hydroxyl group or the thiol group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, an ammonium ion NH4 +one of the organic ammonium cations. Further, there can also be a salt-forming group in the delivery group, such as a phosphate group. For the purpose of improving solubility and / or improving bioavailability, in some embodiments, the pharmaceutically acceptable salt is a water-soluble salt of part or all of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the water-soluble salt can be an amine salt, an alkali metal salt, or an alkaline earth metal salt, in some embodiments, the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is selected from a potassium salt or a sodium salt, and the alkaline earth metal salt is selected from a magnesium salt or a calcium salt. In some embodiments, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or a N,N-diisopropylethylamine salt. In some embodiments, the pharmaceutically acceptable salt is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate, the salt being one or more of a methylamine salt, a triethylamine salt, or a sodium salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. In some embodiments, the pharmaceutically acceptable salt of the double-stranded oligonucleotide or the oligonucleotide conjugate is a mixture of a methylamine salt and an ammonium salt of the double-stranded oligonucleotide or the oligonucleotide conjugate. Pharmaceutical composition In another aspect, the present disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salts thereof provided by the present disclosure, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is one or more of various ingredients conventionally employed in the art, such as one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and other pharmaceutically acceptable carriers. For example, when the pharmaceutical composition is an injection solution, the pharmaceutically acceptable excipient is a solvent, such as one or more of deionized water, water for injection, physiological saline, ethanol, an aqueous ethanol solution, a pH buffer. The pH buffer can be a tris-hydroxymethyl aminomethane hydrochloride buffer having a pH value of 7.5-8.5 and / or a phosphate buffer having a pH value of 5.5-8.5, such as a phosphate buffer having a pH value of 5.5-8.5. The amount of the solvent is adjusted according to the desired concentration of the solution, and 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, based on the oligonucleotide group. The protective agent can be at least one of inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The protective agent can be contained in an amount of 0.01 to 30% by weight, based on the total weight of the pharmaceutical composition. The osmotic pressure adjusting agent can be sodium chloride and / or potassium chloride. The osmotic pressure adjusting agent can be contained in an amount such that the osmotic pressure of the pharmaceutical composition is 200 to 700 milliosmoles per kilogram (mOsm / kg). The amount of the osmotic pressure adjusting agent can be easily determined by one skilled in the art according to the desired osmotic pressure. In some embodiments, the formulation of the pharmaceutical composition can be adjusted in dosage during administration according to the administration method. In some embodiments, the pharmaceutical composition can be a liquid formulation, such as an injection solution, or a lyophilized powder formulation that is mixed with a liquid excipient to prepare a liquid formulation for administration. The liquid formulation can be, but is not limited to, used for subcutaneous, intramuscular, or intravenous injection, or can be, but is not limited to, delivered to the lung by spraying, or to other organ tissues (e.g., the liver) by spraying through the lung, or by oral administration, etc. In some embodiments, the pharmaceutical composition is administered by subcutaneous injection. The pharmaceutically acceptable additional carrier can be one or more of the carriers conventionally used in the field of double-stranded oligonucleotide administration, such as, but not limited to, magnetic nanoparticles (e.g., nanoparticles based on Fe3O4 or Fe2O3), 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), poly(2-aminoethyl ethylene phosphate) (PPEEA), and poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), and derivatives thereof. In some embodiments, the content of the oligonucleotide and the pharmaceutically acceptable carrier in the pharmaceutical composition is not particularly required, and in some embodiments, the weight ratio of the oligonucleotide or the oligonucleotide conjugate and the pharmaceutically acceptable carrier can be 1: (1-500), and in some embodiments, the above weight ratio is 1: (1-50). In some embodiments, the pharmaceutical composition can be in the form of a liposome preparation. In some embodiments, the pharmaceutically acceptable carrier used in the liposome preparation comprises an amine-containing transfection compound (hereinafter can also be referred to as an organic amine), a helper lipid, and / or a pegylated lipid. Among them, the organic amine, the helper lipid, and the pegylated lipid can be selected from one or more of the amine-containing transfection compounds or pharmaceutically acceptable salts or derivatives thereof, the helper lipids, and the pegylated lipids described in Chinese Patent Application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine can be a compound represented by formula (201) or a pharmaceutically acceptable salt thereof described in Chinese Patent Application CN103380113A: wherein: X 101 and X 102 each independently is O, S, N-A, or C-A, wherein A is hydrogen or a C1-C 20 hydrocarbon chain; Y 101 and Z 101 each independently is 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 independently is hydrogen, a cyclic or acyclic, substituted or unsubstituted, branched or straight chain aliphatic group, a cyclic or acyclic, substituted or unsubstituted, branched or straight chain heteroaliphatic group, a substituted or unsubstituted, branched or straight chain acyl group, a substituted or unsubstituted, branched or straight chain aryl group, a substituted or unsubstituted, branched or straight chain 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; wherein, if m=p=0, R 102 is hydrogen; and if at least one of n or m is 2, then R 103and the nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): wherein g, e, and f are each independently an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some embodiments, R 103 is a polyamine. In other embodiments, R 103 is a ketal. In some embodiments, R 101 and R 102 each independently is any substituted or unsubstituted, branched or straight chain alkyl or alkenyl group having from 3 to about 20 carbon atoms, such as from 8 to about 18 carbon atoms, and from 0 to 4 double bonds, such as from 0 to 2 double bonds. In some embodiments, if each of n and m independently has a value of 1 or 3, then R 103 may be any one of the following formula (204) - formula (213): wherein in formula (204) - formula (213), g, e, and f are each independently an integer from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * shows a possible point of attachment to the nitrogen atom in formula (201), wherein each H at any * position can be replaced to achieve attachment to the nitrogen atom in formula (201). 