Oligonucleotide, oligonucleotide conjugate, composition, and use

Abstract

A single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide and complement component C3 (CC3) mRNA have sufficient complementarity to mediate 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 the at least one nucleotide is a fluoro-modified nucleotide; moreover, according to a direction from the 5' end to the 3' end, at least one nucleotide X is located after an eighth nucleotide and is spaced apart from the eighth nucleotide in the single-stranded oligonucleotide by 4-7 nucleotides; and each nucleotide X is a deoxynucleotide or an unmodified nucleotide. The present invention further relates to 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, and also relates to a double-stranded oligonucleotide comprising the single-stranded oligonucleotide as an antisense strand, an oligonucleotide conjugate, a composition, uses thereof and a preparation method. The present disclosure provides a double-stranded oligonucleotide for inhibiting the expression of complement component C3 (CC3) gene and applications in treating, preventing or ameliorating complement system related diseases. BACKGROUND Complement is a kind of enzyme-active protein existing in normal human blood and tissue fluid. The complement system is composed of three parts, the classical pathway, the lectin pathway and the alternative pathway, which all converge at the formation of the complement component C3 (CC3, also known as complement component C3 or complement 3) convertase complex. These enzyme complexes can cleave the complement component C3 protein into CC3a and CC3b. Once CC3 is cleaved, CC3b becomes part of a complex that then cleaves C5 into C5a and C5b. Cleaved C5b is one of the key components of the membrane attack complex (main complement pathway effector). Therefore, CC3 is considered as a core component in the activation pathway of the complement system, which participates in the complex immune functions of the human body. Unwanted activation of the complement system can trigger a series of serious diseases, including CC3 glomerulopathy, systemic lupus erythematosus (SLE, such as lupus nephritis), IgA nephropathy, diabetic nephropathy, polycystic kidney disease, membranous nephropathy, age-related macular degeneration, atypical hemolytic uremic syndrome, thrombotic microangiopathy, myasthenia gravis (MG), ischemia-reperfusion injury, paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis and periodontitis, etc. Given the significant threat of these diseases to patient health, there is an urgent need in the art to develop and apply therapeutic solutions that can effectively regulate the imbalance of the complement system, aiming to improve the quality of life of patients and curb disease progression. In siRNA drugs, the antisense strand is the most important part that determines the performance of double-stranded oligonucleotides, which can specifically pair with the messenger RNA (mRNA) of the target gene, leading to the degradation or inactivation of mRNA, thereby inhibiting or blocking the expression of the gene. Given this unique mechanism, siRNA drugs show great potential and are expected to become an effective means of precisely regulating the imbalance of the complement system and treating complement-related diseases. In the drug research of double-stranded oligonucleotide targeting complement component C3, the improvement of modification of double-stranded oligonucleotide, such as siRNA, has never stopped, and in the double-stranded oligonucleotide, the antisense strand is the most important part to determine the performance of the double-stranded oligonucleotide, although a large number of modification schemes of oligonucleotide are disclosed in the prior art, how to improve the modification of oligonucleotide, especially the antisense strand, to obtain oligonucleotide capable of regulating the mRNA level of complement component C3 with high activity, high stability and / or long-acting is still the research direction in the field. SUMMARY The present application provides a single-stranded oligonucleotide, a double-stranded oligonucleotide containing the single-stranded oligonucleotide of the present disclosure as an antisense strand, and an oligonucleotide conjugate, which all exhibit good pharmaceutical activity and stability when the nucleotide sequences are different and target CC3 mRNA. In one aspect, the present application provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, which has sufficient complementarity with CC3 mRNA to mediate 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 one 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, if, in the direction from the 5' end to the 3' end, 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 alkoxyl-modified nucleotide, alkyl-modified nucleotide, substituted alkyl-modified nucleotide, amine-modified nucleotide, thermally unstable nucleotide and BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In another aspect, the present disclosure provides a double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse complementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide of the present disclosure. In yet another aspect, the present disclosure also provides an oligonucleotide conjugate containing a double-stranded oligonucleotide group and a delivery group conjugated to the double-stranded oligonucleotide group, the double-stranded oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from the double-stranded oligonucleotide of the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the double-stranded oligonucleotide or the oligonucleotide conjugate of the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutical composition containing one or more of the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt of the present disclosure, and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure also provides a use of the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, or the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease or a symptom associated with the level of CC3 mRNA. In yet another aspect, the present disclosure also provides a method of treating and / or preventing a disease or a symptom associated with the level of CC3 mRNA, the method comprising administering to a subject in need thereof an effective amount of one or more of the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure. In yet another aspect, the present disclosure also provides a method of modulating the level of CC3 mRNA expression in a cell, the method comprising contacting the cell with an effective amount of one or more of the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure. In yet another aspect, the present disclosure also provides 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 for use as a medicament. In yet another aspect, the present disclosure also provides a cell expressing CC3 mRNA, the cell comprising 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 addition, the present disclosure also provides a kit comprising 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. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Advantages The double-stranded oligonucleotide, the oligonucleotide conjugate, and / or the pharmaceutical composition comprising the single-stranded oligonucleotide of the present disclosure as an antisense strand has higher activity in modulating CC3 mRNA, and has higher long-acting property. In one aspect, the siRNA of the present disclosure, the oligonucleotide conjugate of the present disclosure and / or the pharmaceutical composition containing the single-stranded oligonucleotide of the present disclosure as the antisense strand show excellent CC3 mRNA inhibition effect. For example, compared with the reference conjugate, the conjugate of the present disclosure containing the single-stranded oligonucleotide of the present disclosure as the antisense strand shows significantly higher inhibition activity on CC3 mRNA in liver tissue at different administration doses, and the inhibition rate of the conjugate of the present disclosure on CC3 mRNA is 33.8%, 21.0% and 17.4% higher than that of the reference conjugate at the administration doses of 3 mg / Kg, 1 mg / Kg and 0.03 mg / Kg, respectively, and the inhibition rate of the conjugate of the present disclosure on CC3 mRNA is increased by 77.8%, 79.2% and 80.6% compared with the reference conjugate, respectively. Therefore, the siRNA conjugate containing the single-stranded oligonucleotide of the present disclosure as the antisense strand has significantly improved inhibition activity on CC3 mRNA, and has better pharmaceutical activity. In another aspect, the siRNA of the present disclosure, the conjugate of the present disclosure and / or the pharmaceutical composition containing the single-stranded oligonucleotide of the present disclosure as the antisense strand have long-term inhibition effect on CC3 mRNA and protein expression. For example, in a 29-day experimental period, the mice administered with the conjugate of the present disclosure show higher inhibition rate of CC3 mRNA expression than the mice administered with the reference conjugate, and the high inhibition rate is maintained throughout the experimental period, and the inhibition rate of CC3 protein level is still maintained at more than 60% on the 29th day. Therefore, the conjugate of the present disclosure can inhibit the expression of CC3 mRNA for a long time to reduce the CC3 protein level in serum. For another example, in the in vivo experiment of mice, the conjugate of the present disclosure shows comparable inhibition activity on CC3 mRNA in liver tissue and inhibition rate of serum CC3 protein level to the reference conjugate at different concentrations on the 15th day after administration, and the highest inhibition rate can reach 72%; at the administration dose of 3 mg / Kg, the inhibition rate of the conjugate of the present disclosure on CC3 protein level is at least 24%-28% higher than that of the reference conjugate on the 43rd day after administration. Therefore, the conjugate of the present disclosure can stably and efficiently inhibit the expression of CC3 mRNA for a long time. The conjugate of the present disclosure has good CC3 mRNA regulation activity, shows significantly long-term pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to CC3 mRNA expression, and has excellent development prospect. DETAILED DESCRIPTION The detailed description of the present disclosure is described 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 some embodiments, CC3 mRNA refers to mRNA of the sequence set forth in Genbank Accession No. NM_000064.4. Further, the term "CC3 gene" used in the present disclosure refers to a gene transcribing the aforementioned CC3 mRNA, unless otherwise specified. Definitions In the context herein, 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 hydrogen bonds between base pairs in a complementary manner with the bases on the other strand, achieving base pairing, forming Watson-Crick base pairs. "Base pair" refers to two bases forming a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or uracil (U) in RNA); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair includes 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 above-mentioned 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 pairing. 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 includes a non-base nucleotide, it is also considered to form a mismatch with the base on the other strand. In the above and below, "there are X continuous identical nucleotides between nucleotide sequence A and nucleotide sequence B, and the continuous identical nucleotides include no more than Y base differences or no base differences", refers to that there is a continuous nucleotide sequence A' of length X in nucleotide sequence A, which is continuous and identical with a continuous nucleotide sequence B' of the same length X in nucleotide sequence B, and there are no more than Y base differences or no base differences between the nucleotide sequence A' and the nucleotide sequence B'. Unless otherwise specified, in the context, the oligonucleotides and / or oligonucleotide conjugates mentioned alone in the applications or methods provided by the present disclosure, including but not limited to the oligonucleotides and / or oligonucleotide conjugates represented by any structural formula mentioned in the applications or methods provided by the present disclosure, also refer to the pharmaceutically acceptable salts of the conjugates according to the context. In the foregoing and hereinafter, particularly in describing the preparation of a double stranded oligonucleotide, a pharmaceutical composition, or an oligonucleotide conjugate of the disclosure, unless otherwise indicated, 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 double stranded oligonucleotide or oligonucleotide conjugate to be prepared. The phosphoramidite solid phase synthesis is a method commonly known to those skilled in the art for use in RNA synthesis. All nucleoside monomers used in the present disclosure are commercially available. Those skilled in the art will appreciate that for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is not physically or synthetically realistic. As used herein, "alkyl" refers to saturated straight and / or branched chain hydrocarbon groups having the specified number of carbon atoms, typically from 1 to 20 carbon atoms, for example, from 1 to 10 carbon atoms, such as from 1 to 8 or from 1 to 6 carbon atoms. For example, C1-C6 alkyl includes straight and branched chain alkyl groups of from 1 to 6 carbon atoms. When reference is made to an alkyl residue having a particular number of carbons, it is intended to encompass all branched and straight chain forms having that number of carbons; thus, for example, "butyl" is meant 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 residues as alkyl, but having two points of attachment. As used herein, "alkoxy" refers to an alkyl group of the specified number of carbon atoms attached 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 from 1 to 10, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms attached via an oxygen bridge. As used herein, "alkoxy-modified alkyl" refers to a group formed upon substitution of one or more hydrogen atoms in an alkyl group with an alkoxy group, for example, methoxymethyl (CH3OCH2-), ethoxymethyl (CH3CH2OCH2-), methoxyethyl (CH3OCH2CH2-), and the like. As used herein, "alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond, obtained by removing one molecule of hydrogen from adjacent 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, but-1,3-dien-1 -yl, but-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 with 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 molecules of hydrogen 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, alkynyl groups have 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 groups as alkynyl, but with two points of attachment. 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. Arylene is a subset of aryl, referring to the same groups as aryl, but with two points of attachment. As used herein, "heterocyclyl" refers to a radical derived from a monocyclic saturated or partially unsaturated, non-aromatic ring or bicyclic saturated or partially unsaturated heterocyclic hydrocarbon radical, wherein the bicyclic ring system is non-aromatic, the monocyclic or bicyclic ring has, for example, 3 to 10 members or 5 to 10 members, wherein at least 1 member and up to 5 members, particularly 1, 2, or 3 ring members are a heteroatom selected from N, O, and S, and the remaining ring atoms are carbon atoms, in stable combinations known to those skilled in the art. Among these, the heterocyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. As used herein, the heterocycle can form a bicyclic ring with another ring system, i.e., one or two of the atoms making up the heterocycle are shared with another ring system. The heterocyclyl group can be attached to the rest of the molecule by a carbon or heteroatom; and, in the case where the heterocyclyl group is a bicyclic radical, the aforementioned attachment can be via a heteroatom-containing ring or a fused ring. Examples of heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g., 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, dihydropyrrolopyridinyl, dihydrobenzoxazinyl, pyrrolopyridinyl, dihydronaphthridinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl. Heterocyclylenyl is a subset of heterocyclyl, referring to the same residues as heterocyclyl, but with two points of attachment. As used herein, "heteroaryl" refers to a radical derived by the removal of one hydrogen atom from a 3- to 18-membered aromatic ring radical, containing 2 to 17 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., contains a cyclic delocalized (4n+2) p-electron system according to Hückel theory. Heteroaryl groups include fused or bridged ring systems. In some embodiments, a heteroatom in a heteroaryl group is an oxidized heteroatom. In some embodiments, a heteroaryl group contains one or more nitrogen atoms. In some embodiments, one or more of the nitrogen atoms in a heteroaryl group is a quaternized nitrogen atom. A heteroaryl group is attached to the rest of the molecule through any ring atom. Examples of heteroaryl groups include, but are not limited to: azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzo-thieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, diphenfuranyl, diphenylthiophenyl, furanyl, furanonyl, furopyrido[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, dihydroindolyl, isoindolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxepinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]dioxinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridazinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyranonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]furanonyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thienyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiophenyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thieno[3,2-d]pyrimidinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiadiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]oxazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]thiazolyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]cinnolinyl, 5,6-methano-5,6-dihydrobenzo[b][l,4]pyridaz8-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]pridinyl, and thiophenyl / thienyl. Heteroarylenyl is a subset of heteroaryl, referring to the same residues as heteroaryl, but with two points of attachment. In the foregoing or hereinafter, a “substituted” or “substituted” group, such as a substituted amino, substituted alkyl, or substituted aryl. Where no indication is given, a “substituted” or “substituted” group refers to a group in which one or more hydrogen atoms are replaced with one or more substituents. For example, a “substituted alkyl” refers to a group in which one or more hydrogen atoms of an alkyl group are replaced with a substituent. Those skilled in the art will appreciate that various substituents can be included in the compounds useful in the present disclosure, as long as the introduction of the substituent does not affect the function of the present disclosure and achieve the purpose of the present disclosure, which can be used in the present disclosure. 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-C 10haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkyl, -SC1-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 alkyl), N(C1-C 10 alkyl), -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 alkyl, 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. It will be understood by one skilled in the art that for any group containing one or more substituents, the group is not intended to introduce any substitution or substitution pattern that is not physically or synthetically realistic. Various protecting groups can be used in the present disclosure, such as hydroxyl protecting groups or amino protecting groups. Hereinabove and below, protecting groups render a chemical functionality insensitive to particular reaction conditions, and can be added to and removed from that functionality in a molecule without substantially disturbing the remainder of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, 2d ed, John Wiley & Sons, New York, 1991, each of which is incorporated herein by reference in its entirety. In some embodiments, the protecting group is stable under basic conditions, but can be removed under acidic conditions. In some embodiments, nonexclusive 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, nonexclusive 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 eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding the fact that the subject can still be afflicted with the disorder. As used herein, "prevent" refers to an approach that results in a beneficial or desired result, including but not limited to prophylactic benefit. To obtain "prophylactic benefit", a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate can be administered to a subject at risk of suffering from a disease associated with CC3 mRNA, or to a subject with one or more physiological symptoms of a disease associated with CC3 mRNA, even though the diagnosis of the disease can not have been made. In some embodiments, "prevention" includes reducing or eliminating a disease risk by administering a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate to a subject at risk of suffering from a particular disease, intervening in the level of CC3 mRNA or CC3 protein before the particular disease risk progresses to an explicit disease process. Single-stranded oligonucleotide of the present disclosure In one aspect, the present disclosure provides a single-stranded oligonucleotide having a length of 16-30 nucleotides, the single-stranded oligonucleotide having sufficient complementarity to CC3 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, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X in the direction from the 5' end to the 3' end, and all nucleotides from the 15th nucleotide and thereafter 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, diseases associated with the expression level of CC3 gene and / or the level of CC3 protein are treated or prevented by regulating the expression level of CC3 mRNA and / or changing the level of the corresponding protein. The inventors have surprisingly found that double-stranded oligonucleotides and oligonucleotide conjugates comprising the single-stranded oligonucleotides of the present disclosure as the antisense strand have good stability and CC3 mRNA inhibitory activity in cells and / or in subjects, 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 of the present disclosure, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide as the antisense strand, and the oligonucleotide conjugate have a better balance between 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 4-7 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide. The inventors have particularly found that the single-stranded oligonucleotide conjugate of the present disclosure can effectively maintain high inhibitory activity of the single-stranded oligonucleotide, the double-stranded oligonucleotide and the oligonucleotide conjugate against CC3 mRNA while maintaining stability by comprising the fluorine-modified nucleotide and the nucleotide X. In some embodiments, the number of nucleotides X is 1-3, for example, 1 or 2. In some embodiments, each nucleotide X is spaced 3, 5, 7 or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, one of the nucleotides X is spaced 5 nucleotides from the 8th nucleotide, i.e., the 14th nucleotide in the single-stranded oligonucleotide is the nucleotide X in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises only one nucleotide X, which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end. In some embodiments, the single-stranded oligonucleotide comprises 2 nucleotides X, wherein one nucleotide X is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide, and the other nucleotide X is spaced 3, 7 or 10 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide. 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 are the nucleotides X in the direction from the 5' end to the 3' end. 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 the base, the phosphate group and the ribose are unmodified, i.e. the nucleotide base is a natural ribose base (one of A, U, C, G, T) and the nucleotide ribose 2' position is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide in which the base is modified, the hydroxyl group at the 2' position of the nucleotide ribose is replaced by another atom or group, the phosphate group is modified, or the nucleotide is a nucleotide analogue. In some embodiments, the 14thnucleotide or the 12thand 14thnucleotides in the single-stranded oligonucleotide, in the 5' end to 3' end direction, are deoxynucleotides and the other nucleotides X are unmodified nucleotides. In some embodiments, the 14thnucleotide in the single-stranded oligonucleotide, in the 5' end to 3' end direction, is a deoxynucleotide and the number of unmodified nucleotides among the other nucleotides is one or zero. 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 or no more than 3. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotide is two or one. In some embodiments, all the nucleotides in the single-stranded oligonucleotide are modified nucleotides. As previously described, the single-stranded oligonucleotide described herein can include 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 and 11th-12th, 1 or 2 of the 5th-7th, and 0-2 of the 16th-19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to 2-5 of the 2nd, 5th, 6th, 7th, 12th, 16th, 18th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd and 6th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 5th, 7th, 12th, and 16th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 7th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, the fluorine-modified nucleotides refer to the 2nd, 6th, 12th, 16th, and 19th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, each modified nucleotide in the single-stranded oligonucleotide other than 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 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 is no more than 2. In some embodiments, the number of thermally unstable nucleotides is 1 or 2. In some embodiments, the single-stranded oligonucleotide contains only 1 thermally unstable nucleotide. In some embodiments, each modified nucleotide 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, “thermally unstable nucleotide” refers to a nucleotide having a thermally unstable modification, which means a modification that results in a reduction of at least 0.5 °C in the thermal dissociation temperature of a double-stranded oligonucleotide having the modification as compared to a double-stranded oligonucleotide having an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification of PCT Publication No. WO 2018 / 098328 Al

