Oligonucleotide, oligonucleotide conjugate and composition, and use

Abstract

Provided is a single-stranded oligonucleotide having a length of 16-30 nucleotides. The single-stranded oligonucleotide has complementarity to FXI mRNA sufficient to mediate the RNAi effect. Each nucleotide in the single-stranded oligonucleotide is either modified or unmodified, wherein in the single-stranded oligonucleotide, at least one nucleotide is nucleotide X and at least one nucleotide is a fluoro-modified nucleotide. Furthermore, 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 of the single-stranded oligonucleotide by 4 to 7 nucleotides; and each nucleotide X is either a deoxynucleotide or an unmodified nucleotide. Further provided are a double-stranded oligonucleotide, an oligonucleotide conjugate and a pharmaceutical composition that comprise the single-stranded oligonucleotide as an antisense strand.

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 a Factor XI (FXI) gene and use in treating, preventing or ameliorating a disease related to FXI mRNA. BACKGROUND Plasma coagulation factor XI (Factor XI, hereinafter referred to as FXI) is a key component of the contact activation pathway, which contributes to the generation of thrombin, an important component involved in the formation of fibrin and the protection of fibrinolysis. High FXI levels are a risk factor for venous thrombosis. By inhibiting the expression of the FXI gene, it is possible to prevent and treat thrombotic diseases, particularly venous thrombosis and ischemic stroke at the cellular level. Small interfering RNA (siRNA) can inhibit or block the expression of any target gene of interest in a sequence-specific manner based on the mechanism of RNA interference (RNAi), thereby achieving the purpose of treating diseases. In siRNA drugs, the antisense strand is the most important part of the performance of the double-stranded oligonucleotide, although a large number of modification schemes of oligonucleotides are disclosed in the prior art, how to improve the modification of oligonucleotides, especially the antisense strand of oligonucleotides, to obtain oligonucleotides with higher activity, higher stability and / or long-acting is still the direction of research and development in the field. SUMMARY The present disclosure provides a single-stranded oligonucleotide, a double-stranded oligonucleotide comprising the single-stranded oligonucleotide of the present disclosure as an antisense strand and an oligonucleotide conjugate, which exhibit good pharmaceutical activity and stability when targeting FXI mRNA. In one aspect, the present disclosure provides a single-stranded oligonucleotide, the length of the single-stranded oligonucleotide is 16-30 nucleotides, the single-stranded oligonucleotide has sufficient complementarity with FXI 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 and is spaced apart from the 8th nucleotide by 4-7 nucleotides. and if the 14th nucleotide of the single-stranded oligonucleotide is nucleotide X and all nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides in the direction from the 5' end to the 3' end, 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 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 an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group being independently a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide or the double-stranded oligonucleotide of the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate of the present disclosure. In yet another aspect, the present disclosure also provides a pharmaceutical composition containing one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt of the present disclosure, and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure also provides a use of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease or a symptom associated with FXI mRNA level. In yet another aspect, the present disclosure also provides a method of treating and / or preventing a disease or a symptom associated with FXI mRNA level, the method comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure. In yet another aspect, the present disclosure also provides a method of modulating the expression level of FXI mRNA in a cell, the method comprising contacting the cell with an effective amount of one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, the pharmaceutically acceptable salt, and the pharmaceutical composition of the present disclosure. In yet another aspect, the present disclosure also provides one or more of the single- stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and pharmaceutical composition of the present disclosure for use as a medicament. In yet another aspect, the present disclosure also provides a cell expressing FXI mRNA, which comprises one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and pharmaceutical composition of the present disclosure. In addition, the present disclosure also provides a kit comprising one or more of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt, and 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 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 incorporated by reference. Beneficial effects The double-stranded oligonucleotide, oligonucleotide conjugate, and pharmaceutical composition comprising the single-stranded oligonucleotide of the present disclosure as an antisense strand have higher activity in modulating FXI mRNA and have higher long-acting property. For example, the siRNA, oligonucleotide conjugate, and / or pharmaceutical composition containing the single-stranded oligonucleotide of the present disclosure as an antisense strand shows excellent FXI mRNA inhibition effect. For example, in vitro HepG2 cells, the inhibition rate of the siRNA conjugate provided by the present disclosure to FXI mRNA can reach 83.3% at a siRNA concentration of 50 nM. The inhibition rate to the target sequence in HEK293A cells is 58.51% at a siRNA concentration of 0.1 nM, showing concentration dependence, showing good FXI mRNA inhibition effect, and having good in vitro inhibition activity to the target sequence. For another example, in monkey liver primary cells, the inhibition rate of the siRNA conjugate provided by the present disclosure to FXI mRNA can reach 72.2% or more, even 98.4% at a concentration of 50 nM; the inhibition rate of the siRNA conjugate provided by the present disclosure to FXI mRNA still reaches 94.5% or more, even 97.2% at a concentration of 5 nM, having good in vitro inhibition activity. Moreover, the IC 50 value of the conjugate provided by the present disclosure in monkey liver primary cells can reach 0.003 μM, and the IC 50 value in human liver primary cells can reach 0.0003 μM, indicating that the conjugate provided by the present disclosure has strong inhibition capacity to the expression of FXI mRNA. For example, in a mouse (C57BL / 6N) in vivo experiment, the conjugate of the present disclosure can show an FXI mRNA inhibition rate of 56.0% at a siRNA administration dose of 3 mg / kg; and the FXI mRNA inhibition rate can be as high as 77.0% at a siRNA concentration of 9 mg / kg. In a hFXI transgenic mouse in vivo experiment, the conjugate provided by the present disclosure can show an FXI mRNA inhibition rate of more than 77.5% at a siRNA administration dose of 3 mg / kg, and can even reach 94.9%, which can show a better FXI mRNA inhibition effect. For example, in a mouse in vivo experiment, the conjugate provided by the present disclosure can show a higher FXI mRNA inhibition rate at a dose of 3 mg / kg within a 43-day administration period, and the FXI mRNA inhibition rate can be as high as 88.3% on the 15th day after administration, can still be as high as 80.4% on the 29th day after administration, and can still reach 51.4% on the 43rd day after administration. In an activated partial thromboplastin time ratio (APTT ratio) experiment, the APTT multiple can be significantly prolonged within a 43-day administration period, and the highest average APTT multiple can be 1.61, and the average APTT multiple can still be 1.08 on the 43rd day after administration, which indicates that the mouse blood clotting time is effectively prolonged. Moreover, the conjugate of the present disclosure can better inhibit the expression of human FXI protein, and the relative inhibition rate of FXI protein can be as high as 94.2% on the 15th day after administration, and can still reach 56.3% on the 43rd day after administration. For example, in a cynomolgus monkey in vivo experiment, the conjugate of the present disclosure can show a better inhibition effect on the expression of human FXI protein within an 84-day administration period, and the relative inhibition rate of FXI protein in the plasma of the cynomolgus monkey can be as high as 88.53% on D28 when the administration dose is 9 mg / kg, and can still reach 65.30% on D84, and even when the administration dose is as low as 1 mg / kg, the relative inhibition rate of FXI protein can still be 51.88% on D42. It is shown that the conjugate provided by the present disclosure has an excellent application prospect in the treatment and / or prevention of thrombotic diseases and ischemic stroke. 