103 A person skilled in the art can obtain the compound shown in formula (201) by any reasonable method. In some embodiments, the compound shown in 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 helper lipid is cholesterol, an analog of cholesterol, and / or a derivative of cholesterol; the pegylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio among the organic amine, the helper lipid, and the pegylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, can be (50-70):(20-40):(3-20). ​In some embodiments, the pharmaceutical composition particles formed from the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, 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 the present disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide or oligonucleotide conjugate to the total lipids (e.g., organic amine, helper lipid, and / or PEGylated lipid) is in the range of 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 1:17, 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 oligonucleotide or oligonucleotide conjugate of the present disclosure to the 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 can exist independently at the time of sale and in the form of a liquid preparation at the time of use. In some embodiments, the pharmaceutical composition formed from the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned pharmaceutically acceptable carrier can be prepared according to various known methods, except that the existing siRNA is replaced with the oligonucleotide or oligonucleotide conjugate of the present disclosure; in some embodiments, it can be prepared according to the following method: The organic amine, helper lipid, and PEGylated lipid are suspended in alcohol in the above-mentioned molar ratio and mixed to obtain a lipid solution; the amount of alcohol is such that the total mass concentration of the obtained lipid solution is 2-25 mg / mL, for example, it can be 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, polyethylene glycol 400, for example, it can be ethanol. The oligonucleotide or oligonucleotide conjugate provided by the present 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, it can be 0.1-0.2M, the pH of the buffer salt solution is adjusted to 4.0-5.5, for example, it can be 5.0-5.2, and the amount of the buffer salt solution is used to ensure that the concentration of the oligonucleotide in the oligonucleotide or oligonucleotide conjugate is not more than 0.6mg / mL, for example, it can be 0.2-0.4mg / mL. The buffer salt is selected from one or more of soluble acetate, soluble citrate, for example, it can be sodium acetate and / or potassium acetate. The lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate are mixed, and the product obtained after mixing is incubated at 40-60℃ for at least 2 minutes, for example, it can be 5-30 minutes, to obtain the liposome preparation after incubation. The volume ratio of the lipid solution to the aqueous solution of the oligonucleotide or oligonucleotide conjugate is 1:(2-5). The liposome preparation after incubation is concentrated or diluted, impurities are removed, and sterilization is performed to obtain the pharmaceutical composition provided by the present disclosure, and the physicochemical parameters thereof are as follows: the pH value is 6.5-8, the encapsulation efficiency is not less than 80%, the particle size is 40-200nm, the polydispersity index is not higher than 0.30, and the osmotic pressure is 250-400mOsm / kg; for example, the physicochemical parameters can be as follows: the pH value is 7.2-7.6, the encapsulation efficiency is not less than 90%, the particle size is 60-100nm, the polydispersity index is not higher than 0.20, and the osmotic pressure is 300-400mOsm / kg. The concentration or dilution can be performed before, after or simultaneously with the removal of impurities. The method for removing impurities can use various existing methods, for example, a tangential flow system or a hollow fiber column can be used, and the ultrafiltration is performed under the condition of 100K Da, and the ultrafiltration exchange solution is a phosphate buffer solution (PBS) with a pH of 7.4. The method for sterilization can use various existing methods, for example, sterilization can be performed by filtering through a 0.22μm filter. Applications of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt and pharmaceutical composition of the present disclosure The present disclosure also provides the use of the single-stranded oligonucleotide of the present disclosure, the double-stranded oligonucleotide of the present disclosure, the oligonucleotide conjugate of the present disclosure and the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease or symptom related to the APOC3 mRNA level of the target gene expression. In some embodiments, the disease or symptom related to the APOC3 mRNA level is dyslipidemia; or the dyslipidemia is hypercholesterolemia, hypertriglyceridemia or atherosclerosis. The present disclosure also provides a method of treating and / or preventing a disease or condition associated with APOC3 mRNA levels, comprising administering to a subject in need thereof an effective amount of one or more of the double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts thereof, and the pharmaceutical compositions of the present disclosure. Further, the present disclosure also provides a method of modulating the level of APOC3 mRNA expression in a cell, comprising contacting the cell with an effective amount of one or more of the double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts thereof, and the pharmaceutical compositions of the present disclosure. The term "administering / administration" as used herein refers to the placement of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure into the subject's body by a method or route which results in at least partial localization of the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure to the desired site(s) to produce the desired effect. Suitable routes of administration for the methods of the present disclosure include local and systemic administration. In general, local administration results in delivery of more of the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure to a particular site as compared to the entire body of the subject; while systemic administration results in delivery of the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure to substantially the entire body of the subject. The one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure can be administered to a subject by 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 topical administration (including buccal administration and sublingual administration). The frequency of administration can be one or more times per day, per week, per two weeks, per three weeks, per month, or per year. The dosage of the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure can be a conventional dosage in the art, which can be determined according to various parameters, especially the age, weight, and sex of the subject. Toxicity and therapeutic efficacy of the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. In administering the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and / or pharmaceutical compositions of the disclosure, for example, to male or female, 6-12 week old, 18-25 g body weight C57BL / 6J or C3H / HeNCrlVr mice, the amount of siRNA in the siRNA, pharmaceutical composition, and / or siRNA conjugate can 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 still further embodiments 0.1-15 mg / kg body weight, in yet further embodiments 0.1-10 mg / kg body weight, for siRNA conjugates formed with pharmaceutically acceptable conjugate molecules. The above amounts can be preferred in administering the siRNA, pharmaceutical composition, and / or siRNA conjugate of the disclosure. The amount of double-stranded oligonucleotide in one or more of the provided oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions provided by the methods of the disclosure to inhibit expression of APOC3 mRNA in a cell is readily determined by one of skill in the art depending on the desired effect to be obtained. For example, in some embodiments, the oligonucleotide is an siRNA, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the provided siRNA conjugate is an amount sufficient to reduce the level of APOC3 mRNA and result in an extracellular concentration of 1 pM to 1 mM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM or to about 5 nM at the surface of the target cell. The amount required to achieve this local concentration will vary depending on various factors including the method of delivery, the site of delivery, the number of cell layers between the site of delivery and the target cell or tissue, whether the delivery is local or systemic, etc. The concentration at the site of delivery can be significantly higher than the concentration at the surface of the target cell or tissue. Kits The disclosure provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions provided by the disclosure. In some embodiments, the kits described herein can provide one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the disclosure in one container. In some embodiments, the kits described herein can include one container providing a pharmaceutically acceptable excipient. In some embodiments, the kits can further include other ingredients such as stabilizers or preservatives, etc. In some embodiments, the kits described herein can include at least one other therapeutic agent in a container different from 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 kits can include instructions for admixing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the disclosure with a pharmaceutically acceptable carrier and / or excipient or other ingredients, if any. In the kits of the disclosure, the one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and / or pharmaceutically acceptable excipients can be provided in any form, such as liquid form, dry form, or lyophilized form. In some embodiments, the 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 can be provided in the kits of the disclosure. The present disclosure will be further described by way of Examples, but the present disclosure is not in any way limited thereto. Without wishing to be limited, the present application is further described in detail in the following embodiments and examples of exemplary embodiments of double-stranded oligonucleotides in the pharmaceutical compositions, oligonucleotides and / or oligonucleotide conjugates of the present disclosure, which are exemplary embodiments of small interfering RNA (siRNA). In this case, the double-stranded oligonucleotides, the pharmaceutical compositions and the oligonucleotide conjugates of the present disclosure are siRNA, the pharmaceutical compositions comprising siRNA and the siRNA conjugates, respectively. In the context of the present disclosure, for ease of description, the siRNA, the pharmaceutical compositions comprising siRNA and the siRNA conjugates in these embodiments are also referred to as siRNA of the present disclosure, the pharmaceutical compositions of the present disclosure and the siRNA conjugates of the present disclosure. This does not mean that the double-stranded oligonucleotides of the present disclosure can only be siRNA, on the contrary, the double-stranded oligonucleotides can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA) and the like. It is envisaged that, based on the detailed description of siRNA, the pharmaceutical compositions comprising siRNA and the siRNA conjugates, other double-stranded oligonucleotides will similarly function when used alone, or form the pharmaceutical compositions and / or oligonucleotide conjugates described in the present disclosure. Examples Unless otherwise specified, the reagents and culture used in the following examples are commercially available, and the nucleic acid electrophoresis, real-time PCR and other operations are carried out according to the methods described in Molecular Cloning (Cold Spring Harbor Laboratory (1989)). Preparation of siRNA conjugates provided by the present disclosure According to the preparation method described in Preparation Example 13 of CN110959011A, the following conjugates 1-7 in Table 2 were prepared, the only difference being that the sense strand and the antisense strand of the siRNA contained in each siRNA conjugate are shown in Table 2; for the nucleic acid sequences having the sense strand and the antisense strand sequences of the siRNA numbered as conjugates 1-7 in Table 2 below, the nucleoside phosphoramidite monomers were connected one by one to synthesize the sense strand and the antisense strand of the siRNA conjugate. After the synthesis was completed, the synthesized product was first purified by ion exchange with a strong anion exchange filler self-packed column, and then desalted by HiPrep 26 / 13 Desalting desalting pre-packed column. The conjugates 1-7 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 oxygen atom of the inverted deoxy abasic nucleotide (ia) shown in formula (35) connected to the ribose ring by a methylene group at the 3' end of the sense strand of the siRNA represented by Nu, thereby covalently linking to the sense strand of the siRNA. And the siRNA contained in the siRNA conjugate has the siRNA sequence corresponding to the conjugate 1-7 in Table 2; After each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (calculated as siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight was detected by liquid chromatography-mass spectrometry (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters Company, model: LCT Premier). Among them, the theoretical value of the sense strand of conjugate 1 is 7441.406, and the measured value is 7440.36, the theoretical value of the antisense strand is 6900.626, and the measured value is 6899.66; the theoretical value of the sense strand of conjugate 2 is 7486.506, and the measured value is 7485.79, the theoretical value of the antisense strand is 6887.524, and the measured value is 6886.78; the theoretical value of the sense strand of conjugate 3 is 7409.353, and the measured value is 7408.36, the theoretical value of the antisense strand is 6924.656, and the measured value is 6923.85, the theoretical value of the sense strand of conjugate 4 is 7453.442, and the measured value is 7454.32, the theoretical value of the antisense strand is 6900.626, and the measured value is 6901.45; the theoretical value of the sense strand of conjugate 5 is 7421.0, and the measured value is 7421.0, the theoretical value of the antisense strand is 7000.55, and the measured value is 7000.0; the theoretical value of the sense strand of conjugate 6 is 7421.0, and the measured value is 7421.0, the theoretical value of the antisense strand is 7000.55, and the measured value is 7000.0; the theoretical value of the sense strand of conjugate 7 is 7453.06, and the measured value is 7453.0, the theoretical value of the antisense strand is 6976.52, and the measured value is 6976.0. The measured value is consistent with the theoretical value, indicating that the synthesized conjugates 1-7 contain the target designed double-stranded nucleic acid sequence. Table 2 siRNA sequence in siRNA conjugate wherein the capital letters C, G, U, A and T represent the base composition of the nucleotides; the lower case letter m represents that the nucleotide represented by the capital letter adjacent to the left of the letter m is a 2'-methoxy modified nucleotide; the lower case letter f represents that the nucleotide