[0236] -

[0251] The thermally unstable modification described in the paragraph. In some embodiments, the thermally unstable 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). An iso-nucleotide refers to a compound in which the position of the base on the ribose ring of the nucleotide 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 nucleotides are 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), and h'GNA as shown in formula (27J), UNA as shown in formula (27K), or 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, 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 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, ENA, cET BNA, etc., where LNA is shown in formula (12), ENA is shown in formula (13), and 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 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 fluorinated 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 fluorinated 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 fluorinated nucleotides, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is 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 and the 16th nucleotide are nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, 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 fluorinated nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 3' end to 5' end direction, 1 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. 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, one of the 17th-19th nucleotides and the 14th nucleotide is a nucleotide X, the 2nd, 6th and 16th nucleotides are fluorinated 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, 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 17th or 19th nucleotide and the 14th nucleotide is a nucleotide X, and wherein the 14th nucleotide is a deoxynucleotide or an unmodified nucleotide, and the 17th 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 14thnucleotide is a deoxy nucleotide, the 2nd, 5th, 7th, 12th, and 16thnucleotides are fluoro-modified nucleotides, 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 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 7th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, 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 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 2nd, 6th, 12th, 16th, and 19thnucleotides are fluoro-modified nucleotides, 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 21 nucleotides in length and, in the 5' end to 3' end direction, the 12thand 14thnucleotides are deoxy nucleotides, the 2nd, 7th, and 16thnucleotides are fluoro-modified nucleotides, 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 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 16thnucleotide is an unmodified nucleotide, the 2ndand 6thnucleotides are fluoro-modified nucleotides, the 5thand 13thnucleotides are each independently a substituted alkoxy-modified nucleotide or an alkoxy-modified nucleotide, the 2ndnucleotide in the 3' end to 5' end direction is a thermally destabilizing 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 21 nucleotides in length and, in the 5' end to 3' end direction, the 14thnucleotide is a deoxy nucleotide, the 19thnucleotide is an unmodified nucleotide, the 2nd, 6th, and 16thnucleotides are fluoro-modified nucleotides, the 5thand 13thnucleotides are each independently a substituted alkoxy-modified nucleotide or an alkoxy-modified nucleotide, and each of the remaining nucleotides in the single stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, each of the alkoxyl-modified nucleotides in the single- stranded oligonucleotide of the present disclosure refers to a methoxyl-modified nucleotide. In some embodiments, each of the substituted alkoxyl-modified nucleotides in the single- stranded oligonucleotide of the present disclosure refers to a 2'-0-methoxyethyl-modified nucleotide. In some embodiments, each of the BNA in the single-stranded oligonucleotide of the present disclosure refers to a LNA or a cET BNA. In some embodiments, each of the thermally unstable nucleotides in the single-stranded oligonucleotide of the present disclosure refers to a GNA. In some embodiments, at least 2, or 2-6 of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide of the present disclosure are phosphates with a modification group. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 5' end in the single-stranded oligonucleotide of the present disclosure are phosphates with a modification group. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the first 5 nucleotides at the 3' end in the single-stranded oligonucleotide of the present disclosure are phosphates with a modification group. In some embodiments, if there is an unmodified nucleotide in the single-stranded oligonucleotide of the present disclosure, 1 or both of the 2 linking groups between each of the unmodified nucleotide and its adjacent nucleotides are phosphates with a modification group. In some embodiments, 2-6, or 4 of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide of the present disclosure are phosphates with a modification group. The modified phosphate group can make the single-stranded oligonucleotide of the present disclosure better resistant to exonuclease, and enhance the stability of the oligonucleotide in a subject. In some embodiments, each of the linking groups between adjacent nucleotides in the first 3 nucleotides at the 5' end, and the first 3 nucleotides at the 3' end in the single-stranded oligonucleotide is a phosphate with a modification group. In some embodiments, if there is an unmodified nucleotide in the single-stranded oligonucleotide, 1 or both of the 2 linking groups between each of the unmodified nucleotide and its adjacent nucleotides are phosphates with a modification group. In some embodiments, the phosphate 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 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. 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 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 as described in the present disclosure. In some embodiments, the single-stranded oligonucleotide as described in the present disclosure has a length of 21 nucleotides, and in the direction from the 5' end to the 3' end, 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 from the 1st to the 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides from the 1st to the 3rd nucleotides at the 3' end are phosphorothioate groups; and the 5' terminal nucleotide is a 5'-hydroxyl nucleotide as shown in formula (29) or a 5'- (E)-vinylphosphonate modified nucleotide as shown in formula (31). As previously described, the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to CC3 mRNA to mediate an RNAi effect. In some embodiments, the single-stranded oligonucleotides of the present disclosure are substantially complementary to CC3 mRNA. In the context of the present disclosure, "substantially complementary" means that the single-stranded oligonucleotides of the present disclosure have sufficient complementarity to CC3 mRNA such that the single-stranded oligonucleotides reduce or eliminate the production of a protein encoded by the CC3 mRNA through an RNAi effect. In some embodiments, "substantially complementary" means that the single-stranded oligonucleotides of the present disclosure are essentially, substantially, or completely reverse complementary to CC3 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 CC3 mRNA. In the foregoing and hereinafter, "at least partially reverse complementary," "essentially reverse complementary," "substantially reverse complementary," and "completely reverse complementary" can be used to refer to the base pairing between the nucleotide sequences of two single strands of nucleic acids, between the sense and antisense strands of a double-stranded oligonucleotide, and between the antisense strand of a double-stranded oligonucleotide and CC3 mRNA. Unless otherwise specified, "at least partially reverse complementary" means that there are no more than 50% base mismatches between two nucleotide sequences over a given length of the nucleotide sequences; "essentially reverse complementary" means that there are no more than 3 base mismatches between two nucleotide sequences over a given length of the nucleotide sequences; "substantially reverse complementary" means that there is 1 base mismatch between two nucleotide sequences over a given length of the nucleotide sequences; and "completely reverse complementary" means that there are no base mismatches between two nucleotide sequences over a given length of the nucleotide sequences. When two nucleotide sequences are completely reverse complementary over a given length of the nucleotide sequences, the two nucleotide sequences are capable of annealing to form a double-stranded hybrid consisting solely of Watson-Crick base pairs over the given length of the nucleotide sequences. Unless otherwise specified, when referring to a shorter nucleotide sequence being "completely reverse complementary" to a longer nucleotide sequence, it is meant that the shorter nucleotide sequence is completely reverse complementary to the longer nucleotide sequence over the entire length of the shorter nucleotide sequence. For example, a single-stranded oligonucleotide of the present disclosure being completely reverse complementary to CC3 mRNA means that the single-stranded oligonucleotide is completely reverse complementary over the entire length of the single-stranded oligonucleotide; in other words, the single-stranded oligonucleotide is capable of forming a double-stranded hybrid with CC3 mRNA in which each nucleotide of the single-stranded oligonucleotide forms a Watson-Crick base pair with a nucleotide of CC3 mRNA. In some embodiments, two nucleotide sequences that are "substantially complementary" can include an internal region that is completely reverse complementary (e.g., completely reverse complementary over a length of at least 6, 8, or 10 nucleotides). In some embodiments, the single-stranded oligonucleotide described in the present disclosure is completely reverse complementary to the CC3 mRNA at least within the seed region. The "seed region" refers to a region within the 2nd-8th nucleotide of the single-stranded oligonucleotide described in the present disclosure, at which the single-stranded oligonucleotide described in the present disclosure can better mediate the RNAi effect to inhibit the level of the CC3 mRNA. In some embodiments, the single-stranded oligonucleotide is substantially reverse complementary or completely reverse complementary to the CC3 mRNA over a length of at least 16 nucleotides. In some embodiments, the nucleotide sequence of the 2nd-19th nucleotide of the single-stranded oligonucleotide is completely reverse complementary to the CC3 mRNA in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence of the single-stranded oligonucleotide other than the 1st nucleotide at the 5' end is completely reverse complementary to the CC3 mRNA in the direction from the 5' end to the 3' end. In some embodiments, all the nucleotides of the single-stranded oligonucleotide are completely reverse complementary to the CC3 mRNA. In some embodiments, the single-stranded oligonucleotide of the present disclosure contains a nucleotide sequence II, which is equal in length to the nucleotide sequence shown in SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2AGAUGAUGAGGGUGUUCC-3' (SEQ ID NO: 2), wherein Z2 is U, the nucleotide sequence II contains a nucleotide Z'2 at the position corresponding to Z2, and Z'2 is the 1st nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In the foregoing and hereinafter of the present disclosure, "position corresponding" refers to the same position in a nucleotide sequence, counting from the same end of the nucleotide sequence, e.g., the 1st nucleotide at the 5' end of the nucleotide sequence II is the nucleotide at the position corresponding to the 1st nucleotide of SEQ ID NO: 2. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 2. The base difference between the 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 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: 2 can include a difference at position Z'2 and / or a base difference at a nucleotide position adjacent to Z'2. In some embodiments, the nucleotide sequence II has no base difference from the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the 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 A, C, or G. In some embodiments, the base difference between the 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 A, C, or G. In some embodiments, 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 the non-fluoro-modified nucleotides, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to CC3 mRNA, and 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 1-3 carbon atoms, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition, from the 5' end to the 3' end, is UA. In some embodiments, the single-stranded oligonucleotide of the present disclosure 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, 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 a double-stranded oligonucleotide; and 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 1-3 carbon atoms, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and in the direction from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxyribonucleotides, 2 consecutive uracil ribonucleotides, or fully reverse complementary to CC3 mRNA. In some embodiments, the nucleotide sequence V of the present disclosure is linked to the 3' end of the nucleotide sequence II, and in the direction from 5' end to 3' end, the base composition of the nucleotide sequence V is UU, TT, TA or UA, the T or U is a methoxy-modified nucleotide or GNA, and the A is a methoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of the present disclosure is the antisense strand of any one of siCC1-siCC5 shown in Table 1. In some embodiments, the single-stranded oligonucleotide of the present disclosure is the antisense strand of any one of conjugate 1-conjugate 5 shown in Table 2. Double-stranded oligonucleotide of the present disclosure In another aspect, the present disclosure also provides a double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present disclosure as the antisense strand, the double-stranded oligonucleotide containing a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, the sense strand and the antisense strand being at least partially reverse complementary to form a double-stranded region, wherein the antisense strand is the single-stranded oligonucleotide of the present disclosure described above. In some embodiments, the length of the antisense strand of the double-stranded oligonucleotide of the present disclosure 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 to the length of the antisense strand of the double-stranded oligonucleotide of the present disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, for the sake of synthesis convenience, 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 length of the antisense strand are the same, both being 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. 