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, the FXI mRNA refers to the FXI mRNA expressed in a mammalian cell. In the present disclosure, the FXI mRNA refers to the mRNA of the sequence shown in Genbank registration number NM_000128.3. DEFINITIONS In the context of this document, the expressions "complementary" or "reverse complementary" are used interchangeably and have the meaning well known to the person skilled in the art, i.e. in a double-stranded nucleic acid structure, the bases of one strand each form a hydrogen bond between base pairs in a complementary manner to the bases on the other strand, effecting base pairing, forming Watson-Crick base pairs. A "base pair" refers to two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or in RNA with uracil (U)); the purine base guanine (G) always pairs with the pyrimidine base cytosine (C). Each base pair comprises one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand and guanine always pairs with cytosine, the two strands are considered to be complementary to each other and the sequence of one strand can be deduced from the sequence of its complementary strand. When the bases are modified, as long as the purine-pyrimidine pairing relationship described above is not affected (including but not limited to the number and strength of hydrogen bonds between the bases), the modified bases are also considered to be able to form complementary pairs. Accordingly, "mismatch" or "base mismatch" in the art means that the bases at the corresponding positions between the two single-stranded nucleic acids involved do not pair in a complementary manner; when the corresponding position comprises an abasic nucleotide, it is also considered to form a mismatch with the base on the other strand. In the above and below, "there are X consecutive identical nucleotides between nucleotide sequence A and nucleotide sequence B in length which are substantially reverse complementary, substantially reverse complementary in essence or completely reverse complementary" means that there is a consecutive nucleotide sequence A' of length X in nucleotide sequence A, which is substantially reverse complementary, substantially reverse complementary in essence or completely reverse complementary in length to a consecutive nucleotide sequence B' of the same length X in nucleotide sequence B. Unless specifically stated, in the context of this document, a reference to an oligonucleotide and / or oligonucleotide conjugate provided by the application or method of the present disclosure, including but not limited to an oligonucleotide and / or oligonucleotide conjugate represented by any structural formula provided by the application or method of the present disclosure, also refers to a pharmaceutically acceptable salt of the oligonucleotide and / or conjugate according to the context. In the foregoing and hereinafter, particularly in describing the preparation of a single-stranded oligonucleotide, double-stranded oligonucleotide, pharmaceutical composition, or oligonucleotide conjugate of the present disclosure, unless otherwise specified, the nucleoside monomer refers to modified or unmodified nucleoside phosphoramidite monomers (unmodified or modified RNA phosphoramidites, sometimes also referred to as Nucleoside phosphoramidites) used in the phosphoramidite solid phase synthesis according to the kind and order of nucleotides in the single-stranded oligonucleotide, double-stranded oligonucleotide, or oligonucleotide conjugate to be prepared. The phosphoramidite solid phase synthesis is a method commonly used in RNA synthesis known to those skilled in the art. 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 substituents or substituent patterns unless specifically indicated by the use of those terms. 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, oxazolyl, oxazinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.8-tetrahydroquinazolinyl), naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[H]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]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 not otherwise specified, a “substituted” or “substituted” group means that one or more hydrogen atoms in the group are replaced with one or more substituents. For example, a “substituted alkyl” means an alkyl group in which one or more hydrogen atoms 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, as long as the purpose of the present disclosure can be achieved, it can be used in the present disclosure. In some embodiments, the substituent is 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 alkyl, -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 those skilled in the art that for any group containing one or more substituents, the groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or unstable per se. Various hydroxyl protecting groups can be used in the present disclosure, such as the hydroxyl protecting groups or amino protecting groups. Generally, a protecting group renders a chemical functionality insensitive to specific reaction conditions, and can be added to and removed from that functionality in a molecule without substantially damaging the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Peter G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, Chapter 2, 5th edition, John Wiley & Sons, Inc., New Jersey, 2014, each of which is incorporated by reference herein in its entirety. In some embodiments, the protecting group is stable under basic conditions, but can be removed under acidic conditions. In some embodiments, 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 underlying 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", one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions and oligonucleotide conjugates of the present disclosure can be administered to a subject at risk of developing a disease associated with FXI mRNA, or to a subject reporting one or more physiological symptoms of a disease associated with FXI mRNA, even though a diagnosis of the disease can not have been made. In some embodiments, "prevention" includes reducing or eliminating the risk of a disease associated with FXI mRNA by administering a double-stranded oligonucleotide, a pharmaceutical composition or an oligonucleotide conjugate to a subject at risk of developing the disease associated with FXI mRNA before the risk of the disease associated with FXI mRNA progresses to an explicit disease process, so as to intervene in the level of FXI mRNA or FXI protein, thereby reducing or eliminating the risk of the disease. 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 a complementarity with a FXI mRNA sufficient to mediate an RNAi effect; each nucleotide in the single-stranded oligonucleotide is a modified or unmodified nucleotide, wherein at least one nucleotide in the single-stranded oligonucleotide is a nucleotide X, and at least one nucleotide is a fluorine-modified nucleotide; and, in the direction from the 5' end to the 3' end, at least one nucleotide X is located after the 8th nucleotide and is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 4-7 nucleotides; and, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, in the direction from the 5' end to the 3' end, the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA; Each nucleotide X is a deoxynucleotide or an unmodified nucleotide. In the present disclosure, by modulating the expression level of FXI mRNA and / or changing the protein level, diseases associated with the expression level of FXI mRNA and / or the protein level can be treated or prevented. The inventors have surprisingly found that the single-stranded oligonucleotides, the double-stranded oligonucleotides comprising the single-stranded oligonucleotides as the antisense strand and the oligonucleotide conjugates of the present disclosure have good stability and FXI 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 of synthesis cost, stability, and RNAi activity. In the single-stranded oligonucleotide of the present disclosure, at least one nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide and is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 4-7 nucleotides; and, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide, and a BNA. The inventors have particularly found that the single-stranded oligonucleotide of the present disclosure can effectively maintain high inhibitory activity of the double-stranded oligonucleotide and the oligonucleotide conjugate on FXI mRNA while maintaining stability by comprising a fluorine-modified nucleotide and a nucleotide X. In some embodiments, the number of nucleotides X in the single-stranded oligonucleotide is 1-3, for example, 1 or 2. In some embodiments, in the direction from the 5' end to the 3' end, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, and in the direction from the 5' end to the 3' end, each nucleotide X is spaced apart from the 8th nucleotide of the single-stranded oligonucleotide by 3, 5, 7, or 10 nucleotides. In some embodiments, in the single-stranded oligonucleotide, each nucleotide X is located after the 8th nucleotide of the single-stranded oligonucleotide, one of the nucleotides X is spaced apart from the 8th nucleotide by 5 nucleotides, i.e., in the direction from the 5' end to the 3' end, the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X. In some embodiments, there is only one nucleotide X in the single-stranded oligonucleotide, which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction. In some embodiments, there are 2 nucleotides X in the single-stranded oligonucleotide, in the 5' end to 3' end direction, one of which is spaced 5 nucleotides from the 8th nucleotide in the single-stranded oligonucleotide, and the other of which 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 in the 5' end to 3' end direction are nucleotides X. Each nucleotide X is independently selected from a deoxynucleotide or an unmodified nucleotide. In the present context, "unmodified nucleotide" refers to a ribonucleotide (RNA) in which both the base and the ribose are unmodified, i.e., the nucleotide base is a natural ribose base (one of A, U, C, G, T), and the nucleotide ribose 2' position is an unprotected hydroxyl group (2'-OH). Correspondingly, "modified nucleotide" refers to a nucleotide in which the base is modified, a nucleotide in which the hydroxyl group at the 2' position of the nucleotide ribose is replaced by another atom or group, or a nucleotide analog. In some embodiments, the 14th nucleotide or the 12th and 14th nucleotides in the single-stranded oligonucleotide in the 5' end to 3' end direction are deoxynucleotides, and the other nucleotides X are unmodified nucleotides. In some embodiments, the 14th nucleotide in the single-stranded oligonucleotide in the 5' end to 3' end direction is a deoxynucleotide, and the other nucleotides are modified nucleotides. In some embodiments, the number of modified nucleotides is more than 50%, more than 70%, or more than 85% of the total number of nucleotides in the single-stranded oligonucleotides of the present disclosure; or, the number of unmodified nucleotides in the single-stranded oligonucleotides is no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1. In some embodiments, the number of unmodified nucleotides in the single-stranded oligonucleotides is 2 or 1. In some embodiments, each of the total number of nucleotides in the single-stranded oligonucleotides is independently a modified nucleotide. 