represented by the capital letter adjacent to the left of the letter f is a 2'-fluoro modified nucleotide; the letter combination moe represents that the nucleotide represented by the capital letter adjacent to the left of the letter combination moe is a ribose 2'-0-methoxyethyl modified nucleotide; the lower case letter s represents that the linkage between the nucleotides represented by the two capital letters adjacent to the left and right of the letter s is a phosphorothioate linkage; the lower case letter d represents that the nucleotide represented by the capital letter adjacent to the right of the letter d is a deoxyribonucleotide; the letter combination VP represents that the nucleotide represented by the capital letter adjacent to the right of the letter combination VP is a 5'-vinylphosphonate (E-VP) modified nucleotide; ia represents an inverted abasic deoxyribonucleotide. Synthesis of Comparative Preparation Example 1 Reference Conjugate 1 Reference Conjugate 1 in Table 2 was prepared by solid phase synthesis according to the same method as in Preparation Example 1. Reference Conjugate 1 is a sodium salt of a compound having the structure shown in Formula (403), wherein the conjugate group is attached to the ribose 3' position of the terminal nucleotide of the sense strand of the siRNA represented by Nu. And the siRNA sequence contained in the reference conjugate has the siRNA sequence corresponding to reference conjugate 1 in Table 2, and reference conjugate 1 has the same sequence as conjugate 1, conjugate 7, but the modification scheme is different. Experimental Example 1 In vivo inhibitory activity of the conjugates of the present disclosure The prepared conjugates 1-4 and reference conjugate 1 were dissolved in PBS to prepare an injection solution at 5.0 mg / mL. B6;CBA-Tg(APOC3)3707Bres / J mice purchased from JAX were caged in a one male to one female ratio, and after the pups were more than 21 days old, they were weaned, and serum lipid detection was used to screen hApoC3 positive mice, and the serum TG (Triglycerides) value was detected, and female mice with TG value > 2 mmol / L were used as positive mice for the test, which is hereinafter referred to as hAPOC3 transgenic mice. Thirty hAPOC3 transgenic mice were randomly divided into 5 groups of 5 mice each, designated as test groups 1-5 and a blank control group. The mice in test groups 1-5 were given an injection solution of conjugates 1-4 and reference conjugate 1 by subcutaneous injection in the abdomen at a dosage of 3 mg / kg of mouse body weight, and the mice in the blank control group were given a PBS solution at a dosage of 5 mL / kg of mouse body weight. All animals were taken blood from the orbit once before dosing, and each group was taken blood once at the 8th day, the 14th day, the 31st day, the 43rd day and the 57th day after dosing, respectively, with the day of dosing as the 1st day. The animals were fasted for 4-6 hours before blood sampling, and EDTA K2 anticoagulant blood collection tubes were used for all blood sampling operations. After centrifugation at 1800g for 15 min at 2-8°C, the plasma was separated from the supernatant, and the APOC3 protein level was detected using a human APOC3 ELISA detection kit (Thermo, EHAPOC3). The inhibition rate of the plasma APOC3 protein of the test group was calculated based on the pre-dose value: Inhibition rate of the plasma APOC3 protein of the test group = (1 - post-dose value / pre-dose value) * 100%. The results are summarized in Table 4. Table 4 Inhibition rate of APOC3 protein in mice As can be seen from Table 4, the conjugates provided by the present disclosure can maintain the inhibitory activity on the plasma APOC3 protein in vivo for a long time. In the in vivo test of the hAPOC3 transgenic mice, the conjugates provided by the present disclosure showed a good inhibition rate on the APOC3 mRNA during the entire test period of 57 days, indicating that the conjugates provided by the present disclosure have good long-acting properties. Compared with the reference conjugate, the conjugates provided by the present disclosure had significantly higher inhibition rates on the plasma APOC3 protein than the reference conjugate during the entire test period. Specifically, the conjugates of the present disclosure had an inhibition rate on the plasma APOC3 protein of more than 87% at the 8th day, an inhibition rate on the plasma APOC3 protein of more than 86% at the 14th day, an inhibition rate on the plasma APOC3 protein of more than 74% at the 31st day, an inhibition rate on the plasma APOC3 protein of more than 58% at the 43rd day, and still maintained effective inhibition on the plasma APOC3 protein at the 57th day, with an inhibition rate of more than 13%, and even more than 62%. In the case of the same sequence and different modifications, the inhibition rate of Conjugate 1 on the APOC3 protein during the entire test period was higher than that of the reference Conjugate 1, and the difference in the inhibition rate on the APOC3 protein between the two reached 20% after the 31st day. In vivo inhibition activity of the conjugates of the present disclosure The in vivo inhibition activity of Conjugate 5-Conjugate 7 on the plasma APOC3 protein in hAPOC3 transgenic mice was determined by the method of Experimental Example 1, except that Conjugate 5-Conjugate 7 and the reference Conjugate 1 were used, and the dosing amount was 1 mg / kg and 3 mg / kg of the mouse body weight, respectively. The results are listed in Table 5. The in vivo inhibition activity of Conjugate 5-Conjugate 7 on the plasma APOC3 protein in hAPOC3 transgenic mice was determined by the method of Experimental Example 1, except that Conjugate 5-Conjugate 7 and the reference Conjugate 1 were used, and the dosing amount was 1 mg / kg and 3 mg / kg of the mouse body weight, respectively. The results are listed in Table 5. Table 5 Inhibition rate of the plasma APOC3 protein in mice​ As shown in Table 5, the conjugate of this disclosure maintains inhibitory activity against plasma APOC3 protein in mice for a relatively long period, indicating that the conjugate provided by this disclosure has good long-term efficacy. At a dosage of 3 mg / kg, the conjugate of this disclosure showed an inhibition rate of over 80% against plasma APOC3 protein in mice on day 29, even reaching 86%; at a lower dosage of 1 mg / kg, the inhibition rate was over 74% against plasma APOC3 protein in mice on day 29, even reaching 80%. Even on day 57, at a dosage of 3 mg / kg, the conjugate of this disclosure still showed an inhibition rate of over 56% against plasma APOC3 protein in mice; at a dosage of 1 mg / kg, the conjugate of this disclosure still showed an inhibition rate of over 41% against plasma APOC3 protein in mice. With identical sequences but different modifications, conjugate 7 showed higher inhibition rates of APOC3 protein at the same dosage throughout the entire experimental period than reference conjugate 1. On day 29 and thereafter, the inhibition rates of APOC3 protein by the two conjugates differed by up to 40% at a dosage of 1 mg / kg. On day 43 and thereafter, the inhibition rates of APOC3 protein by the two conjugates differed by more than 45% at a dosage of 3 mg / kg. 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 of 16-30 nucleotides in length having sufficient complementarity to an APOC3 mRNA to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein, at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least 1 nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all nucleotides from the 15th nucleotide and after of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide.