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, in the direction from the 3' end to the 5' end, 2-3 of the 11th-13th nucleotides of the sense strand are fluorine-modified nucleotides, the 1st 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)), and the nucleotides at the remaining positions 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 directly connected to the ribose ring shown in formula (35) 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 directly connected to the ribose ring shown in formula (35) can be connected to the 3' phosphate group of the 3' terminal nucleotide of the sense strand, and the oxygen atom shown in formula (35) connected to the ribose ring via a methylene group can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the methylene-linked oxygen atom shown in formula (35) can be linked to the 5' phosphate group of the 5' terminal second last nucleotide of the sense strand. In some embodiments, the methylene-linked oxygen atom shown in formula (35) is linked to the 5' phosphate group of the 5' terminal second last nucleotide of the sense strand, and the directly linked oxygen atom shown in formula (35) can be linked to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, in the sense strand of the double-stranded oligonucleotide of the present disclosure, the 11th and 13th nucleotides, or 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 abasic deoxynucleotide, and the remaining positions are alkoxy-modified nucleotides. At this time, by the position cooperation of the modified nucleotides of the sense strand and the antisense strand, the double-stranded oligonucleotide of the present disclosure has better stability and / or activity of forming a RISC complex, 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 two adjacent nucleotides is a phosphate group with a modification group, which is present between two adjacent nucleotides in the 1stto 5thnucleotide from the 5' end and between two adjacent nucleotides in the 1stto 5thnucleotide from the 3' end of the sense strand. In this case, the double-stranded oligonucleotide of the present disclosure has the ability to resist nucleic acid exonuclease and good balance of CC3 mRNA, so as to have high efficient CC3 mRNA inhibitory activity while improving stability. In some embodiments, 1-4 of the linking groups between adjacent nucleotides in the 1stto 5thnucleotide from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1stto 5thnucleotide from the 3' end of the sense strand are phosphate groups with a modification group. In some embodiments, each of all 4 of the linking groups between adjacent nucleotides in the 1stto 5thnucleotide from the 5' end of the sense strand is independently a phosphate group with a modification group. In some embodiments, each of all 4 of the linking groups between adjacent nucleotides in the 1stto 5thnucleotide from the 3' end of the sense strand is independently a phosphate group with a modification group. In some embodiments, the linking group linking two adjacent nucleotides in the 1stto 3rd, 1stto 4thor 1stto 5thnucleotide from the 5' end and / or 3' end of the sense strand is a phosphate group with a modification group. In some embodiments, the linking group between adjacent nucleotides in the 1stto 3rdnucleotide from 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 that 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 siCC1-siCC5 shown in Table 1; in some embodiments, the sense strand is the sense strand possessed by any one of conjugate 1-conjugate 5 shown in Table 2. In some embodiments, the sense strand comprises 19-21 nucleotides, the antisense strand comprises 21-23 nucleotides; the 11th and 13th nucleotides, or the 11th-13th nucleotides of the sense strand from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide of the sense strand is a methoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all methoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides at the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides at the 1st-5th nucleotides at the 3' end of the sense strand are phosphorothioate groups. In some embodiments, the linking group between every two adjacent nucleotides at the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 5' end and / or the 3' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are connected by phosphate groups. In some embodiments, the linking group between every two adjacent nucleotides at the 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 5' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are connected by phosphate groups. In some embodiments, the linking group between every two adjacent nucleotides at the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides at the 3' end of the sense strand is a phosphorothioate group, and the remaining adjacent nucleotides in the sense strand are connected by phosphate groups. In some embodiments, all adjacent nucleotides in the sense strand are connected by phosphate groups. In some embodiments, in the double-stranded oligonucleotide of the present disclosure, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; in the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is a methoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy (such as methoxy) -modified nucleotides; 1-4 of the linking groups between adjacent nucleotides at the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides at the 1st-5th nucleotides at the 3' end of the sense strand are phosphorothioate groups. 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 is an alkoxy-modified nucleotide or an inverted deoxy nucleotide, and each of the remaining nucleotides is independently an alkoxy-modified nucleotide; 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 each independently a phosphate group with a modification group; in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxy nucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In some embodiments, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxy nucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In some embodiments, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxy nucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide. In some embodiments, in the antisense strand, the 12th and 14th nucleotides from the 5' end to the 3' end are deoxy nucleotides, the 2nd, 7th and 16th nucleotides are fluoro-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide.In some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluoro-modified nucleotides, the 5th and 13th nucleotides are each independently a substituted alkoxy-modified nucleotide or an alkoxy-modified nucleotide, the 2nd nucleotide of the antisense strand is a thermally unstable nucleotide in the 5' end to 3' end direction, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; in some embodiments, in the antisense strand, the 14th nucleotide is a deoxy nucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluoro-modified nucleotides, the 5th and 13th nucleotides are each independently a substituted alkoxy-modified nucleotide or an alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; in the antisense strand, the linkage between two adjacent nucleotides of the 1st to 3rd nucleotides at the 5' end of the antisense strand and the linkage between two adjacent nucleotides of the 1st to 3rd nucleotides at the 3' end of the antisense strand are phosphodiester groups with a modification group, and if there is an unmodified nucleotide, 1-2 of the 2 linkages between each of the unmodified nucleotides and the adjacent nucleotides are phosphodiester groups with a modification group. In some embodiments, the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (34) or a 5'-vinylphosphonate-modified nucleotide represented by formula (30). The double-stranded oligonucleotide of the present disclosure can achieve a good balance between gene expression regulation 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, 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 can achieve a good balance between gene expression regulation 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, and the double-stranded oligonucleotide of the present disclosure can achieve a good balance between CC3 mRNA inhibition 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 complemented or fully reverse complemented, 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 complemented or fully reverse complemented, and one overhanging end of the antisense strand. In the context of the present disclosure, a "double stranded region" is a double stranded structure formed between the shortest nucleotide sequence of all base-paired bases and all base mismatches located between the base-paired bases on each single strand in a double stranded nucleic acid structure. Thus, a 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, a double stranded nucleic acid structure includes a double stranded region and one or more overhanging ends consisting of unpaired nucleotides on one or both single strands. In some embodiments, a double stranded nucleic acid structure includes only a double stranded region. In some embodiments, the sense strand and the antisense strand form a double stranded region spanning at least 16 nucleotide positions. The sense strand and the antisense strand form a double stranded region spanning 16-23 nucleotide positions. In some embodiments, the sense strand and the antisense strand form a double stranded region spanning 18, 19, 20, or 21 nucleotide positions. In some embodiments, the sense strand and the antisense strand are substantially reverse complemented or fully reverse complemented 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 complemented or fully reverse complemented over the entire length of the nucleotides. In some embodiments, the number of base differences between the sense strand and the CC3 mRNA is no more than 3, or no more than 2, or no more than 1. In some embodiments, there is no base difference between the sense strand and the CC3 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 the same position in the former is different from that in the latter, e.g., if the base type of a nucleotide in the latter is A, and the base type of a corresponding nucleotide in the former is U, C, G, or T, then the two nucleotide sequences are considered to have a base difference at the position. When a base is modified, as long as the modified base does not affect the purine-pyrimidine pairing relationship when forming the double-stranded nucleic acid structure described above, the modified base and the original base are considered to have no base difference. In some embodiments, U and T are considered to have no base difference. In some embodiments, C and 5-methylcytosine (5mC) are considered to have no base difference. In some embodiments, a nucleotide at a position is replaced with an abasic nucleotide or an equivalent thereof, and the replacement is considered to result in a base difference 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. In this case, "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, then "the same position" refers to nucleotide sequence A position 1 aligned with nucleotide sequence B position 2, nucleotide sequence A position 2 aligned 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 CC3 gene. In some embodiments, the double-stranded oligonucleotide can be one that inhibits or down-regulates the expression of CC3 gene, such as siRNA; in some embodiments, the double-stranded oligonucleotide can be one that activates or up-regulates the expression of CC3 gene, such as saRNA. In some embodiments, the double-stranded oligonucleotide is siRNA. In some embodiments, the present disclosure provides a siRNA. The siRNA contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence I, the nucleotide sequence I consists of 19 nucleotides, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 1, and has no more than 3 base differences, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-GGAACACCCUCAUCAUCUZ1-3' (SEQ ID NO: 1); 5'-Z2AGAUGAUGAGGGUGUUCC-3' (SEQ ID NO: 2), wherein Z1 is A or ia, Z2 is U, the nucleotide sequence I contains a nucleotide Z'1 at a position corresponding to Z1, 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' end of the single-stranded oligonucleotide sequence. In some embodiments, the sense strand contains only the nucleotide sequence I, and the antisense strand contains 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: 1, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 can include a difference at the Z'1 position 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: 1 can include a base difference at the Z'1 position and / or at a nucleotide position adjacent to Z'1. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 is a base difference at the Z'1 position, preferably, Z'1 is an alkoxy-modified nucleotide or an inverted deoxy nucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 includes a difference at the Z'2 position, and Z'2 is selected from A, C or G. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 is a difference at the Z'2 position, and Z'2 is selected from A, C or G. In some embodiments, the nucleotide at position 3-19 of the nucleotide sequence II is fully reverse-complementary to the CC3 mRNA in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence II is fully reverse-complementary to the nucleotide sequence I. Alternatively, the 2nd nucleotide in the nucleotide sequence II is base-mismatched with the 2nd nucleotide in the nucleotide sequence I in the 3' end to 5' end direction. By including the base-mismatch, one can have higher CC3 gene expression 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 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 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 5' to 3' direction; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20; or the length of the nucleotide sequence III and IV is 2 nucleotides, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21; or the length of the nucleotide sequence III and IV is 3 nucleotides, the base composition of the nucleotide sequence III is AGG, and the base composition of the nucleotide sequence IV is CCU, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22; or the length of the nucleotide sequence III and IV is 4 nucleotides, the base composition of the nucleotide sequence III is AAGG, and the base composition of the nucleotide sequence IV is CCUU, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some embodiments, the length of the nucleotide sequence III and the nucleotide sequence IV is 2 nucleotides, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. In some embodiments, the antisense strand of the present disclosure further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently one of the non-fluorine-modified nucleotides, the length of the nucleotide sequence V is 1 to 3 nucleotides, and the nucleotide sequence V is connected to the 3' end of the nucleotide sequence II or IV to form the 3' overhanging end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 to 3 nucleotides, one of the nucleotides in the nucleotide sequence V is a thermally unstable nucleotide, and the remaining nucleotides are methoxy-modified nucleotides. In some embodiments, in order to obtain good pharmaceutical activity, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or completely reverse complementary to CC3 mRNA, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence V is connected to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is TA or UA, in the 5' end to 3' end direction. In some embodiments, the aforementioned thermally unstable nucleotide refers to the second nucleotide of the nucleotide sequence V, in the 3' end to 5' end direction. In some embodiments, one of the nucleotides in the nucleotide sequence V is a thermally unstable nucleotide, and the other nucleotide is a methoxy-modified nucleotide. In some embodiments, 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 5' end to 3' end direction, is TA or UA, wherein the T or U is a methoxy-modified nucleotide or GNA, and the A is a methoxy-modified nucleotide. In some embodiments, the double-stranded oligonucleotide is one of siCC1, siCC2, siCC3, siCC4, or siCC5 shown in Table 1 below: Table 1 siRNA sequences of the disclosure wherein, capital letters C, G, U, A and T represent the base composition of the nucleotides; the lower case letter o represents that the nucleotide represented by the capital letter adjacent to the left of the letter o is an alkoxy-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 fluoro-modified nucleotide; the combination of capital letters in brackets (NS) represents that the nucleotide represented by the capital letter adjacent to the left of the letter S is a substituted alkoxy-modified nucleotide, wherein N is C, G, U, A or T; the italic capital letter U represents a heat-unstable modified uracil nucleotide; the lower case letter s represents that the two nucleotides represented by the two capital letters adjacent to the left and right of the letter are connected by a phosphorothioate group; the lower case letter d represents that the nucleotide represented by the capital letter adjacent to the right of the letter is a deoxy-nucleotide; ia represents an inverted abasic deoxy-nucleotide; the lower case letter r represents that the nucleotide represented by the letter adjacent to the right of the letter is an unmodified nucleotide; and each X in the above sequence is independently T or U. The antisense strand and / or the double-stranded oligonucleotide provided by the disclosure can be obtained by the conventional oligonucleotide preparation methods in the art, such as the methods of solid-phase synthesis and liquid-phase synthesis. Among them, the solid-phase synthesis has been commercialized and can be ordered. The methods of preparing nucleoside monomers with corresponding modifications and introducing modified nucleotide groups into the antisense strand and / or the double-stranded oligonucleotide described by the disclosure can also be well known to those skilled in the art by using nucleoside monomers with corresponding modifications. All modified nucleoside monomers can be commercially available or prepared by known methods. The double-stranded oligonucleotide provided by the disclosure can be used alone, or form a pharmaceutical composition with a pharmaceutically acceptable carrier, or be combined with a delivery group to form an oligonucleotide conjugate, or be used in any other suitable form. An effective amount of the double-stranded oligonucleotide, 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 double-stranded oligonucleotide, 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 conjugates In another aspect, the present disclosure provides an oligonucleotide conjugate containing a double-stranded oligonucleotide group and a delivery group conjugated to the double-stranded oligonucleotide group, the double-stranded oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from a double-stranded oligonucleotide provided by the present disclosure. In the context of the present disclosure, "conjugation" refers to the connection of two or more chemical moieties each having a specific function to each other in a covalent linkage; correspondingly, "conjugate" refers to a compound formed by the covalent linkage between the respective chemical moieties. Further, "oligonucleotide conjugate" denotes 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, "conjugation molecule" should be understood as a specific compound that can be conjugated to