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 12th nucleotides, 1 or 2 of the 5th-7th nucleotides, and 0-2 of the 16th-19th nucleotides in the single-stranded oligonucleotide in the 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 in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide, is selected from an alkoxy-modified nucleotide, a substituted alkoxy-modified nucleotide, or a thermally unstable nucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 0-2. In some embodiments, there is no thermally unstable nucleotide in the single stranded oligonucleotide. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is no more than 2. In some embodiments, the number of thermally unstable nucleotides in the single stranded oligonucleotide is 1 or 2. In some embodiments, the single stranded oligonucleotide contains only 1 thermally unstable nucleotide. In some embodiments, each modified nucleotide in the single stranded oligonucleotide, other than nucleotide X and the fluorine-modified nucleotide and the thermally unstable nucleotide, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide. In the present context, a “thermally unstable nucleotide” refers to a nucleotide having a thermally unstable modification, which is a modification that results in a decrease in the thermal dissociation temperature of a duplex of an oligonucleotide having the modification at the corresponding position by at least 0.5 °C as compared to a duplex of an oligonucleotide having an unmodified nucleotide at the corresponding position. Exemplary thermally unstable modifications can be found in the specification of PCT publication WO2018 / 098328A1

[0236] -

[0251] The thermally unstable modification described in the paragraph. In some embodiments, the thermally unstable modification nucleotide is one of an acyclic nucleotide or an iso-nucleotide. An acyclic nucleotide is a class of nucleotides in which the sugar ring of the nucleotide is opened. In some embodiments, the acyclic nucleotide can be an unlocked nucleic acid (UNA) or a glycerol nucleic acid (GNA), wherein the UNA is shown in formula (15) and the GNA is shown in formula (16): In the above formula (15) and formula (16), R is selected from H, OH, or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C, or T. An iso-nucleotide refers to a compound in which the position of the base on the ribose ring is changed. In some embodiments, the iso-nucleotide can be a compound in which the base is moved from the 1'-position to the 2'-position or the 3'-position on the ribose ring, as shown in formula (17) or (18). In the above formula (17)-(18) compounds, Base represents a nucleic acid base, such as A, U, G, C, or T; and R is selected from H, OH, F, or a non-fluorine group as described above. In some embodiments, the thermally unstable 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 at this position is chiral, and the compound can be in the R configuration, the S configuration, or a racemic mixture of the R and S configurations. In some embodiments, each thermally unstable modified nucleotide is independently a GNA as shown in formula (27A). In the above context, BNA refers to a constrained or inaccessible nucleotide. A BNA can contain a five-, six-, or seven-membered ring bridged structure with a "fixed" C3'-endo sugar conformation. The bridge is typically incorporated at the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be a LNA, 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, as shown in formula (8). In some embodiments, the 2'-amino-modified nucleotide (2'-NH2) is shown in formula (9). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in formula (10): In the above compounds of formula (7)-(10) and formula (12)-(14), Base represents a nucleic acid base, such as A, U, G, C, or T. In the foregoing and hereinafter, "fluoro-modified nucleotide", "2'-fluoro-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by fluorine" and "nucleotide having a 2'-fluoro-ribosyl group" have the same meaning and refer to a nucleotide whose 2'-hydroxyl is replaced by fluorine to form a compound having a structure as shown in Formula (7); "methoxy-modified nucleotide", "2'-methoxy-modified nucleotide", "nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy" and "nucleotide having a 2'-methoxy-ribosyl group" have the same meaning and refer to a nucleotide whose 2'-hydroxyl of the ribose group is replaced by methoxy to form a compound having a structure as shown in Formula (8). In some embodiments, the single stranded oligonucleotide of the present disclosure is 19-23 nucleotides in length and, in the 5' end to 3' end direction, the 14th nucleotide is a nucleotide X, 2 of the 5th-7th nucleotides and the 19th nucleotide and the 2nd, 12th and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 5th nucleotide is not a fluorinated nucleotide, the 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide of the present disclosure is 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 of 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 or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide; 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 of 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 16th-19th nucleotides and the 14th nucleotide is nucleotide X, the 2nd and 6th nucleotides are fluorinated nucleotides, the 16th nucleotide is a fluorinated nucleotide when the 16th nucleotide is not nucleotide X, the 13th nucleotide is a substituted alkoxy modified nucleotide or a BNA, the 3rd or 5th nucleotide is an alkoxy modified nucleotide or a substituted alkoxy modified nucleotide, the 20th nucleotide is an alkoxy modified nucleotide or a thermally unstable nucleotide, and each of the remaining nucleotides of the single stranded oligonucleotide is an alkoxy modified nucleotide. In some embodiments, the single stranded oligonucleotide is 21 nucleotides in length, wherein the 16th or 19th nucleotide and the 14th nucleotide is nucleotide X, and wherein the 14th nucleotide is a deoxynucleotide or an unmodified nucleotide, the 16th or 19th nucleotide is an unmodified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxyribonucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxyribonucleotide, the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxyribonucleotide, the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxylated nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from the 5' end to the 3' end, the 12th and 14th nucleotides are deoxyribonucleotides, the 2nd, 7th, and 16th nucleotides are fluorinated nucleotides, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxylated nucleotide. In some embodiments, the single-stranded oligonucleotide of this disclosure is 21 nucleotides in length, and in the direction from 5' end to 3' end, the 14th nucleotide is a deoxyribonucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and in the direction from 3' end to 5' end, the 2nd nucleotide of the single-stranded oligonucleotide is a heat-labile 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 this disclosure is 21 nucleotides in length, and in the direction from 5' end to 3' end, the 14th nucleotide is a deoxyribonucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorinated nucleotides, the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the single-stranded oligonucleotide is an alkoxy-modified nucleotide. In some embodiments, each nucleotide X in the single-stranded oligonucleotide of the present disclosure refers to a deoxynucleotide. In some embodiments, each alkoxy-modified nucleotide in the single-stranded oligonucleotide of the present disclosure refers to a methoxy-modified nucleotide. In some embodiments, each substituted alkoxy-modified nucleotide in the single-stranded oligonucleotide of the present disclosure refers to a 2'-0-methoxyethyl-modified nucleotide. In some embodiments, each BNA in the single-stranded oligonucleotide of the present disclosure refers to a LNA or a cET BNA. In some embodiments, each thermally unstable nucleotide in the single-stranded oligonucleotide of the present disclosure refers to a GNA. In some embodiments, at least 2, or each of 2-6, of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide of the present disclosure independently refer to a phosphorothioate group 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 of the single-stranded oligonucleotide of the present disclosure independently refer to a phosphorothioate group 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 of the single-stranded oligonucleotide of the present disclosure independently refer to a phosphorothioate group 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 two linking groups between each of the unmodified nucleotide and its adjacent nucleotides refer to a phosphorothioate group with a modification group. The phosphorothioate group with a modification 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 two linking groups between adjacent nucleotides in the first 3 nucleotides at the 5' end of the single-stranded oligonucleotide, and each of the two linking groups between adjacent nucleotides in the first 3 nucleotides at the 3' end of the single-stranded oligonucleotide, refer to a phosphorothioate group with a modification group. In some embodiments, if there is an unmodified nucleotide in the single-stranded oligonucleotide, each of 1 or both of the two linking groups between each of the