2. The single stranded oligonucleotide of claim 1, wherein, The single-stranded oligonucleotide has a length of 17-28, 19-26, or 20-24 nucleotides; or the single-stranded oligonucleotide has a length of 19, 21, or 23 nucleotides.

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

4. The single stranded oligonucleotide of any one of claims 1-3, wherein, Each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide; and, in the direction from the 5' end to the 3' end, each nucleotide X is spaced 3, 5, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide; or one of the nucleotides X is spaced 5 nucleotides from the 8th nucleotide.

5. The single stranded oligonucleotide of claim 4, wherein, The single-stranded oligonucleotide contains only one nucleotide X, which is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide in the direction from the 5' end to the 3' end; Or, the single-stranded oligonucleotide contains 2 nucleotides X, in which 1 nucleotide X is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, and the other nucleotide X is spaced 3, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, in the direction from the 5' end to the 3' end.

6. The single stranded oligonucleotide of any one of claims 1-5, wherein, The number of modified nucleotides accounts for more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotide; or the number of unmodified nucleotides in the single-stranded oligonucleotide is not more than 5, not more than 4, not more than 3, not more than 2, or not more than 1; or each of the total nucleotides in the single-stranded oligonucleotide is independently a modified nucleotide.

7. The single stranded oligonucleotide of any one of claims 1-6, wherein, The number of fluorine-modified nucleotides is 2-7.

8. The single stranded oligonucleotide of claim 7, wherein, In the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 11th, 12th, 16th, 18th, and 19th nucleotides of the single-stranded oligonucleotide; Or, in the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to 1 or 2 of the 2nd, 11th, and 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides of the single-stranded oligonucleotide.

9. The single stranded oligonucleotide of claim 8, wherein, In the direction from the 5' end to the 3' end, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides; or, the 2nd, 6th and 16th nucleotides; or, the 2nd, 5th, 7th, 12th and 16th nucleotides; or, the 2nd, 5th, 7th, 11th and 16th nucleotides; or, the 2nd, 7th, 12th, 16th and 19th nucleotides; or, the 2nd, 6th, 12th, 16th and 19th nucleotides in the single-stranded oligonucleotide.

10. The single stranded oligonucleotide of claim 9, wherein, In the single-stranded oligonucleotide, each modified nucleotide except for the nucleotide X and the fluorine-modified nucleotide is independently selected from one of an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA.

11. The single stranded oligonucleotide of claim 10, wherein, In the single-stranded oligonucleotide, there is no thermally unstable nucleotide, or the number of thermally unstable nucleotides is 1 or 2; or, each modified nucleotide except for the nucleotide X, the fluorine-modified nucleotide and the thermally unstable nucleotide is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide.