an oligonucleotide by a reaction to eventually form an oligonucleotide conjugate of the present disclosure. The delivery group is a group for delivering the double-stranded oligonucleotide group into a cell expressing CC3 mRNA. In some embodiments, the delivery group comprises a linker and a pharmaceutically acceptable targeting group, and the double-stranded oligonucleotide group, the linker 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. In some embodiments, each of the targeting groups independently targets one or more of the central nervous system, the liver, the kidney, the lung, the muscle and the eye. In some embodiments, the targeting groups are 1-6. In one embodiment, the targeting groups are 2-4. The double-stranded oligonucleotide group can be non-covalently or covalently conjugated to the delivery group, for example, can be covalently conjugated to the delivery group. The conjugation site of the double-stranded oligonucleotide group to the delivery group can be at the 3' end or the 5' end of the sense strand of the double-stranded oligonucleotide, can also be at the 5' end of the antisense strand, and can also be 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 at 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 at the 3'- or 5'-terminal of 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 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 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 double-stranded 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 double-stranded oligonucleotide. For non-degradable conjugation, the delivery group can be connected to the sense strand of 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 double-stranded oligonucleotide group via a suitable linker, which can be selected by a person skilled in the art according to the specific type of the targeting group. The types of these linkers, targeting groups, and the connection methods to the double-stranded 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 commonly used in the field of double-stranded oligonucleotide administration, such as various ligands described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of said targeting groups is selected from a ligand capable of binding to a cell surface receptor expressing CC3 mRNA. In some embodiments, at least one or each of said targeting groups is selected from a group capable of increasing the biocompatibility of said oligonucleotide conjugate in the central nervous system. In some embodiments, at least one or each of said targeting groups is selected from a polypeptide ligand group capable of having affinity to a receptor at the surface of a kidney cell. In some embodiments, at least one or each of said targeting groups is selected from a small molecule ligand group capable of having affinity to an asialoglycoprotein receptor at the surface of a liver parenchymal cell. Depending on the system, organ, tissue or cell targeted, the targeting groups can be selected from groups having different targeting properties. For example, all targeting groups in each delivery group have the same targeting property and are independently selected from one of the following groups: a lipophilic group or a targeting peptide group formed by a targeting peptide capable of increasing the compatibility of said conjugate in the central nervous system; a targeting peptide group, an antibody group or a small molecule group formed by a targeting peptide, an antibody or a small molecule having affinity to a muscle tissue or a muscle cell surface receptor; a targeting peptide group or an antibody group formed by a targeting peptide or an antibody having affinity to a transferrin receptor (TfR); a targeting peptide group formed by a targeting peptide having affinity to a lung, a lung tissue or a lung cell surface receptor; a small molecule ligand group having affinity to an avb6 receptor; a targeting peptide group, an aptamer group or an antibody group formed by a targeting peptide, an aptamer or an antibody having affinity to a tumor cell surface receptor; a targeting peptide group having affinity to a kidney cell surface receptor; a small molecule ligand group having affinity to an asialoglycoprotein receptor at the surface of a liver parenchymal cell. In some embodiments, at least one or each of said targeting groups is selected from one of a lipophilic group or a targeting peptide group. In some embodiments, each of said targeting groups is a C5-C 18 In some embodiments, at least one or each of said targeting groups is selected from one of a targeting peptide group or an antibody group formed by a targeting peptide or an antibody having affinity to a transferrin receptor (TfR). In some embodiments, at least one or each of said targeting groups is selected from a small molecule ligand group having affinity to an avb6 receptor. In some embodiments, at least one or each of said targeting groups is selected from one of a targeting peptide group, an aptamer group or an antibody group formed by a targeting peptide, an aptamer or an antibody having affinity to a tumor cell surface receptor. In some embodiments, at least one or each of said targeting groups is selected from a targeting peptide group having affinity to a kidney cell surface receptor. In some embodiments, at least one or each of the targeting groups is selected from a ligand that is 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 that has 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 sugar. In some embodiments, each of the targeting groups is independently selected from one 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. In some embodiments, at least one or each of the targeting groups is galactose or N-acetylgalactosamine. In some embodiments, the double-stranded oligonucleotide group is capable of modulating the expression level of CC3 mRNA in liver parenchymal cells. 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 linker 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, denotes the site of covalent attachment of the group; all L A attached to the same atom in C ; or each L Aindependently connected to L C different atoms. independently connected to L C has a structure of -NH-C(H) n301 (CH2O-) k as shown in the structure, 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. independently connected to L A has a structure containing an amide bond as shown in formula (302), L B has a structure as shown in 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, denotes the site of covalent attachment of the group. In some embodiments, the linker has a structure as shown in formula (304) or formula (305): In the linker, each L A is connected to one of the targeting groups through an ether bond, respectively, and is connected through the oxygen atom of the hydroxyl group in the L C moiety to form an ether bond with the L C moiety; L B is connected through the carbonyl group in formula (303) to the nitrogen atom of the amino group in the L C moiety to form an amide bond, and is connected through the oxygen atom in formula (303) to the double-stranded oligonucleotide group through an oxygen atom to form a phosphonate bond or a thiophosphonate bond. In some embodiments, the oligonucleotide conjugate provided by the present disclosure has a structure as shown in formula (309): wherein Nu represents a double-stranded oligonucleotide group formed by the double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the linkers in the oligonucleotide conjugates of this disclosure have the structure shown in formula (306): Where, n 306 For each p, the integer is between 0 and 3. 306 Independently, integers from 1 to 6. The site indicates a covalently linked group; the linking group is connected to the target group by an ether bond formed by an oxygen atom marked with *; the linking group is connected to the double-stranded oligonucleotide by at least one of the oxygen atoms marked with # forming a phosphate ester bond or a thiophosphate ester bond, and the remaining oxygen atoms marked with # are connected to hydrogen atoms to form hydroxyl groups, or connected to C1-CC3 alkyl groups to form C1-CC3 alkoxy groups; In some embodiments, the oligonucleotide conjugates of this disclosure have a structure as shown in formula (307): Wherein, Nu represents the double-stranded oligonucleotide group formed from the double-stranded oligonucleotides provided in this disclosure. In some embodiments, the oligonucleotide conjugates of this disclosure have the structure shown in formula (308): in, n 308 The integers are selected from 2 to 4; Each m 308 Independently selected as an integer from 2 to 5; Each R 308 Independently a hydrogen atom, methyl or ethyl, or two R atoms attached to the same carbon atom. 308 Together with this carbon atom, they form a carbonyl group; One A0 is a double-stranded oligonucleotide group, which is a group formed by removing one atom or group of atoms from the double-stranded oligonucleotide described in this disclosure; the remaining A0s are all targeting groups, each of which may be the same or different, and their definition and selection range are as described above. In some embodiments, each targeting group is independently selected from a ligand that has an affinity for the desialylate glycoprotein receptor on the surface of mammalian hepatocytes. Each L1 is independently a divalent linker with a length of 3-25 atoms; This indicates the site where the group is covalently linked. In some embodiments, each L1 is independently a straight-chain alkylene group with a length of 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C10 alkenylene, C2-C 10 alkynylene, C6-C 10 arylene, CC3-C 18 heterocyclylene, and C5-C 10 heteroarylene; and said straight-chain alkylene can optionally have one or more substituents 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-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-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 10haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). It will be understood by the skilled person that, although for convenience L1is defined as being a linker group formed by replacement or substitution from a linear alkylene, it can not be a linear group or an amine or alkenyl group resulting from the above-mentioned replacement and / or substitution. Unless otherwise stated, the "length" of any group in the chemical structures recited in this disclosure refers to the number of atoms in the longest chain of atoms in the group, not counting hydrogen atoms; in the calculation of the length of a group, where there are multiple ways of connecting two atoms (e.g., the two atoms belong to the same cyclic group, so that there are at least 2 chains of atoms that include the two atoms), the length is calculated 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 calculated as 4 atoms in length, while 1,2-cyclopentanediyl is calculated as only 2 atoms in length. The role of L1covalently linked to A0representing a double-stranded oligonucleotide group is to covalently link the double-stranded oligonucleotide group to the targeting group, to enable the oligonucleotide conjugate comprising the double-stranded oligonucleotide group to enter a cell expressing CC3 mRNA via the targeting of the targeting group, and not to affect the CC3 mRNA level modulating effect of the double-stranded oligonucleotide group after entering the cell expressing CC3 mRNA. Thus, in some embodiments, L1covalently linked to A0representing a double-stranded oligonucleotide group has a length of 3-20 atoms, or 4-15 atoms, or 5-12 atoms. In some embodiments, L1covalently linked to A0representing a double-stranded oligonucleotide group is selected from one or more of the following combinations of A1, A2, A4, A5, A10, A16, A18, and A19 with 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 A16 with a phosphate group or a modified phosphate group; in some embodiments, R2is selected from at least two of the following combinations of A1, A2, A10 with a phosphate group or a modified phosphate group. In some embodiments, L1covalently linked to A0representing a double-stranded oligonucleotide group has a structure as shown in formula (B1), (B2), (B3) or (B4): wherein, represents a site where a group is covalently linked, L B1 and L B2 are the same or different, 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 q1is an integer from 1 to 6, L B1 and L B2 each independently have a length of from 1 to 20 atoms. In some embodiments, L B1 and L B2 each independently have a length of from 1 to 10 atoms. In some embodiments, L B1 and L B2 each independently have a length of from 1 to 6 atoms. L B3 is selected from one of a phosphate group, a thiophosphate group, a dithiophosphate group, covalently linked 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 phosphate group, covalently linked 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, where the oligonucleotide conjugate of the disclosure is prepared by a process of solid phase synthesis, L1covalently linked to A0representing a double-stranded oligonucleotide group needs to contain simultaneously a linking site to N on the nitrogen-containing backbone, a linking site to the double-stranded oligonucleotide group and a functional group capable of linking to a solid support. In some embodiments, the linking site to N on the nitrogen-containing backbone forms an amide bond with N, the double-stranded oligonucleotide group is covalently linked by a phosphate bond and the functional group capable of linking to a solid support is a hydroxyl group or an amino group in L1covalently linked to A0representing a double-stranded oligonucleotide group. In some embodiments, R2is B5, B6, B5’ or B6’: wherein, represents a site where a group is covalently linked. q2 can be an integer from 1 to 10, and in some embodiments, q2 is 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 a mammalian hepatocyte surface receptor, thereby specifically targeting and entering the liver cell. Thus, 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 chemical properties do not significantly affect 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 independently 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 formulas (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, the site to which the group is covalently linked. 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 formulas (L3)-(L7). In some embodiments, each connection unit independently has a structure represented by any one of formulas (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 connected 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 the number and spacing that can provide a proper spatial configuration of multiple targeting groups. 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, which does not affect 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 one of ligands having affinity to receptors on the surface of mammalian liver parenchymal cells. In some embodiments, at least one or each targeting group is one of ligands having affinity to asialoglycoprotein receptor (ASGPR) on the surface of mammalian liver parenchymal cells. In some embodiments, each targeting group is a galactose group or an N-acetylgalactosamine group formed by removing one atom or group from galactose or N-acetylgalactosamine. 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 an inverted abasic deoxynucleotide, 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 inverted abasic deoxynucleotide 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) to (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) to (422) is covalently linked to the oxygen atom of the inverted abasic deoxynucleotide ia shown in formula (35) at the 3’ terminal of the sense strand of the siRNA represented by Nu via a methylene group to the ribose ring, thereby covalently linking to the sense strand of the siRNA. In some embodiments, the double-stranded 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 double-stranded 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 CC3 mRNA inhibitory activity. In some embodiments, the oligonucleotide conjugate of the present disclosure is one of Conjugate 1 to Conjugate 5 listed in Table 2. Preparation of the oligonucleotide conjugate of the present disclosure The above oligonucleotide conjugate can be synthesized by methods that have been described in detail in the prior art. For example, the preparation of various siRNA conjugates is described in detail in WO2015006740A2. In the case of the double-stranded oligonucleotide being an siRNA, the oligonucleotide conjugate of the present disclosure can also be obtained by means well known to those skilled in the art. The preparation of the structure shown in formula (305) is described in WO2014025805A1, and the preparation of the structure shown in formula (307) is described in Rajeev et al., ChemBioChem 2015, 16, 903-908. The preparation 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. Pharmaceutically acceptable salts are 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 exhibit better solubility, bioavailability or stability than the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate per se. In the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate described in the present disclosure, each adjacent nucleotide is connected by a phosphodiester bond or a phosphorothioate bond, and the non-bridging oxygen atom or the sulfur atom in the phosphodiester bond or the phosphorothioate bond 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 + Further, there can also be a salt-forming group in the delivery 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 calcium salt or a magnesium 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 of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate, which is selected from a calcium salt, a magnesium salt or a sodium salt. 