unmodified nucleotide and its adjacent nucleotides independently refer to a phosphorothioate group with a modification group. In some embodiments, the phosphorothioate group with a modification group refers to 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, a 5'-phosphate nucleotide, or a 5'-phosphate analog modified nucleotide, the 5'-hydroxyl nucleotide has a structure as shown in formula (29); the 5'-phosphate nucleotide has a structure as shown in formula (30); and the 5'-phosphate analog modified nucleotide has a structure selected from one of the structures as shown in 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. In some embodiments, the 5'-phosphate nucleotide is a 5'-phosphate modified nucleotide as shown in formula (30), the 5'-phosphate analog modified nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide as shown in formula (31), or a 5'-phosphorothioate modified nucleotide as shown in formula (33). In some embodiments, the 5' terminal nucleotide of the single-stranded oligonucleotide is a 5'-hydroxyl nucleotide or a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide. In some embodiments, the 5' terminal nucleotide is a 5'- (E)-vinylphosphonate (E-VP) modified nucleotide, which can further increase one or more of the stability, the pharmacodynamic activity in a subject, and the long-acting property of the single-stranded oligonucleotide, the double-stranded oligonucleotide comprising the single-stranded oligonucleotide, and the oligonucleotide conjugate of the present disclosure. In some embodiments, the single-stranded oligonucleotide 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 or the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorine-modified nucleotides or the 2nd, 6th, 12th, 16th, and 19th 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 is a phosphorothioate group; 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 FXI mRNA to mediate an RNAi effect. In some embodiments, the single-stranded oligonucleotides of the present disclosure are sufficiently complementary to FXI mRNA. In the context of the present disclosure, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure are sufficiently complementary to FXI mRNA such that the single-stranded oligonucleotides reduce or eliminate the production of a protein encoded by the FXI mRNA through an RNAi effect. In some embodiments, "sufficiently complementary" means that the single-stranded oligonucleotides of the present disclosure are substantially, substantially, or completely reverse complementary to FXI mRNA over a length of at least 16 nucleotides, e.g., 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 FXI mRNA. In the foregoing and hereinafter, "at least partially reverse complementary," "substantially reverse complementary," "essentially reverse complementary," "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 FXI 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; "substantially reverse complementary" means that there are no more than 3 base mismatches between two nucleotide sequences over a given length of the nucleotide sequences; "essentially 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 FXI 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 FXI mRNA in which each nucleotide of the single-stranded oligonucleotide forms a Watson-Crick base pair with a nucleotide of FXI 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 of the present disclosure is completely reverse complementary to the FXI mRNA at least within the seed region. The "seed region" refers to a region within the 2nd-8th nucleotide of the single-stranded oligonucleotide of the present disclosure, at which the single-stranded oligonucleotide of the present disclosure is capable of better mediating the RNAi effect to inhibit the level of the FXI mRNA. In some embodiments, the single-stranded oligonucleotide is substantially reverse complementary or completely reverse complementary to the FXI 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 FXI mRNA in the direction from the 5' end to the 3' end. In some embodiments, the nucleotide sequence other than the 1st nucleotide at the 5' end of the single-stranded oligonucleotide is completely reverse complementary to the FXI 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 FXI mRNA. In some embodiments, the single-stranded oligonucleotide of the present disclosure can be the first, second, or third single-stranded oligonucleotide, each of which is described below. The first single-stranded oligonucleotide In some embodiments, the present disclosure provides the first single-stranded oligonucleotide. The single-stranded oligonucleotide contains a nucleotide sequence II, which is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and has no more than 3 base differences: 5'-Z2AGAAUCCAGUCCACGUAC-3' (SEQ ID NO: 2), wherein Z2 is C or U, the nucleotide sequence II contains a nucleotide Z4 at a position corresponding to Z2, and Z4 is the first 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 first 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. 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 the Z4 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 2 can include a difference at the Z4 position and / or a base difference at a nucleotide position adjacent to Z4. 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 the Z4 position, and Z4 is selected from A, U, 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 the Z4 position, and Z4 is selected from A, U, 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 the FXI 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 carbon number 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is U; or the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is UC from the 5' end to the 3' end; or the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is UCG from the 5' end to the 3' end; or the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is UCGA from the 5' end to the 3' end. 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, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II to form a 3' overhang end of the antisense strand after forming a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure is 2 nucleotides in length, and in the 5' end to 3' end direction, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the FXI 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 5' end to 3' end direction, the base composition of the nucleotide sequence V is UU or UC. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, and the base composition of the nucleotide sequence V is UC. A second single-stranded oligonucleotide In some embodiments, the present disclosure provides a second single-stranded oligonucleotide. Wherein the single-stranded oligonucleotide contains a nucleotide sequence II, the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 29, and has no more than 3 base differences from the nucleotide sequence set forth in SEQ ID NO: 29: 5'-Z6GAAAGAAUACCCAGAAAU-3' (SEQ ID NO: 29), Wherein Z6 is U, the nucleotide sequence II contains a nucleotide Z8 at the position corresponding to Z6, and Z8 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II has no more than 1 base difference from the nucleotide sequence set forth in SEQ ID NO: 29. Wherein the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 29 can include a difference at the Z8 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, wherein the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 29 can include a difference at the Z8 position and / or a base difference at a nucleotide position adjacent to Z8. In some embodiments, the nucleotide sequence II has no base difference from the nucleotide sequence set forth in SEQ ID NO: 29. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 29 includes a difference at the Z8 position, and Z8 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: 29 is a difference at the Z8 position, and Z8 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 the FXI mRNA, and each of the non-fluoro-modified nucleotides is independently selected from one of 2'-methoxy-modified nucleotide, 2'-alkyl-modified nucleotide with carbon number of 1-3, 2'-amino-modified nucleotide, 2'-substituted amino-modified nucleotide, and heat-unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is C; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is CG from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is CGC from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is CGCU from 5' end to 3' end. 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, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II to form a 3' overhang end of the antisense strand after forming a double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or is fully reverse-complementary to the FXI mRNA. In some embodiments, the nucleotide sequence V in the present disclosure is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is CG. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 29, and the base composition of the nucleotide sequence V is CG. The third single-stranded oligonucleotide In some embodiments, the present disclosure provides a third single-stranded oligonucleotide. The single-stranded oligonucleotide comprises a nucleotide sequence II, the nucleotide sequence II has a length equal to the nucleotide sequence shown in SEQ ID NO: 31, and has no more than 3 base differences: 5'-Z10 GAGUUUUCUCCAGAAUCC-3' (SEQ ID NO: 31), wherein Z 10 is U, the nucleotide sequence II comprises a nucleotide Z 10 at a position corresponding to Z 12 , the Z 12 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence. In some embodiments, the nucleotide sequence II differs from the nucleotide sequence set forth in SEQ ID NO: 31 by no more than 1 base difference. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31 can include a difference at the Z 12 position and / or a base difference at any other nucleotide position in the nucleotide sequence II. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31 can include a difference at the Z 12 position and / or at a nucleotide position adjacent to Z 12 . In some embodiments, there is no base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31. In some embodiments, the base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31 includes a difference at the Z 12 position, and Z 12 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: 31 is a difference at the Z 12 position, and Z 12 is selected from A, C, or G. In some embodiments, the single-stranded oligonucleotide further comprises a nucleotide sequence IV, the nucleotide sequence IV is linked to the 3' end of the nucleotide sequence II, the nucleotide sequence IV has a length of 1, 2, 3, or 4 nucleotides, each nucleotide in the nucleotide sequence IV is independently one of a non-fluoro-modified nucleotide, the nucleotide sequence IV is substantially reverse-complementary or fully reverse-complementary to FXI mRNA, and each non-fluoro-modified nucleotide is independently selected from one of a 2'-methoxy-modified nucleotide, a 2'-alkyl-modified nucleotide having an alkyl group of carbon number 1-3, a 2'-amino-modified nucleotide, a 2'-substituted amino-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, the nucleotide sequence IV has a length of 2 nucleotides. In some embodiments, the nucleotide sequence IV has a length of 1 nucleotide, and the base is A; or, the nucleotide sequence IV has a length of 2 nucleotides, and the base composition is AG from 5' end to 3' end; or, the nucleotide sequence IV has a length of 3 nucleotides, and the base composition is AGU from 5' end to 3' end; or, the nucleotide sequence IV has a length of 4 nucleotides, and the base composition is AGUC from 5' end to 3' end. In some embodiments, the single-stranded oligonucleotide of the present disclosure further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, and is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, to form a 3' overhang end of the antisense strand of the double-stranded oligonucleotide after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V of the present disclosure has a length of 2 nucleotides, and from 5' end to 3' end, the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to FXI mRNA. In some embodiments, the nucleotide sequence V of the present disclosure is linked to the 3' end of the nucleotide sequence II, and from 5' end to 3' end, the base composition of the nucleotide sequence V is AG. In some embodiments, the single-stranded oligonucleotide comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 31, and the base composition of the nucleotide sequence V is AG. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of siRNAa1, siRNAb1, siRNAb2, or siRNAb3 listed in Table 1. In some embodiments, the single-stranded oligonucleotide is the antisense strand of any one of Conjugate 1-Conjugate 7 listed in Table 2. In some embodiments, the single-stranded oligonucleotide of the present disclosure can independently exert a pharmacodynamic activity. In some embodiments, the single-stranded oligonucleotide of the present disclosure is an antisense oligonucleotide (ASO). In some embodiments, the single-stranded oligonucleotide of the present disclosure is a single-stranded RNAi (ssRNAi) compound. In some embodiments, the single-stranded oligonucleotide of the present disclosure exerts a pharmacodynamic activity as a single strand (e.g., an antisense strand) of a double-stranded oligonucleotide. Double-stranded oligonucleotide of the present disclosure In another aspect, the disclosure also provides a double-stranded oligonucleotide comprising an antisense strand of the disclosure, 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 a single-stranded oligonucleotide as described in the disclosure above. In the double-stranded oligonucleotide of the disclosure, the length of the sense strand and the antisense strand is 19-26 nucleotides. In some embodiments, the length of the antisense strand is not less than the length of the sense strand. In some embodiments, the length of the sense strand is 19-23 nucleotides. Thus, the ratio of the length of the sense strand and the antisense strand of the double-stranded oligonucleotide of the 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 convenience of synthesis, the length of the sense strand is 19-21 nucleotides, and the length of the antisense strand is 19-23 nucleotides. In some embodiments, the length of the sense strand and the antisense strand is the same, 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 and / or the last nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having a structure as shown in formula (35)), 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, in addition to the above-mentioned fluorine modification and inverted abasic deoxyribonucleotide, the nucleotides at the remaining positions of the sense strand are non-fluorine-modified nucleotides, each of which is independently selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, an amine-modified nucleotide, and a thermally unstable nucleotide. In some embodiments, the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to the 3' phosphate group of the 3' end second last nucleotide of the sense strand. In some embodiments, the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to the 3' phosphate group of the 3' end nucleotide of the sense strand, and the oxygen atom shown in formula (35) connected to the ribose ring by methylene can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the oxygen atom shown in formula (35) connected to the ribose ring by methylene can be connected to the 5' phosphate group of the 5' end second last nucleotide of the sense strand. In some embodiments, the oxygen atom shown in formula (35) connected to the ribose ring by methylene is connected to the 5' phosphate group of the 5' end second last nucleotide of the sense strand, and the oxygen atom shown in formula (35) directly connected to the ribose ring can be connected to a hydrogen atom, a hydroxyl protecting group, or a delivery group described below. In some embodiments, the sense strand comprises 19-21 nucleotides, and 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 and / or the last nucleotide of the sense strand is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are alkoxy-modified nucleotides. In this case, the double-stranded oligonucleotide of the present disclosure has better stability and / or activity of forming a RISC complex through the position matching of the modified nucleotides of the sense strand and the antisense strand, thereby showing stable and efficient FXI 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 of the 1st to 5th nucleotides at the 5' end of the sense strand and between two adjacent nucleotides of the 1st to 5th nucleotides at 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 APOC3 mRNA, thereby having high efficient APOC3 mRNA inhibitory activity while improving stability. In some embodiments, 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 5' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, all 4 of the linking groups between adjacent nucleotides of the 1st-5th nucleotides at the 3' end of the sense strand are each independently a phosphate group with a modification group. In some embodiments, the linking groups linking two adjacent nucleotides of the 1st-3rd, 1st-4th or 1st-5th nucleotides at the 5' end and / or 3' end of the sense strand are phosphate groups with a modification group. In some embodiments, the linking groups between adjacent nucleotides of the 1st-3rd nucleotides at the 5' end of the sense strand are phosphate groups with a modification group. The definition and selection range of the phosphate group with a modification group are the same as those of the phosphate group with a modification group described above in the antisense strand of the present disclosure. In some embodiments, each of the phosphate groups 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 of siRNAal, siRNAbI, siRNAb2, or siRNAb3 listed in Table 1; in some embodiments, the sense strand is the sense strand of any one of Conjugate 1-Conjugate 7 listed in Table 2. In some embodiments, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides, from the 3' end to the 5' end are fluoro-modified nucleotides, the 1st nucleotide of the sense strand is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are alkoxy-modified nucleotides; In some embodiments, the linkage between every two adjacent nucleotides at the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 5' end and / or from the 3' end of the sense strand is a phosphorothioate linkage having a modification group, and the remaining adjacent nucleotides in the sense strand are connected by phosphorothioate linkages. In some embodiments, the linkage between every two adjacent nucleotides at the 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 5' end and / or from the 3' end of the sense strand is a phosphorothioate linkage having a modification group, and the remaining adjacent nucleotides in the sense strand are connected by phosphorothioate linkages. In some embodiments, the linkage between every two adjacent nucleotides at the 1st-2nd, 1st-3rd, 1st-4th, or 1st-5th nucleotides from the 3' end of the sense strand is a phosphorothioate linkage having a modification group, and the remaining adjacent nucleotides in the sense strand are connected by phosphorothioate linkages. In some embodiments, all adjacent nucleotides in the sense strand are connected by phosphorothioate linkages. In some embodiments, the phosphorothioate linkage having a modification group is a phosphorothioate linkage represented by the structure of Formula (28), and the alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide. 