12. The single stranded oligonucleotide of claim 11, wherein, The single-stranded oligonucleotide has a length of 19-23 nucleotides, and In the direction from the 5' end to the 3' end, the 14th nucleotide is the nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide when it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, the 14th nucleotide is the nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, the 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide when it is not a fluorine-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, the 12th and 14th nucleotides are the nucleotide X, the 2nd, 7th and 16th nucleotides are fluorine-modified 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 an alkoxy-modified nucleotide; or, In the direction from the 5' end to the 3' end, the 12th and 14th nucleotides are the nucleotide X, the 2nd, 7th and 16th nucleotides are fluorine-modified 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 an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, the 14th and 16th nucleotides are nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide or BNA, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; in the 3' end to 5' end direction, one of the 1st-2nd nucleotides of the single-stranded oligonucleotide is a thermally unstable nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, one of the 16th-19th nucleotides and the 14th nucleotide is nucleotide X, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 16th nucleotide is a fluorine-modified nucleotide when it is not nucleotide X, the 13th nucleotide is a substituted alkoxy-modified nucleotide or BNA, and the 3rd or 5th nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide; the 20th nucleotide is an alkoxy-modified nucleotide or a thermally unstable nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide.

13. The single stranded oligonucleotide of claim 12, wherein, The length of the single-stranded oligonucleotide is 21 nucleotides, and In the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, In the 5' end to 3' end direction, the 12th and 14th nucleotides are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide; or, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorinated modified nucleotides, the 13th nucleotide is a substituted alkoxy modified nucleotide, and the 2nd nucleotide of the single stranded oligonucleotide is a thermally unstable nucleotide in the 3' to 5' direction, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy modified nucleotide; or, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorinated modified nucleotides, the 13th nucleotide is a substituted alkoxy modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy modified nucleotide.

14. The single stranded oligonucleotide of any one of claims 10-13, wherein, each alkoxy modified nucleotide is a methoxy modified nucleotide; and / or each substituted alkoxy modified nucleotide is a 2'-O-methoxyethyl modified nucleotide; and / or each BNA is a LNA, ENA or cET BNA; and / or each thermally unstable nucleotide is a GNA.

15. The single stranded oligonucleotide of any one of claims 1-14, wherein, each of at least 2 of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphoramidate group.

16. The single stranded oligonucleotide of claim 15, wherein, each of 1-4, and / or 3, of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end, and / or the 1st-5th nucleotides at the 3' end of the single stranded oligonucleotide is independently a phosphoramidate group; and / or each of 1 or 2 of the 2 linking groups between each unmodified nucleotide and an adjacent nucleotide in the single stranded oligonucleotide is independently a phosphoramidate group; and / or each of 2-6, or 4, of the linking groups between adjacent nucleotides in the single stranded oligonucleotide is independently a phosphoramidate group.

17. The single stranded oligonucleotide of claim 15 or 16, wherein, each of the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end, and / or the 1st-3rd nucleotides at the 3' end of the single stranded oligonucleotide is independently a phosphoramidate group; and / or each of 1 or 2 of the 2 linking groups between each unmodified nucleotide and an adjacent nucleotide in the single stranded oligonucleotide is independently a phosphoramidate group.

18. The single stranded oligonucleotide of any one of claims 15-17, wherein, Phosphonate groups having a modifying group are phosphorothioate groups having the structure of formula (28):

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

20. The single stranded oligonucleotide of any one of claims 1-19, wherein, the single stranded oligonucleotide is 21 nucleotides in length, and in the 5' to 3' direction, the 2nd, 5th, 7th, 12thand 16thnucleotides are fluorine-modified nucleotides, the 3rdnucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide, or the 14thnucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 11thand 16thnucleotides are fluorine-modified nucleotides, the 3rdnucleotide is a methoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is a methoxy-modified nucleotide; the linking group between any two adjacent nucleotides of the 1stto 3rdnucleotides at the 5' end and the linking group between any two adjacent nucleotides of the 1stto 3rdnucleotides at the 3' end are phosphorothioate groups; the 5'terminal nucleotide is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinylphosphonate-modified nucleotide represented by formula (31).

21. The single stranded oligonucleotide of any one of claims 1-20, wherein, the single-stranded oligonucleotide is substantially, substantially or completely reverse complementary to the APOC3 mRNA over a span of at least 16 nucleotides, over a span of 16-25 nucleotides, over a span of 18-23 nucleotides or over a span of 19-21 nucleotides; and / or the nucleotide sequence of the single-stranded oligonucleotide, except for the 1stposition, is completely reverse complementary to the APOC3 mRNA in the direction from the 5'terminal end to the 3'terminal end; or all the nucleotides of the single-stranded oligonucleotide are completely reverse complementary to the APOC3 mRNA.

22. The single stranded oligonucleotide of any one of claims 1-21, wherein, the single-stranded oligonucleotide contains a nucleotide sequence II, which is selected from one of the following i)-iii): i) the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 2 and has no more than 3 base differences: 5'-Z2GAAUACUGUCCCUUUUAA-3' (SEQ ID NO: 2), wherein Z2 is A or U, the nucleotide sequence II contains a nucleotide Z'2 at a position corresponding to Z2, and Z'2 is the first nucleotide at the 5'terminal end of the single-stranded oligonucleotide; ii) the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 4 and has no more than 3 base differences: 5'-Z4UCUUGUCCAGCUUUAUUG-3' (SEQ ID NO: 4), wherein Z4 is A or U, the nucleotide sequence II contains a nucleotide Z'4 at a position corresponding to Z4, and Z'4 is the first nucleotide at the 5'terminal end of the single-stranded oligonucleotide; iii) the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 6 and has no more than 3 base differences: 5'-Z6GCACUGAGAAUACUGUCC-3' (SEQ ID NO: 6), wherein Z6 is A or U, the nucleotide sequence II contains a nucleotide Z'6 at a position corresponding to Z6, and Z'6 is the first nucleotide at the 5'terminal end of the single-stranded oligonucleotide.