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 double-stranded oligonucleotide, the oligonucleotide conjugate and the pharmaceutically acceptable salt provided in the present disclosure, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is one or more of various ingredients conventionally used in the art, such as one or more of a solvent, a protective agent, an osmotic pressure regulator 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, a pH buffer, physiological saline, ethanol, an aqueous ethanol solution. The pH buffer can be a tris-hydroxymethyl aminomethane hydrochloride buffer having a pH of 7.5 to 8.5 and / or a phosphate buffer having a pH of 5.5 to 8.5, for example, a phosphate buffer having a pH of 5.5 to 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 to 20 mg / mL, 0.1 mg / mL to 10 mg / mL, or 0.5 mg / mL to 5 mg / mL, based on the amount of the oligonucleotide group in the oligonucleotide. The protective agent can be at least one of inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The content of the protective agent can be 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 content of the osmotic pressure adjusting agent is such that the osmotic pressure of the pharmaceutical composition is 200 to 700 milliosmoles per kilogram (mOsm / kg). The content 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 dose of the pharmaceutical composition prepared as a formulation is adjusted according to the administration method during administration. In some embodiments, the pharmaceutical composition can be a liquid formulation such as an injection solution, or a lyophilized powder for injection 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 administration, and can be, but is not limited to, delivered by spraying to the lungs, or by spraying to other organ tissues (e.g., the liver) via the lungs, or by oral administration, etc. In some embodiments, the pharmaceutical composition is administered by subcutaneous injection. The pharmaceutically acceptable carrier can be one or more of the carriers conventionally used in the field of administration of double-stranded oligonucleotides, such as, but not limited to, magnetic nanoparticles (e.g., nanoparticles based on Fe3O4or 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 group in the oligonucleotide conjugate to the pharmaceutically acceptable carrier can be 1: (1-500), and in some embodiments, the 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 (herein incorporated 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 as 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 C1-C 20 hydrocarbon chain; Y 101 and Z 101 each independently is C=0, C=S, S=0, CH-OH, or S02; 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 unbranched aliphatic group, a cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic group, a substituted or unsubstituted, branched or unbranched acyl group, a substituted or unsubstituted, branched or unbranched aryl group, a substituted or unsubstituted, branched or unbranched 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 103 and 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, each of R 101 and R 102 in formula (201) is independently any substituted or unsubstituted, branched or unbranched 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 formulas (204)-(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 R 103 possible points 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). 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 auxiliary lipid is cholesterol, an analog of cholesterol, and / or a derivative of cholesterol; The PEGylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine-N- [methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio among the organic amine, the auxiliary lipid, and the PEGylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, it can be (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed by the double-stranded oligonucleotide of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm, for example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, in the pharmaceutical composition formed by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of the oligonucleotide or oligonucleotide conjugate (calculated as the oligonucleotide group) to the total lipid (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 (calculated as the oligonucleotide group) to the total lipid 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 by 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 double-stranded oligonucleotide 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 according to the above-mentioned molar ratio and mixed uniformly 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 of the present disclosure is dissolved in a buffered salt solution to obtain an aqueous double-stranded oligonucleotide solution. The concentration of the buffered salt solution is 0.05-0.5 M, for example, it can be 0.1-0.2 M, the pH of the buffered salt solution is adjusted to 4.0-5.5, for example, it can be 5.0-5.2, the amount of buffered salt solution is such that the concentration of the oligonucleotide or oligonucleotide conjugate (calculated as the oligonucleotide group) does not exceed 0.6 mg / mL, for example, it can be 0.2-0.4 mg / mL. The buffered 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 oligonucleotide or oligonucleotide conjugate aqueous solution are mixed, and the product obtained after mixing is incubated at 40-60°C for at least 2 minutes, for example, 5-30 minutes, to obtain the liposome preparation after incubation. The volume ratio of the lipid solution and the oligonucleotide or oligonucleotide conjugate aqueous solution is 1:(2-5), for example, 1:4. 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, which has the physicochemical parameters of pH 6.5-8, encapsulation efficiency not less than 80%, particle size 40-200 nm, polydispersity index not higher than 0.30, and osmotic pressure 250-400 mOsm / kg; for example, the physicochemical parameters can be pH 7.2-7.6, encapsulation efficiency not less than 90%, particle size 60-100 nm, polydispersity index not higher than 0.20, and osmotic pressure 300-400 mOsm / 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, a hollow fiber column, ultrafiltration under the condition of 100 KDa, and the ultrafiltration exchange solution is a phosphate buffer (PBS) with pH 7.4. The method for sterilization can use various existing methods, for example, filtration sterilization on a 0.22 μm filter. Applications of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate and pharmaceutical composition of the present disclosure The present disclosure also provides the use of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate of the present disclosure, pharmaceutically acceptable salt of the present disclosure or pharmaceutical composition of the present disclosure in a medicament for treating and / or preventing a disease or symptom associated with the level of CC3 mRNA. The present disclosure also provides a method for treating and / or preventing a disease or symptom associated with the level of CC3 mRNA, which comprises administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate of the present disclosure, pharmaceutically acceptable salt of the present disclosure and pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition associated with CC3 mRNA levels is selected from the group consisting of primary membranous nephropathy, hemolytic uremic syndrome, CC3 glomerulopathy, IgA nephropathy, diabetic nephropathy, polycystic kidney disease, membranous nephropathy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), age-related macular degeneration, an ophthalmic disease, rheumatoid arthritis, and periodontitis. In some embodiments, the disease or condition associated with CC3 mRNA levels is selected from the group consisting of CC3 glomerulopathy, myasthenia gravis (MG), IgA nephropathy, diabetic nephropathy, polycystic kidney disease, and periodontitis. The present disclosure also provides a method of treating and / or preventing a disease or condition associated with CC3 mRNA levels, the method comprising administering to a subject in need thereof an effective amount of a double-stranded oligonucleotide and / or oligonucleotide conjugate of the present disclosure and / or a pharmaceutical composition of the present disclosure. Further, the present disclosure also provides a method of modulating the level of CC3 mRNA expression in a cell, the method comprising contacting an effective amount of a double-stranded oligonucleotide and / or oligonucleotide conjugate and / or pharmaceutically acceptable salt and / or pharmaceutical composition of the present disclosure with a cell expressing CC3 mRNA. The term "administering / administration" as used herein refers to the placement of an oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition into the subject's body by a method or route which results in at least partial localization of the oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition at 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 oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition to a particular site as compared to the entire body of the subject, while systemic administration results in delivery of the oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition to substantially the entire body of the subject. The subject can be administered 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 oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition described herein can be a conventional dosage in the art, which can be determined according to various parameters, especially the age, weight, and gender of the subject. Toxicity and therapeutic efficacy of the siRNA, pharmaceutical composition, and / or siRNA conjugate described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose range for humans can be based on data obtained from cell culture assays and animal studies. In administering the siRNA, pharmaceutical composition, and / or siRNA conjugate described herein, for example, for male or female, 6-12 week old, 18-25 g body weight C57BL / 6J or CC3H / HeNCrlVr mice, the amount of siRNA in the siRNA, pharmaceutical composition, and / or siRNA conjugate described herein 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, and in yet further embodiments, 0.1-10 mg / kg body weight, of siRNA formed by the siRNA and the pharmaceutically acceptable conjugate molecule. The above amounts can be preferred in administering the siRNA, pharmaceutical composition, and / or siRNA conjugate described herein. The amount of oligonucleotide in the oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and / or pharmaceutical composition provided herein for use in inhibiting the expression of CC3 mRNA in a cell can be readily determined by one skilled in the art depending on the desired effect. For example, in some embodiments, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the siRNA conjugate provided is an amount sufficient to reduce the level of CC3 mRNA and result in an extracellular concentration of 1 pM to 1 μM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM, or 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. Cells The present disclosure provides a cell expressing CC3 mRNA, the cell comprising one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate of the present disclosure, the pharmaceutically acceptable salt of the present disclosure, and the pharmaceutical composition of the present disclosure. Kit The present disclosure provides a kit comprising the oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and / or the pharmaceutical composition provided by the present disclosure. In some embodiments, the kits described herein can provide the oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and / or the pharmaceutical composition in one container. In some embodiments, the kits described herein can comprise one container providing a pharmaceutically acceptable excipient. In some embodiments, the kits can further comprise other ingredients, such as stabilizers or preservatives, etc. In some embodiments, the kits described herein can comprise at least one other therapeutic agent in a container different from the container providing the double-stranded oligonucleotide, the pharmaceutical composition, the pharmaceutically acceptable salt, and / or the conjugate described herein. In some embodiments, the kits can comprise instructions for admixing the oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and / or the pharmaceutical composition with a pharmaceutically acceptable carrier and / or adjuvant or other ingredients, if any. In the kits of the present disclosure, the oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and / or the pharmaceutical composition, and / or the pharmaceutically acceptable adjuvant can be provided in any form, such as liquid form, dry form, or lyophilized form. In some embodiments, the oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and / or the pharmaceutical composition and the pharmaceutically acceptable carrier and / or adjuvant are substantially pure and / or sterile. In some embodiments, sterile water can be provided in the kits of the present disclosure. The present disclosure will be further described by way of Examples below, but the present disclosure is not intended to be limited by any of the following. 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 and / or oligonucleotide conjugates of the present disclosure, which are examples 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), etc. 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 when forming the pharmaceutical compositions and / or oligonucleotide conjugates described in the present disclosure. Examples Unless otherwise specified, the reagents and media used in the following examples are commercially available products, and the nucleic acid electrophoresis, real-time PCR, etc. used in the following examples are performed according to the methods described in Molecular Cloning (Cold Spring Harbor Liboratory Press (1989)). Preparation Example 1-5 Synthesis of siRNA conjugates provided by the present disclosure The conjugates 1-5 in Table 2 below were prepared according to the preparation method described in Preparation Example 13 of CN110959011A, with the only difference being that the sense strand and the antisense strand of the siRNA contained in each siRNA conjugate were as shown in Table 2; for the nucleic acid sense strand and the antisense strand sequences of the siRNA with the nucleic acid numbered as the siRNA of conjugates 1-5 in Table 2 below, the nucleoside phosphoramidite monomers were connected one by one, respectively, to synthesize the sense strand and the antisense strand of the siRNA. In addition, the conjugate 1, the conjugate 2, the conjugate 4, the conjugate 5 and the reference conjugate 1 were purified by centrifugal ultrafiltration desalting using a 3K (MWCO) ultrafiltration tube. After each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (calculated based on siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight was detected by a liquid chromatograph-mass spectrometer (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters Company, model: LCT Premier), and the detection results are shown in Table 2a. The measured value is consistent with the theoretical value, indicating that the synthesized conjugates 1-5 have the target designed double-stranded nucleic acid sequence. The conjugate 1, the conjugate 2, the conjugate 4, the conjugate 5 are mixtures of methylamine salts and ammonium salts of compounds having the structure shown in formula (403); the conjugate 3 is a sodium salt of a compound having the structure shown in formula (403), wherein the P atom shown in formula (403) is covalently linked to the 3' oxygen atom of the ribose of the 3' terminal nucleotide of the sense strand of the siRNA represented by Nu or the oxygen atom connected to the ribose ring by methylene in the reverse debased deoxynucleotide ia as shown in formula (35), thereby covalently linked to the sense strand of the siRNA. And the siRNA group contained in the siRNA conjugate has the siRNA sequence corresponding to the conjugates 1-5 in Table 2, respectively. Table 2 siRNA conjugates wherein, capital letters C, G, U, A and T represent the base composition of the nucleotides; lower case letter m represents that the nucleotide represented by the letter m adjacent to the left side thereof is a 2'-methoxy modified nucleotide; lower case letter f represents that the nucleotide represented by the letter f adjacent to the left side thereof is a 2'-fluoro modified nucleotide; (moe) represents that the nucleotide represented by the letter adjacent to the left side thereof is a ribose 2'-0-methoxyethyl modified nucleotide; (gn) represents that the nucleotide represented by the letter adjacent to the left side