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 11-13th nucleotides are fluorine-modified nucleotides, the 1st nucleotide is an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides, in the direction from the 3' end to the 5' end; the linking groups between the adjacent nucleotides in the 1-3rd nucleotides at the 5' end of the sense strand and / or the linking groups between the adjacent nucleotides in the 1-3rd nucleotides at the 3' end of the sense strand are phosphate groups with a modification group; in the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, the 3rd nucleotide is an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide, in the direction from the 5' end to the 3' end; or, in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the direction from the 5' end to the 3' end, the 12th and 14th nucleotides are deoxynucleotides, the 2nd, 7th and 16th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 16th nucleotide is an unmodified nucleotide, the 2nd and 6th nucleotides are fluorine-modified nucleotides, and the 13th nucleotide is a substituted alkoxy-modified nucleotide, in the direction from the 3' end to the 5' end, the 2nd nucleotide of the antisense strand is a thermally unstable nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; or, in the antisense strand, in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 19th nucleotide is an unmodified nucleotide, the 2nd, 6th and 16th nucleotides are fluorine-modified nucleotides, and the 13th nucleotide is a substituted alkoxy-modified nucleotide, and each of the remaining nucleotides in the antisense strand is an alkoxy-modified nucleotide; the linking groups between the two adjacent nucleotides in the 1-3rd nucleotides at the 5' end of the antisense strand and the linking groups between the two adjacent nucleotides in the 1-3rd nucleotides at the 3' end of the antisense strand are phosphate groups with a modification group; and the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29), a 5'-phosphate nucleotide represented by formula (30), or a 5'-vinyl phosphate-modified nucleotide represented by formula (31). 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 from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linkage groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand and / or the linkage groups between adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the sense strand are phosphorothioate groups. In some embodiments, in the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, or the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linkage groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the antisense strand and the linkage groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31). In some embodiments, the sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; In the sense strand, the 11th and 13th nucleotides from the 3' end to the 5' end are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linkage groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; In the antisense strand, the 14th nucleotide from the 5' end to the 3' end is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, or the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linkage groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the antisense strand and the linkage groups between two adjacent nucleotides in the 1st-3rd nucleotides at the 3' end of the antisense strand are phosphorothioate groups; the 5' terminal nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31). The double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between FXI mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme. In the context of the present disclosure, the "modification scheme" refers to a combination of different numbers, positions, and types of nucleotide ribose modifications, phosphate modifications, 5' end modifications, and / or base modifications that are not or weakly related to a specific sequence. In some embodiments, the double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between FXI mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original pharmaceutical activity of the double-stranded oligonucleotide. In some embodiments, the double-stranded oligonucleotide of the present disclosure is siRNA, and the double-stranded oligonucleotide of the present disclosure is capable of achieving a good balance between FXI mRNA expression modulating activity and in vivo stability by having the above-mentioned modification scheme, while maintaining excellent stability without significantly reducing the original RNAi activity of the siRNA. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse complementary or completely reverse complementary, and one or two overhanging ends of the sense strand and / or one or two overhanging ends of the antisense strand. In some embodiments, the double-stranded oligonucleotide of the present disclosure consists of a double-stranded region that is substantially reverse complementary or completely reverse complementary, and one overhanging end of the antisense strand. In the context of the present disclosure, the "double-stranded region" is a double-stranded structure formed between the shortest nucleotide sequences including all base pairs and all base mismatches located between the base pairs on each single strand in a double-stranded nucleic acid structure. Thus, the double-stranded region consists of all base pairs and all base mismatches located between the base pairs in a double-stranded nucleic acid structure. In some embodiments, the number of base mismatches is not more than 20%, 15%, 10%, or 5% of the total number of base pairs forming the double-stranded region. In some embodiments, the number of base mismatches in the double-stranded region is not more than 3, not more than 2, or not more than 1. In some embodiments, the double-stranded nucleic acid structure includes the double-stranded region and one or more overhanging ends composed of nucleotides that do not form base pairs on one or both single strands. In some embodiments, the double-stranded nucleic acid structure includes only the double-stranded region. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning at least 16 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising at least 16 base pairs. In the context of the present disclosure, each base pair forming the double-stranded region is independently complementary or mismatched. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 16-23 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 16-23 base pairs. In some embodiments, the sense strand and the antisense strand form a double-stranded region spanning 18, 19, 20, or 21 nucleotide positions, i.e., the sense strand and the antisense strand form a double-stranded region comprising 18, 19, 20, or 21 base pairs. In some embodiments, the sense strand and the antisense strand are substantially reverse complementary or fully reverse complementary within the double-stranded region. In some embodiments, the sense strand and the antisense strand of the double-stranded oligonucleotide of the present disclosure are substantially reverse complementary or fully reverse complementary over the entire nucleotide length. In some embodiments, the number of base differences between the sense strand and the FXI 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 FXI mRNA. In the foregoing and hereinafter, a nucleotide sequence and another nucleotide sequence have a “base difference” if the base type of a nucleotide at a same position in the former is different from that in the latter, e.g., if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, it is recognized that there is a base difference between the two nucleotide sequences at the position. When a base is modified, as long as the modification does not affect the purine-pyrimidine pairing relationship when forming the double-stranded nucleic acid structure described above, it is also recognized that there is no base difference between the modified base and the original base. In some embodiments, it is recognized that there is no base difference between U and T. In some embodiments, it is recognized that there is no base difference between C and 5-methylcytosine (5mC). In some embodiments, when a nucleotide at a position is replaced by an abasic nucleotide or an equivalent thereof, it is also recognized that a base difference is generated at the position. When aligning two nucleotide sequences to determine the number of base differences, the alignment is performed in a manner that has the least number of base differences among all possible alignments, and the base differences are determined based on the alignment. At this time, the “same position” refers to the corresponding position between the two nucleotide sequences in the alignment. For example, when nucleotide sequence A positions 1-5 are aligned with nucleotide sequence B positions 2-6 in the same direction, and the least number of base differences is compared with other alignments, the “same position” refers to the alignment of nucleotide sequence A position 1 with nucleotide sequence B position 2, nucleotide sequence A position 2 with nucleotide sequence B position 3, and so on. In some embodiments, the number of base differences between two nucleotide sequences of different lengths is the total number of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the number of base differences between two nucleotide sequences of the same length is the total number of base differences between the first nucleotide to the last nucleotide of either nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of different lengths is the absence of base differences between the first nucleotide to the last nucleotide of the shorter nucleotide sequence and each corresponding nucleotide of the other nucleotide sequence, in the same orientation. In some embodiments, the absence of base differences between two nucleotide sequences of the same length is the absence of base differences between the first nucleotide to the last nucleotide of one nucleotide sequence and the first nucleotide to the last nucleotide of the other nucleotide sequence, in the same orientation. The double-stranded oligonucleotide of the present disclosure can be various double-stranded oligonucleotides