23. The single stranded oligonucleotide of claim 22, wherein, no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 2; or, no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 4; or, no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 6; or, no base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 2; or, no base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 4; or, no base difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:

6.

24. The single stranded oligonucleotide of claim 22 or 23, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence IV, which is linked to the 3' end of the nucleotide sequence II, has a length of 1, 2, 3 or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of non-fluorinated modified nucleotides, the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the APOC3 mRNA, each of the non-fluorinated modified nucleotides is independently selected from one of 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with an alkyl group having a carbon number of 1-3, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides and heat unstable nucleotides; or, the length of the nucleotide sequence IV is 2 nucleotides.

25. The single stranded oligonucleotide of any one of claims 22-24, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1-3 nucleotides, which is linked 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' overhanging end of the antisense strand of the double-stranded oligonucleotide; or, the length of the nucleotide sequence V is 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides, two consecutive uracil ribonucleotides or is completely reverse complementary to the APOC3 mRNA; or, the single-stranded oligonucleotide is the antisense strand of any one of siRNA1-siRNA6 listed in Table 1; or, the single-stranded oligonucleotide is the antisense strand of any one of conjugate 1-conjugate 7 listed in Table 2.

26. A double stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and antisense strand being at least partially reverse complementary forming a double stranded region, wherein, The antisense strand is the single-stranded oligonucleotide according to any one of claims 1-25.

27. The double-stranded oligonucleotide of claim 26, wherein, The length of the sense strand is 19-23 nucleotides; or, the length of the sense strand and the antisense strand is the same, and both are 19, 20 or 21 nucleotides; or, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 20-24 nucleotides; or, the length of the sense strand is 20 nucleotides, and the length of the antisense strand is 21-24 nucleotides; or, the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 22-24 nucleotides; or, the sense strand is 19 nucleotides in length and the antisense strand is 21 nucleotides in length; or, the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

28. The double-stranded oligonucleotide of claim 26 or 27, wherein, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide.

29. The double-stranded oligonucleotide of claim 28, wherein, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are alkoxy-modified nucleotides.

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

31. The double-stranded oligonucleotide of any one of claims 26-30, wherein, In the sense strand, at least one of the linking groups between adjacent nucleotides is a phosphate group with a modification group, which is present at least one of the following: between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand.

32. The double-stranded oligonucleotide of claim 31, wherein, each of 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and / or 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand is independently a phosphate group with a modification group; or, the phosphate group with a modification group is a phosphorothioate group with a structure as shown in formula (28); or, the sense strand is the sense strand of any one of siRNA1-siRNA6 listed in Table 1; or, the sense strand is the sense strand of any one of conjugate 1-conjugate 7 listed in Table 2.

33. The double-stranded oligonucleotide of any one of claims 26-32, wherein, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end of the sense strand are fluorine-modified nucleotides, the 1st and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide. each of 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 5' end and / or 1-4 of the linking groups between the adjacent nucleotides of the 1st-5th nucleotides from the 3' end of the sense strand is independently a phosphate group with a modification group.

34. The double-stranded oligonucleotide of claim 33, wherein, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end of the sense strand are phosphate groups with a modification group; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end of the antisense strand is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide.the linking group between the adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end of the antisense strand and the linking group between the adjacent nucleotides in the 1st to 3rd nucleotides from the 3' end are both phosphoric acid ester groups with a modification group, and if there is an unmodified nucleotide, the linking group between each of the unmodified nucleotides and the adjacent nucleotide is a phosphoric acid ester group with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29), a 5'-phosphoric acid nucleotide represented by formula (30), or a 5'-vinyl phosphoric acid ester modified nucleotide represented by formula (31); or, in the sense strand, the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an alkoxy-modified nucleotide or an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; the linking groups between adjacent nucleotides at the 1st-3rd nucleotides from the 5' end to the 3' end of the sense strand are phosphate groups with a modification group; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, the 2nd nucleotide from the 3' end to the 5' end is a heat-unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide.the linking group between the adjacent nucleotides in the 1st to 3rd nucleotides from the 5' end of the antisense strand and the linking group between the adjacent nucleotides in the 1st to 3rd nucleotides from the 3' end are both phosphoric acid ester groups with a modification group, and if there is an unmodified nucleotide, the linking group between each of the unmodified nucleotides and the adjacent nucleotide is a phosphoric acid ester group with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphoric acid ester modified nucleotide represented by formula (31).

35. The double-stranded oligonucleotide of claim 34, wherein, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted de-alkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31); In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted de-alkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 11th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end and the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31).

36. The double-stranded oligonucleotide of any one of claims 26-35, wherein, The double-stranded region formed by the sense strand and the antisense strand contains 16-23 base pairs; or the double-stranded region formed by the sense strand and the antisense strand contains 18, 19, 20 or 21 base pairs; and / or, The sense strand and the antisense strand are substantially reverse complementary or completely reverse complementary within the double-stranded region; and / or, The number of base differences between the sense strand and the APOC3 mRNA is not more than 3, not more than 2 or not more than 1; or there is no base difference between the sense strand and the APOC3 mRNA.