thereof is GNA; lower case letter s represents that the nucleotides represented by the two letters adjacent to the left and right sides thereof are connected by a phosphorothioate group; lower case letter d represents that the nucleotide represented by the letter adjacent to the right side thereof is a deoxynucleotide; lower case letter r represents that the nucleotide represented by the letter adjacent to the right side thereof is an unmodified nucleotide; letter combination VP represents that the nucleotide represented by the capital letter adjacent to the right side of the letter combination is a 5'-vinylphosphonate (VP) modified nucleotide; ia represents an inverted abasic deoxynucleotide; and “_L20” represents the covalent connection of the siRNA group represented by Nu in the structure shown in formula (403) to the connection site of the connection group. Table 2a siRNA conjugate molecular weight detection results Comparative Preparation Example 1: synthesis of reference conjugate 1 In the same manner as in Preparation Example 1, the reference conjugate numbered as reference conjugate 1 in Table 2 was synthesized by solid phase synthesis method, with the difference being that the sense strand and the antisense strand of siRNA were synthesized by connecting the nucleoside phosphoramidite monomers one by one according to the base sequences of the sense strand and the antisense strand of reference conjugate 1. Reference conjugate 1 is a mixture of methylamine salt and ammonium salt of siRNA conjugate which is exactly the same in structure and sequence as conjugate 1, with the difference being in the modification scheme. Experimental Example 1: siRNA conjugate in vivo activity test in mice This experimental example investigates the in vivo activity of different concentrations of conjugate 1 and reference conjugate 1 of the present disclosure in mice. Reference conjugate 1 is a conjugate having the same sense strand as conjugate 1 of the present disclosure, but not having the antisense strand of the present disclosure. The conjugate 1 and reference conjugate 1 prepared in the preparation example were dissolved in PBS to obtain solutions with concentrations of 0.6 mg / mL, 0.2 mg / mL and 0.06 mg / mL (calculated as the amount of siRNA). Seventy mice (strain: C57BL / 6j; grade: SPF; gender: female; age: 6-8 weeks, purchased from SPFBEF) were randomly divided into 7 groups, namely test group 1-test group 3, control test group 4-control test group 6 and blank control group 7, 10 mice per group. The mice in test group 1 were given 0.6 mg / mL conjugate 1 solution by subcutaneous injection in the abdomen; the mice in test group 2 were given 0.2 mg / mL conjugate 1 solution; the mice in test group 3 were given 0.06 mg / mL conjugate 1 solution; the mice in control test group 4 were given 0.6 mg / mL reference conjugate 1 solution; the mice in control test group 5 were given 0.2 mg / mL reference conjugate 1 solution; the mice in control test group 6 were given 0.06 mg / mL reference conjugate 1 solution; the mice in blank control group 7 were given PBS solution. The body weight of each group of mice was recorded before administration, and the administration was performed according to the body weight, with a single administration amount of 5 mL / Kg of mouse body weight. On the 22nd day after administration, the mice were sacrificed, and the liver tissue was collected and stored in RNAlater. The expression level of CC3 mRNA in the liver tissue was detected by real-time fluorescent quantitative PCR. Specifically, cDNA was obtained by reverse transcription using a reverse transcription kit (Promega, item number A3500) according to the operation method of the instruction manual. The expression level of CC3 mRNA was detected using a 2x Ultra SYBR Mixture (with ROX) (Beijing Kangwei Shijisike Biological Technology Co., Ltd., item number CW0956) kit according to the steps of the instruction manual, with cDNA as the template. The PCR primers for amplifying CC3 and GAPDH as the internal reference gene are shown in Table 3. Table 3 Primer information The target gene APOC3 in each test group was relatively quantified by the comparative Ct (ΔΔCt) method, and the calculation method was as follows: ΔCt(test group) = Ct(test group target gene) - Ct(test group internal reference gene) ΔCt(control group) = Ct(control group target gene) - Ct(control group internal reference gene) ΔΔCt(test group) = ΔCt(test group) - ΔCt(control group average) ΔΔCt(control group) = ΔCt(control group) - ΔCt(control group average) Wherein, ΔCt(control group average) is the arithmetic mean of the ΔCt(control group) of each culture well of the blank control group. Thus, each culture well of the test group and the blank control group corresponds to a ΔΔCt value. The expression level of mRNA of the test group was normalized based on the average value of the blank control group, and the average value of mRNA expression level of the blank control group was defined as 100%. Relative expression level of mRNA of test group = 2-ΔΔCt(test group) x 100% Inhibition rate of mRNA of test group = (1-relative expression level of mRNA of test group) x 100%. In the present experimental example, Abcam ab263884 Mouse C3 SimpleStep Kit kit (purchased from Zhongyuanhehe Company) was used according to the instructions. The C3 protein levels in the serum of mice in each test group and the blank control group were detected at 22 days after administration, and the average value of C3 protein level in the serum of mice in the blank control group at 22 days was normalized to 100%. The relative level of serum C3 protein was calculated according to the following equation: Relative level of serum C3 protein = (serum C3 protein level of test group / average value of serum C3 protein level of control group) x 100%. Inhibition rate of serum C3 protein = 100%-relative level of serum C3 protein The inhibition rates of conjugates in mice injected with different doses of conjugate 1 and reference conjugate 1 of the present disclosure on liver tissue CC3 mRNA and serum C3 protein were summarized in Table 4 below. Table 4 Inhibition rates of CC3 mRNA and C3 protein in mice As can be seen from the results in Table 4, under the condition of different administration doses, the conjugate 1 of the present disclosure all showed significantly higher inhibition activity on CC3 mRNA in liver tissue than the reference conjugate 1. Under the condition of administration doses of 3 mg / Kg, 1 mg / Kg and 0.03 mg / Kg, the inhibition rate of CC3 mRNA of the conjugate 1 of the present disclosure was 33.8%, 21.0% and 17.4% higher than that of the reference conjugate 1, respectively. In percentage, the inhibition rate of C3 mRNA of the conjugate 1 of the present disclosure was relatively increased by 77.8%, 79.2% and 80.6% compared with the reference conjugate 1, respectively. On the other hand, the conjugate 1 of the present disclosure also showed excellent inhibition effect on C3 protein level, which was significantly higher than the reference conjugate 1 with the same sequence but different modifications. It can be seen that the double-stranded oligonucleotide conjugate using the antisense strand of the present disclosure has significantly improved inhibition activity on CC3 mRNA and the corresponding protein, and has better pharmaceutical activity. Experimental Example 2 siRNA conjugate in vivo activity test The present experimental example investigates the activity of the conjugate 1, the conjugate 2 and the reference conjugate 1 of the present disclosure in mice at the same concentration. The conjugate 1, the conjugate 2 and the reference conjugate 1 prepared in the preparation example were dissolved in PBS to a concentration of 0.6 mg / mL (in terms of the amount of siRNA) respectively. Twenty mice (strain: C57BL / 6j; grade: SPF; gender: female; age: 6-8 weeks, purchased from SPFBEF) were randomly divided into 4 groups of 5 mice each, designated as test group 2-1 to test group 2-3 and a blank group 2. Each mouse in the test group 2-1 to test group 2-3 was administered with a 0.6 mg / mL solution of the conjugate 1, the conjugate 2 and the reference conjugate 1 respectively by subcutaneous injection in the abdomen; the mice in the blank group 2 were administered with a PBS solution. The body weight of the mice in each group was recorded before administration, and the administration was performed according to the body weight, with a single administration amount of 5 mL / Kg of mouse body weight. The serum of the mice was collected on the 8th day, the 15th day and the 22nd day after administration, with the administration time point as the 1st day, and the C3 protein level in the serum of the mice was detected by using the Abeam ab263884 Mouse C3 SimpleStep The C3 protein level in the serum of the mice in the three test groups was detected on the 22nd day after administration according to the instructions of the Abeam ab263884 Mouse C3 SimpleStep Table 5 C3 protein level reduction rate in mice As can be seen from the results in Table 5, the mice administered with the conjugate 1 and the conjugate 2 of the present disclosure both showed a higher C3 protein level inhibition rate than the mice administered with the reference conjugate 1 in the 22-day experimental period, and maintained a high inhibition rate throughout the experimental period, with the C3 protein level inhibition rate still maintained at more than 60% on the 22nd day. This indicates that the conjugate of the present disclosure containing the antisense strand of the present disclosure can inhibit the expression of CC3 mRNA for a long time to reduce the C3 protein level in the serum. The conjugate of the present disclosure has good, significantly long-acting pharmaceutical activity in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to CC3 mRNA expression, and has excellent development prospects. Experimental Example 3 siRNA conjugate in vivo activity test The present experimental example investigates the activity of the conjugate 1, the conjugate 3 and the reference conjugate 1 of the present disclosure in mice at different concentrations. The conjugate 1, the conjugate 3 and the reference conjugate 1 prepared in the preparation example were dissolved in PBS to obtain solutions with a concentration of 0.6 mg / mL and 0.2 mg / mL (in terms of the amount of siRNA) respectively. Seventy mice (strain: C57BL / 6j; grade: SPF; gender: male; age: 6-8 weeks, purchased from SPFBEF) were randomly divided into 14 groups, namely test group 3-1 to test group 3-4, test group 3-7 to test group 3-9, reference test group 3-10, reference test group 3-5, reference test group 3-6, reference test group 3-11, reference test group 3-12, blank control group 3-13 and 3-14, 5 mice per group. Each mouse in the test group 3-1 and 3-7 was given 0.6 mg / mL of the conjugate 1 solution by subcutaneous injection in the abdomen; each mouse in the test group 3-2 and 3-8 was given 0.2 mg / mL of the conjugate 1 solution; each mouse in the test group 3-3 and 3-9 was given 0.6 mg / mL of the conjugate 3 solution; each mouse in the test group 3-4 and 3-10 was given 0.2 mg / mL of the conjugate 3 solution; each mouse in the reference test group 3-5 and 3-11 was given 0.6 mg / mL of the reference conjugate 1 solution; each mouse in the reference test group 3-6 and 3-12 was given 0.2 mg / mL of the reference conjugate 1 solution; each mouse in the blank control group 3-13 and 3-14 was given PBS solution. The body weight of each mouse in the above groups was recorded before administration, and the administration was performed according to the body weight, and the single administration amount was 5 mL / Kg of mouse body weight. The mice in the test group 3-1 to test group 3-4, the reference test group 3-5, 3-6 and the blank control group 3-13 were sacrificed on the 15th day after administration, and the mice in the test group 3-7 to test group 3-10, the reference test group 3-11, 3-12 and the blank control group 3-14 were sacrificed on the 43rd day after administration, and the liver tissues were collected and stored in RNAlater. The expression amount of C3 mRNA in the liver tissue was detected by real-time fluorescent quantitative PCR. Specifically, cDNA was obtained by reverse transcription using a reverse transcription kit (Promega, product number A3500) according to the operation method of the instruction manual. The expression amount of C3 mRNA was detected using a 2x Ultra SYBR Mixture (with ROX) (Beijing Kangwei Shijisike Biological Technology Co., Ltd., product number CW0956) kit according to the steps of the instruction manual. At the same time, the expression amount of C3 mRNA in the liver tissue was detected by Abcam ab263884 Mouse C3 SimpleStep The levels of C3 protein in the serum of each mouse in test groups 3-7 to 3-10, reference test groups 3-11 and 3-12, and blank control group 3-14 were detected at the 15th day and the 43rd day after administration, respectively, according to the instructions of the kit (purchased from Zhongyuan Company), and normalized to the average level of C3 protein in the serum of the mice in blank control group 3-14 on the day of detection, taken as 100%. The PCR primers for amplifying C3 and GAPDH as the internal reference gene are shown in Table 3, and the calculation methods of C3 mRNA expression, inhibition rate, and C3 protein level and inhibition rate are the same as those described in Example 2. The inhibition rates of the conjugates in mice injected with different doses of conjugate 1, conjugate 3, and reference conjugate 1 on liver tissue CC3 mRNA and serum C3 protein are summarized in Tables 6 and 7 below. Table 6 Inhibition rate of CC3 mRNA in mice Table 7 Inhibition rate of C3 protein in mice Wherein, D15 and D43 represent the detection results at the 15th day and the 43rd day after administration, respectively. As can be seen from the results in Tables 6 and 7, at the 15th day after administration, conjugate 1 and conjugate 3 of the present disclosure all showed comparable inhibition activity on C3 mRNA and inhibition rate of serum C3 protein level to reference conjugate 1 at different concentrations, and the highest inhibition rate reached 72.1%; at the 43rd day after administration, under the condition of a dose of 3 mg / Kg, the inhibition rates of conjugate 1 and conjugate 3 of the present disclosure on C3 protein level were 36.8% and 31.1% higher than those of reference conjugate 1, respectively. It can be seen that the inhibition activity of the double-stranded oligonucleotide conjugate using the antisense strand of the present disclosure on CC3 mRNA and the corresponding protein is significantly improved, and has better long-acting property. Experimental Example 4 In vivo activity test of siRNA conjugate This experimental example investigates the in vivo activity of conjugate 3, conjugate 4, and conjugate 5 of the present disclosure at different concentrations. The test was performed according to the method of Experimental Example 3, except that the conjugates administered were conjugate 3, conjugate 4, and conjugate 5, respectively, and the dose was 3 mg / kg. The inhibition rate of serum C3 protein level was detected at the 8th day, 15th day, 29th day, and 43rd day, and all 5 mice were sacrificed at the 43rd day, and the inhibition rate of liver CC3 mRNA was detected. The results are shown in Table 8. Table 8 Inhibition rate of serum C3 protein level and inhibition rate of liver CC3 mRNA in mice As can be seen from the results in Table 8, the various conjugates of the present disclosure all showed a high serum C3 protein level inhibition rate of at least 27.3% from the 8th day to the 43rd day after administration, and the highest inhibition rate can reach 74.8%; on the 43rd day after administration, the conjugates of the present disclosure all showed a high CC3 mRNA inhibition rate of at least 63.9% under the condition of a 3 mg / Kg administration dose, and the highest inhibition rate can reach 86.3%. The above results show that the conjugates of the present disclosure can efficiently inhibit the levels of CC3 mRNA and CC3 protein in the animal model in vivo experiment for a long time. As can be seen from the above results, the conjugates of the present disclosure have good and significantly long-acting pharmaceutical activities in the preparation of drugs for the treatment and / or prevention of diseases or symptoms related to CC3 mRNA expression, and have excellent development prospects. The above describes some embodiments of the present disclosure in detail, but the present disclosure is not limited to the specific details in the above embodiments, and various simple modifications can be made to the technical solutions of the present disclosure within the technical concept of the present disclosure, and these simple modifications all belong to the protection scope of the present disclosure. In addition, it should be noted that the various specific technical features described in the above embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present disclosure will not further describe various possible combination manners. In addition, various different embodiments of the present disclosure can also be combined in any manner, as long as it does not deviate from the idea of the present disclosure, and it should also be considered as disclosed by the present disclosure.