that modulate the expression of FXI mRNA. In some embodiments, it can be a double-stranded oligonucleotide that inhibits or down-regulates the expression of FXI mRNA, such as siRNA; in some embodiments, it can be a double-stranded oligonucleotide that activates or up-regulates the expression of FXI mRNA, such as saRNA. In some embodiments, the double-stranded oligonucleotide is siRNA. In some embodiments, the siRNA of the present disclosure can be the first, second or third siRNA, each of which is described below. The first siRNA In some embodiments, the present disclosure provides the first siRNA. The first siRNA contains a sense strand containing a nucleotide sequence I and an antisense strand containing a nucleotide sequence II, the nucleotide sequence I consists of 19 nucleotides, the nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO: 1, and has no more than 3 base differences, and the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO: 2, and has no more than 3 base differences: 5'-GUACGUGGACUGGAUUCUZ1-3' (SEQ ID NO: 1) 5'-Z2AGAAUCCAGUCCACGUAC-3' (SEQ ID NO: 2); wherein Z1 is G, A or ia, Z2 is C or U, the nucleotide sequence I comprises a nucleotide Z3 at a position corresponding to Z1, the nucleotide sequence II comprises a nucleotide Z4 at a position corresponding to Z2, and Z4 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there is no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 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 Z3 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 difference at the Z3 position and / or a base difference at a nucleotide position adjacent to Z3. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 1 is a base difference at the Z3 position, preferably, Z3 is an inverted deoxyribonucleotide. 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 Z4 position, and Z4 is selected from A, U 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 Z4 position, and Z4 is selected from A, U or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse complementary to the FXI mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse complementary to the nucleotide sequence I. Alternatively, the 2nd nucleotide in the nucleotide sequence II in the direction from 5' end to 3' end is base mismatched with the 2nd nucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base mismatch, a higher FXI mRNA expression inhibitory activity can be achieved while maintaining a low off-target effect. In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, the nucleotide sequence III has a length of 1, 2, 3, or 4 nucleotides, the nucleotide sequence IV and the nucleotide sequence III have an equal length, and the nucleotide sequence IV and the nucleotide sequence III are substantially reverse complementary or fully reverse complementary, and the nucleotide sequence III is linked to the 5' end of the nucleotide sequence I. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 1 nucleotide, the nucleotide sequence III has a base of A, and the nucleotide sequence IV has a base of U, in the 5' to 3' direction; or the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of GA, and the nucleotide sequence IV has a base composition of UC, in the 5' end to 3' end direction; or the nucleotide sequence III and the nucleotide sequence IV each has a length of 3 nucleotides, the nucleotide sequence III has a base composition of CGA, and the nucleotide sequence IV has a base composition of UCG, in the 5' end to 3' end direction; or the nucleotide sequence III and the nucleotide sequence IV each has a length of 4 nucleotides, the nucleotide sequence III has a base composition of UCGA, and the nucleotide sequence IV has a base composition of UCGA, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV each has a length of 2 nucleotides, the nucleotide sequence III has a base composition of GA, and the nucleotide sequence IV has a base composition of UC, in the 5' end to 3' end direction. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides, and in the 5' end to 3' end direction, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or fully reverse complementary to the FXI mRNA. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and in the 5' end to 3' end direction, the base composition of the nucleotide sequence V is selected from UC or UU. In some embodiments, the sense strand comprises only the nucleotide sequence I, the antisense strand comprises only the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 2, the nucleotide sequence I consists of SEQ ID NO: 1, and the nucleotide sequence V is linked at the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V, in the direction from the 5' end to the 3' end, is UC. The second siRNA In some embodiments, the present disclosure provides a second siRNA. The second siRNA comprises a sense strand comprising a nucleotide sequence I and an antisense strand comprising a nucleotide sequence II, 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: 28 and differs by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 29 and differs by no more than 3 bases: 5'-AUUUCUGGGUAUUCUUUCZ5-3' (SEQ ID NO: 28) 5'-Z6GAAAGAAUACCCAGAAAU-3' (SEQ ID NO: 29); wherein Z5 is A or la, Z6 is U, the nucleotide sequence I comprises a nucleotide Z7 at a position corresponding to Z5, the nucleotide sequence II comprises a nucleotide Z8 at a position corresponding to Z6, and Z8 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, the nucleotide sequence I differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 28, and / or the nucleotide sequence II differs by no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 29. The base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 28 can include a difference at the Z7 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: 28 can include a difference at the Z7 position and / or a base difference at a nucleotide position adjacent to Z7. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 28 is a base difference at the Z7 position, preferably, Z7 is an inverted dealkylated deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 29 comprises a difference at position Z8, and Z8 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: 29 is a difference at position Z8, and Z8 is selected from A, C, or G. In some embodiments, the nucleotide sequence II is fully reverse-complemented to the nucleotide sequence I. Alternatively, the 2ndnucleotide in the nucleotide sequence II is base-mismatched to the 2ndnucleotide in the nucleotide sequence I in the direction from 5' end to 3' end. By including the base-mismatch, one can have higher FXI mRNA 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-complemented or fully reverse-complemented, 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 and 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 CG, and the base composition of the nucleotide sequence IV is CG, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 GCG, and the base composition of the nucleotide sequence IV is CGC, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 AGCG, and the base composition of the nucleotide sequence IV is CGCU, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 CG, and the base composition of the nucleotide sequence IV is CG, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, forming a 3' overhang end of the antisense strand after forming the double-stranded oligonucleotide. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is 2 consecutive thymine deoxynucleotides, 2 consecutive uracil nucleotides, or fully reverse complementary to the FXI mRNA, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is CG, in the 5' end to 3' end direction. In some embodiments, the sense strand only comprises the nucleotide sequence I, the antisense strand only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 29, the nucleotide sequence I consists of SEQ ID NO: 28, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is CG, in the 5' end to 3' end direction. The third siRNA In some embodiments, the present disclosure provides a third siRNA. The third siRNA comprises a sense strand comprising a nucleotide sequence I and an antisense strand comprising a nucleotide sequence II, the nucleotide sequence I consists of 19 nucleotides, the nucleotide sequence I is identical to the nucleotide sequence set forth in SEQ ID NO: 30 except for no more than 3 base differences, and the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 31 except for no more than 3 base differences: 5'-GGAUUCUGGAGAAAACUCZ9-3' (SEQ ID NO: 30) 5'-Z 10 GAGUUUUCUCCAGAAUCC-3' (SEQ ID NO: 31); wherein Z9 is A or U, Z 10 is U, the nucleotide Z 11 corresponding to Z9 is contained in the nucleotide sequence I, and the nucleotide Z 10 corresponding to Z 12 is contained in the nucleotide sequence II, and Z 12 is the first nucleotide at the 5' end of the antisense strand. In some embodiments, the sense strand comprises only the nucleotide sequence I, and the antisense strand comprises only the nucleotide sequence II. In some embodiments, there are no more than 1 base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 30, and / or no more than 1 base difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31. In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 30 can include a difference at the position Z 11 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: 30 can include a difference at the position Z 11 and / or a base difference at the nucleotide position adjacent to Z 11 . In some embodiments, the base difference between the nucleotide sequence I and the nucleotide sequence set forth in SEQ ID NO: 30 is a base difference at the position Z 11 , preferably Z 11 is an inverted dealkylated deoxynucleotide. In some embodiments, the difference between the nucleotide sequence II and the nucleotide sequence set forth in SEQ ID NO: 31 includes a difference at the position Z 12 , and Z12 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: 31 is a difference at position Z 12 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: 