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

38. The double-stranded oligonucleotide of any one of claims 26-37, wherein, The double-stranded oligonucleotide contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, the antisense strand contains a nucleotide sequence II, and the sequence of the double-stranded oligonucleotide is selected from one group consisting of the sequences shown in i)-iii) as follows: i) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 1 and differs by no more than 3 bases; nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2 and differs by no more than 3 bases: 5'-UUAAAAGGGACAGUAUUCZ1-3'(SEQ ID NO: 1); 5'-Z2GAAUACUGUCCCUUUUAA-3'(SEQ ID NO: 2), wherein Z1 is U, A or an inverted abasic deoxynucleotide, Z2 is A or U, nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, nucleotide sequence II comprises a nucleotide Z'2 at a position corresponding to Z2, Z'2 is the first nucleotide at the 5' end of the antisense strand; ii) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 3 and differs by no more than 3 bases; nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 4 and differs by no more than 3 bases: 5'-CAAUAAAGCUGGACAAGAZ3-3'(SEQ ID NO: 3); 5'-Z4UCUUGUCCAGCUUUAUUG-3'(SEQ ID NO: 4), wherein Z3 is U, A or an inverted abasic deoxynucleotide, Z4 is A or U, nucleotide sequence I comprises a nucleotide Z'3 at a position corresponding to Z3, nucleotide sequence II comprises a nucleotide Z'4 at a position corresponding to Z4, Z'4 is the first nucleotide at the 5' end of the antisense strand; iii) nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 5 and differs by no more than 3 bases; nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 6 and differs by no more than 3 bases: 5'-GGACAGUAUUCUCAGUGCZ5-3'(SEQ ID NO: 5); 5'-Z6GCACUGAGAAUACUGUCC-3'(SEQ ID NO: 6), wherein Z5 is U, A or an inverted abasic deoxynucleotide, Z6 is A or U, nucleotide sequence I comprises a nucleotide Z'5 at a position corresponding to Z5, nucleotide sequence II comprises a nucleotide Z'6 at a position corresponding to Z6, Z'6 is the first nucleotide at the 5' end of the antisense strand.

39. The double-stranded oligonucleotide of claim 38, wherein, nucleotide sequence I differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 1, 3 or 5, and nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 2, 4 or 6.

40. The double-stranded oligonucleotide of claim 39, wherein, the double-stranded oligonucleotide is any one of siRNA1-siRNA6 set forth in Table 1.

41. An oligonucleotide conjugate comprising at least one oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide of any one of claims 1-25 or the double-stranded oligonucleotide of any one of claims 26-40.

42. The oligonucleotide conjugate of claim 41, wherein, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the 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 a ligand capable of binding to a cell surface receptor or a group capable of increasing compatibility with a tissue; alternatively, the oligonucleotide conjugate comprises an oligonucleotide group being an siRNA group formed by an siRNA listed in Table 1; Alternatively, the oligonucleotide conjugate has the structure shown in Formula (403): in formula (403), Nu is an oligonucleotide group; alternatively, the oligonucleotide group is a double-stranded oligonucleotide group, the P atom is covalently linked to the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group; or the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is a reverse deoxy-debase nucleotide, the P atom is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group via a methylene linkage to the ribose ring in the reverse deoxy-debase nucleotide of the 3' terminal of the sense strand of the double-stranded oligonucleotide group; alternatively, the oligonucleotide conjugate is one of the conjugates 1-7 listed in Table 2.

43. A pharmaceutically acceptable salt of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40 or the oligonucleotide conjugate of claim 41 or 42; alternatively, the pharmaceutically acceptable salt is a water-soluble salt of part or all 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 or an alkaline earth metal salt; alternatively, the amine salt is one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, the alkali metal salt is one or more of a potassium salt or a sodium salt, and the alkaline earth metal salt is one or more of a calcium salt or a magnesium salt; alternatively, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt or a N,N-diisopropylethylamine salt; alternatively, the pharmaceutically acceptable salt is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate.

44. A pharmaceutical composition comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42 or the pharmaceutically acceptable salt of claim 43, and a pharmaceutically acceptable adjuvant; alternatively, the pharmaceutically acceptable adjuvant is one or more of a solvent, a protective agent, an osmotic pressure regulator and other pharmaceutically acceptable carriers. Alternatively, the solvent is one of deionized water, water for injection, pH buffer, physiological saline, ethanol or aqueous ethanol solution.

45. Use 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 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44 in the manufacture of a medicament for treating and / or preventing a disease or condition associated with APOC3 mRNA level.

46. The use of claim 45, wherein, The disease or condition associated with APOC3 mRNA level is dyslipidemia; or the dyslipidemia is hypercholesterolemia, hypertriglyceridemia or atherosclerosis.

47. A method of treating and / or preventing a disease or condition associated with APOC3 mRNA level, the method comprising administering to a subject in need thereof 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 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44.

48. A method of modulating the expression level of APOC3 gene in a cell in vitro or in vivo, the method comprising contacting 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 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44 with the cell in vitro or in vivo.

49. One or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44 for use as a medicament.

50. A cell expressing APOC3 mRNA, the cell comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44.

51. A kit comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-40, the oligonucleotide conjugate of claim 41 or 42, the pharmaceutically acceptable salt of claim 43 and the pharmaceutical composition of claim 44.

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