Claims

1. A single-stranded oligonucleotide of 16-30 nucleotides in length having sufficient complementarity to a Complement Component C3 mRNA 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 fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced 4-7 nucleotides from the 8th nucleotide; and, if in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all 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; 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 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, one of which is spaced 5 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide, and the other of which is spaced 3, 7, or 10 nucleotides from the 8th nucleotide of the single-stranded oligonucleotide.

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, or not more than 3.

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, 12th, 16th, 18th, and 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; the 2nd, 6th, and 16th nucleotides; the 2nd, 5th, 7th, 12th, and 16th nucleotides; the 2nd, 7th, 12th, 16th, and 19th nucleotides; or the 2nd, 6th, 12th, 16th, and 19th nucleotides of the single-stranded oligonucleotide.

10. The single stranded oligonucleotide of claim 9, wherein, In the single-stranded oligonucleotide, each modified nucleotide other than 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, the number of the heat unstable nucleotides is 1 or 2; or, each of the nucleotide X and the fluorine-modified nucleotide and each of the modified nucleotides other than the heat unstable nucleotide is selected from the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide.

12. The single stranded oligonucleotide of claim 11, wherein, the length of the single-stranded oligonucleotide is 19-23 nucleotides, and in the direction from the 5' end to the 3' end, the 14th nucleotide is the nucleotide X, two of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are the fluorine-modified nucleotides, the 3rd nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide, the 5th nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide when the 5th nucleotide is not the fluorine-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is the 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 the fluorine-modified nucleotides, and the 3rd or 5th nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is the alkoxy-modified nucleotide; or, in the direction from the 5' end to the 3' end, the 14th nucleotide and the 16th nucleotide are the nucleotide X, the 2nd and 6th nucleotides are the fluorine-modified nucleotides, the 13th nucleotide is the substituted alkoxy-modified nucleotide or BNA, and the 3rd nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide; the 5th nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide when the 5th nucleotide is not the fluorine-modified nucleotide; in the direction from the 3' end to the 5' end, one of the 1st-2nd nucleotides in the single-stranded oligonucleotide is the heat unstable nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is the alkoxy-modified nucleotide; or, in the direction from the 5' end to the 3' end, one of the 17th-19th nucleotides and the 14th nucleotide is the nucleotide X, the 2nd, 6th and 16th nucleotides are the fluorine-modified nucleotides, the 13th nucleotide is the substituted alkoxy-modified nucleotide or BNA, and the 3rd or 5th nucleotide is the alkoxy-modified nucleotide or the substituted alkoxy-modified nucleotide; and each of the remaining nucleotides in the single-stranded oligonucleotide is the 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 direction from the 5' end to the 3' end, the 14th nucleotide is the deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are the fluorine-modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is the alkoxy-modified nucleotide; or, in the direction from the 5' end to the 3' end, the 14th nucleotide is the deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are the fluorine-modified nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is the alkoxy-modified nucleotide; or, 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 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 deoxy nucleotides, the 2nd, 7th, and 16th nucleotides are fluoro-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 deoxy nucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluoro-modified nucleotides, the 5th and 13th nucleotides are each independently a substituted alkoxy-modified nucleotide or an alkoxy-modified nucleotide, in the 3' end to 5' end direction, the 2nd nucleotide 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, the 14th nucleotide is a deoxy nucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th, and 16th nucleotides are fluoro-modified nucleotides, the 5th and 13th nucleotides are each independently a substituted alkoxy-modified nucleotide or an 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 refers to a methoxy-modified nucleotide; and / or each substituted alkoxy-modified nucleotide refers to a 2'-0-methoxyethyl-modified nucleotide; and / or each BNA refers to a LNA or a cET BNA; and / or each thermally unstable nucleotide refers to a GNA.

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

16. The single stranded oligonucleotide of claim 15, wherein, 1-4, and / or 3-4, of the linking groups between adjacent nucleotides in the 1st-5th nucleotides in the 5' end, and / or the 1st-5th nucleotides in the 3' end, of the single stranded oligonucleotide are phosphoramidate groups; and / or if there are unmodified nucleotides in the single stranded oligonucleotide, 1 or both of the 2 linking groups between each of the unmodified nucleotides and the adjacent nucleotides are phosphoramidate groups; and / or 2-6, or 4, of the linking groups between adjacent nucleotides in the single stranded oligonucleotide are phosphoramidate groups.

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

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, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide, the 5'-hydroxyl nucleotide has a structure shown as formula (29); the 5'-phosphate nucleotide has a structure shown as formula (30); and the 5'-phosphate analog modified nucleotide has one selected from structures shown as formula (31) to 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; or the single-stranded oligonucleotide has a length of 21 nucleotides, and in a direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, 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 deoxynucleotide, 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 from the 1st to the 3rd nucleotides at the 5' end and the linking group between any two adjacent nucleotides from the 1st to the 3rd nucleotides 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).

20. The single stranded oligonucleotide of any one of claims 1-19, wherein, the single-stranded oligonucleotide and the CC3 mRNA are substantially complementary or completely complementary over a length of at least 16 nucleotides, or over a length of 16-25 nucleotides, or over a length of 18-23 nucleotides, or over a length of 19-21 nucleotides; and / or the nucleotide sequence of the single-stranded oligonucleotide, except for the 1st nucleotide, is completely complementary to the CC3 mRNA in a direction from the 5' end to the 3' end; or all of the nucleotides of the single-stranded oligonucleotide are completely complementary to the CC3 mRNA.

21. The single stranded oligonucleotide of any one of claims 1-20, wherein, the single-stranded oligonucleotide contains a nucleotide sequence II, which is equal in length to the nucleotide sequence represented by SEQ ID NO: 2 and has no more than 3 base differences: 5'-Z2AGAUGAUGAGGGUGUUCC-3' (SEQ ID NO: 2), wherein Z2 is 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' end of the single-stranded oligonucleotide sequence.

22. The single stranded oligonucleotide of claim 21, wherein, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence represented by SEQ ID NO: 2, or the nucleotide sequence II has no base difference from the nucleotide sequence represented by SEQ ID NO:

2.

23. The single stranded oligonucleotide of claim 21 or 22, 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 CC3 mRNA, each of the non-fluorinated modified nucleotides is independently selected from one of 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with carbon number of 1-3, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides and heat unstable nucleotides; Alternatively, the nucleotide sequence IV has a length of 2 nucleotides.

24. The single stranded oligonucleotide of claim 21 or 23, wherein, The single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide in the nucleotide sequence V is a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1-3 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 forming a double-stranded oligonucleotide; each of the non-fluorinated modified nucleotides is independently selected from one of 2'-methoxy modified nucleotides, 2'-alkyl modified nucleotides with carbon number of 1-3, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides and heat unstable nucleotides; Alternatively, the nucleotide sequence V has a length of 2 nucleotides, and in the direction from 5' end to 3' end, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides, two consecutive uracil ribonucleotides, or is completely reverse complementary to the CC3 mRNA; Alternatively, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the direction from 5' end to 3' end, the base composition of the nucleotide sequence V is TA or UA, the T or U is a methoxy modified nucleotide or GNA, and the A is a methoxy modified nucleotide; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of siCC1-siCC5 shown in Table 1; Alternatively, the single-stranded oligonucleotide is the antisense strand of any one of conjugate 1-conjugate 5 shown in Table 2.

25. A double stranded oligonucleotide comprising a sense strand and an antisense strand, each nucleotide in the sense strand being a modified or unmodified nucleotide, 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 1-24.

26. The double-stranded oligonucleotide of claim 25, wherein, The length of the sense strand is 19-21 nucleotides.

27. The double-stranded oligonucleotide of claim 26, wherein, The length of the sense strand and the antisense strand is the same, and is 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; Alternatively, the length of the sense strand is 19 nucleotides, and the length of the antisense strand is 21 nucleotides; or the length of the sense strand is 21 nucleotides, and the length of the antisense strand is 23 nucleotides.

28. The double-stranded oligonucleotide of any one of claims 25-27, wherein, In the sense strand, 2-3 of 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 abasic deoxynucleotide, and the nucleotides at the remaining positions 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, In the sense strand, 2-3 of 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 abasic deoxynucleotide, and the nucleotides at the remaining positions 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.

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 25-30, wherein, In the sense strand, at least one of the linking groups connecting two adjacent nucleotides is a phosphate group with a modification group, which exists between two adjacent nucleotides from the 1st to the 5th nucleotide at the 5' end and between two adjacent nucleotides from the 1st to the 5th nucleotide at the 3' end.

32. The double-stranded oligonucleotide of claim 31, wherein, 1-4 of the linking groups between adjacent nucleotides from the 1st to the 5th nucleotide at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides from the 1st to the 5th nucleotide at the 3' end of the sense strand are phosphate groups with modification groups; or each of the phosphate groups with modification groups is a phosphorothioate group with a structure as shown in formula (28).

33. The double-stranded oligonucleotide of any one of claims 25-32, wherein, The sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides. In the sense strand, 2-3 of the 11th-13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is a methoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; 1-4 of the linking groups between adjacent nucleotides from the 1st to the 5th nucleotide at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides from the 1st to the 5th nucleotide at the 3' end of the sense strand are phosphorothioate groups; Alternatively, the sense strand is the sense strand of any one of siCC1-siCC5 shown in Table 1; Alternatively, the sense strand is the sense strand of any one of conjugate 1-conjugate 5 shown in Table 2.

34. The double-stranded oligonucleotide of claim 33, wherein, The sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides. In the sense strand, the 11th and 13th nucleotides, or the 11-13th 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; 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides in the 1st-5th nucleotides at the 3' end of the sense strand are thiophosphonate groups; In the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, and the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; 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 the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; 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 the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; 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 the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; or, in the antisense strand, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, the 5th and 13th nucleotides are each independently substituted alkoxy-modified nucleotides or alkoxy-modified nucleotides, in the 3' end to 5' end direction, the 2nd nucleotide of the antisense strand is a thermally unstable nucleotide, and the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; or, in the antisense strand, in the 5' end to 3' end direction, the 14th nucleotide is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, the 5th and 13th nucleotides are each independently substituted alkoxy-modified nucleotides or alkoxy-modified nucleotides, and the remaining nucleotides in the antisense strand are all alkoxy-modified nucleotides; the linking groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the antisense strand and the linking groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the antisense strand are phosphonate groups with a modification group, and if there are unmodified nucleotides, the linking groups between each of the unmodified nucleotides and the adjacent nucleotides are phosphonate groups with a modification group; and The 5'-terminal nucleotide of the antisense strand is 5'-hydroxyl nucleotide represented by formula (34) or 5'-vinylphosphonate modified nucleotide represented by formula (30).

35. The double-stranded oligonucleotide of any one of claims 25-34, wherein, The double-stranded region formed by the sense strand and the antisense strand comprises 16-23 base pairs; or, the double-stranded region formed by the sense strand and the antisense strand comprises 18, 19, 20 or 21 base pairs; and / or, the sense strand and the antisense strand are substantially or completely reverse complementary to each other within the double-stranded region; And / or, the number of base differences between the sense strand and the CC3 mRNA is no more than 3, or no more than 2, or no more than 1; or, there is no base difference between the sense strand and the CC3 mRNA.

36. The double-stranded oligonucleotide of claim 35, wherein, The double-stranded oligonucleotide is siRNA.

37. The double-stranded oligonucleotide of claim 36, wherein, The sense strand comprises a nucleotide sequence I, and the antisense strand comprises a nucleotide sequence II; The nucleotide sequence I is equal in length to the nucleotide sequence represented by SEQ ID NO: 1 with no more than 3 base differences, and the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 2 with no more than 3 base differences: 5'-GGAACACCCUCAUCAUCUZ1-3' (SEQ ID NO: 1); 5'-Z2AGAUGAUGAGGGUGUUCC-3' (SEQ ID NO: 2), wherein Z1 is A or ia, Z2 is U, the nucleotide sequence I comprises a nucleotide Z'1 at a position corresponding to Z1, the 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 single-stranded oligonucleotide sequence.

38. The double-stranded oligonucleotide of claim 37, wherein, The number of base differences between the nucleotide sequence I and the nucleotide sequence represented by SEQ ID NO: 1 is no more than 1, and the number of base differences between the nucleotide sequence II and the nucleotide sequence represented by SEQ ID NO: 2 is no more than 1.

39. The double-stranded oligonucleotide of claim 38, wherein, The double-stranded oligonucleotide is one represented by siCC1, siCC2, siCC3, siCC4 or siCC5 in Table 1.

40. An oligonucleotide conjugate comprising a double-stranded oligonucleotide group and a delivery group conjugated to the double-stranded oligonucleotide group, the double-stranded oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from the double-stranded oligonucleotide of any one of claims 25-39.

41. The oligonucleotide conjugate of claim 40, wherein, The delivery group comprises a linker and a pharmaceutically acceptable targeting group, and the double-stranded oligonucleotide group, the linker 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 the compatibility with a tissue; Or, the oligonucleotide conjugate is one of Conjugate 1-Conjugate 5 listed in Table 2.

42. A pharmaceutically acceptable salt of the double-stranded oligonucleotide of any one of claims 25-39 or the oligonucleotide conjugate of claim 40 or 41. or, the pharmaceutically acceptable salt is a water-soluble salt of the oligonucleotide conjugate; or, the water-soluble salt is an amine salt or an alkali metal salt; or, the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, a quaternary ammonium salt, and the alkali metal salt is selected from a potassium salt or a sodium salt; or, the tertiary amine salt is a triethylamine salt or a triisopropylamine salt; or, the pharmaceutically acceptable salt is a sodium salt or a partial sodium salt of the double-stranded oligonucleotide or the oligonucleotide conjugate.

43. A pharmaceutical composition comprising one or more of the double-stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, and the pharmaceutically acceptable salt of claim 42, and a pharmaceutically acceptable excipient; or, the pharmaceutically acceptable excipient is one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and a pharmaceutically acceptable other carrier; or, the solvent is one of deionized water, water for injection, a pH buffer, physiological saline, ethanol, or an aqueous ethanol solution.

44. Use of the double-stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, or the pharmaceutical composition of claim 43, in the manufacture of a medicament for treating and / or preventing a disease or condition associated with CC3 mRNA level.

45. The use of claim 44, wherein, the disease or condition associated with CC3 mRNA level is selected from one or more of primary membranous nephropathy, hemolytic uremic syndrome, CC3 glomerulopathy, IgA nephropathy, diabetic nephropathy, polycystic kidney disease, membranous nephropathy, paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), age-related macular degeneration, an ophthalmic disease, rheumatoid arthritis, and periodontitis; or, the disease or condition associated with CC3 mRNA level is selected from one or more of periodontitis, CC3 glomerulopathy, myasthenia gravis, IgA nephropathy, diabetic nephropathy, and polycystic kidney disease.

46. A method of treating and / or preventing a disease or condition associated with CC3 mRNA level, the method comprising administering to a subject in need thereof an effective amount of one or more of the double-stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

47. A method of modulating CC3 mRNA expression level in a cell, the method comprising contacting the cell with an effective amount of one or more of the double-stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

48. One or more of the single stranded oligonucleotide of any one of claims 1-24, the double stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43 for use as a medicament.

49. A cell expressing CC3 mRNA, the cell comprising one or more of the single stranded oligonucleotide of any one of claims 1-24, the double stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

50. A kit comprising one or more of the single stranded oligonucleotide of any one of claims 1-24, the double stranded oligonucleotide of any one of claims 25-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

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