31 is a difference at position Z 12 selected from A, C, or G. In some embodiments, the nucleotide at position 2-19 of the nucleotide sequence II is fully reverse-complemented to the FXI mRNA in the direction from 5' end to 3' end. In some embodiments, the nucleotide sequence II is fully reverse-complemented to the nucleotide sequence I. Alternatively, the 2ndnucleotide in the nucleotide sequence II is base-mismatched to the 2ndnucleotide in the nucleotide sequence I in the direction from 3' end to 5' end. By including the base-mismatch, one can have higher FXI mRNA 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-complemented or fully reverse-complemented, 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 U, and the base of the nucleotide sequence IV is A, in the 5' to 3' direction; in this case, the length ratio of the sense strand and 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 CU, and the base composition of the nucleotide sequence IV is AG, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 ACU, and the base composition of the nucleotide sequence IV is AGU, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 GACU, and the base composition of the nucleotide sequence IV is AGUC, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and 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 CU, and the base composition of the nucleotide sequence IV is AG, in the 5' end to 3' end direction; in this case, the length ratio of the sense strand and the antisense strand is 21 / 21. In some embodiments, the antisense strand further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluorinated modified nucleotide, the length of the nucleotide sequence V is 1 to 3 nucleotides, and the nucleotide sequence V is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II to form a 3' overhang end of the antisense strand after the double-stranded oligonucleotide is formed. In some embodiments, the length of the nucleotide sequence V is 2 nucleotides, and the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or fully reverse complementary to the FXI mRNA, in the 5' end to 3' end direction. In some embodiments, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AG, in the 5' end to 3' end direction. In some embodiments, the sense strand only comprises the nucleotide sequence I, the antisense strand only comprises the nucleotide sequence II and the nucleotide sequence V, the nucleotide sequence II consists of SEQ ID NO: 30, the nucleotide sequence I consists of SEQ ID NO: 31, the nucleotide sequence V is linked to the 3' end of the nucleotide sequence II, and the base composition of the nucleotide sequence V is AG, in the 5' end to 3' end direction. In some embodiments, the double-stranded oligonucleotide is one of siRNAa1, siRNAb1, siRNAb2, and siRNAb3 listed 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 a nucleotide; 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; 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; lower case letter s between two adjacent nucleotides represents that the two nucleotides are connected by a phosphorothioate group; lower case letter x between two adjacent nucleotides represents that the two nucleotides are connected by a phosphate group or a phosphorothioate group, and at least two lower case letters x in the same nucleotide sequence represent phosphorothioate connection; lower case letter d represents that the nucleotide represented by the capital letter adjacent to the right of the letter d is a deoxyribonucleotide; letter combination P1 represents that the nucleotide represented by the capital letter adjacent to the right of the letter combination is a 5'-phosphate nucleotide, a 5'-hydroxyl nucleotide, a 5'-phosphorothioate-modified nucleotide (Ps), or a 5'-vinylphosphonate-modified nucleotide; ia represents an inverted abasic deoxyribonucleotide. In some embodiments, in each sense strand, lower case letter x between every two adjacent nucleotides in the 1st-3rd nucleotides independently represents phosphorothioate connection in the 5'-3' direction, and lower case letter x between every two adjacent nucleotides in the 1st-3rd nucleotides independently represents phosphate connection in the 3'-5' direction; in some embodiments, each alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide; each P1 is independently a 5'-hydroxyl nucleotide or a 5'-vinylphosphonate (VP)-modified nucleotide. 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 customized services. The methods of using nucleoside monomers with corresponding modifications to introduce modified nucleotide groups into the antisense strand and / or the double-stranded oligonucleotide described by the disclosure, and the methods of introducing modified nucleotide groups into the antisense strand and / or the double-stranded oligonucleotide using nucleoside monomers with corresponding modifications are also well known to those skilled in the art. All modified nucleoside monomers can be commercially available or prepared by known methods. The double-stranded oligonucleotides provided by the present disclosure can be used alone, or in the formation of a pharmaceutical composition with a pharmaceutically acceptable carrier, or in the formation of an oligonucleotide conjugate with a delivery group, or in any other suitable form. An effective amount of the double-stranded oligonucleotides, the pharmaceutical composition, or the oligonucleotide conjugate is contacted with a cell to modulate the expression of FXI mRNA, or an effective amount of the double-stranded oligonucleotides, the oligonucleotide conjugate, or the pharmaceutical composition is administered to a subject to modulate the expression of FXI mRNA, for the purpose of treating a pathological condition or a disease associated with the expression level of FXI mRNA. Oligonucleotide conjugate In another aspect, the present disclosure provides an oligonucleotide conjugate containing an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group independently being a group formed by removing one or more atoms or atom groups from a single-stranded oligonucleotide, a double-stranded oligonucleotide, or an siRNA provided by the present disclosure. In the context of the present disclosure, unless otherwise specified, "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 through 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 FXI mRNA. In some embodiments, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the double-stranded oligonucleotide group, the linker group, and the targeting group are covalently or non-covalently connected in sequence, each of the targeting groups being independently selected from a ligand group capable of binding to a hepatocyte surface receptor. In some embodiments, the targeting group targets the liver. In some embodiments, at least one or each targeting group is independently selected from a ligand group capable of binding to a mammalian hepatocyte surface asialoglycoprotein receptor. In some embodiments, the targeting group is 1-6. In one embodiment, the targeting group is 2-4. The oligonucleotide group can be conjugated to the delivery group non- covalently or covalently, for example, can be covalently conjugated to the delivery group. In some embodiments, the oligonucleotide group is a double-stranded oligonucleotide group, and the conjugation site of the double-stranded oligonucleotide group to the delivery group can be at the 3' end or 5' end of the sense strand of the double-stranded oligonucleotide, or at the 5' end of the antisense strand, or in the internal sequence of the double-stranded oligonucleotide. In some embodiments, the conjugation site of the double-stranded oligonucleotide group to the delivery group is at the 3' end of the sense strand of the double-stranded oligonucleotide. In some embodiments, the delivery group can be linked to any position of the nucleotide, such as the phosphate group, the 2'-, 3'- or 5'-position hydroxyl of the ribose, or the base. When the delivery group is linked to the 3'- or 5'-end of the sense strand of the double-stranded oligonucleotide, the delivery group is usually linked 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 linked to the internal sequence of the double-stranded oligonucleotide, the delivery group is usually linked to the phosphate group, the ribose sugar ring, or the base. In some embodiments, the delivery group can be linked 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 connection methods can be referred to in the following non-patent literature: Muthiah Manoharan et. al. siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5): 1181-7. The disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the oligonucleotide and the delivery group can be connected by acid-labile or reducible chemical bonds, which can be degraded in the acidic environment of the endosome of the cell, thereby converting the double-stranded oligonucleotide group into a free oligonucleotide. For non-degradable conjugation, the delivery group can be linked 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 groups can be attached to the oligonucleotide group via a suitable linker group, which can be selected by one skilled in the art depending on the specific type of targeting group. For example, when the targeting group is a group that targets a receptor on the surface of a hepatocyte cell, such linker groups, types of targeting groups, and ways of attaching to the oligonucleotide can be found in the disclosure of WO2015006740A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the targeting group can be a ligand group that is routinely used in the art of oligonucleotide drug delivery, such as the various ligand groups described in WO2009082607A2, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, at least one or each of the targeting groups is selected from a ligand group that is capable of binding to a receptor on the surface of a cell that expresses FXI mRNA. In some embodiments, at least one or each of the targeting groups is selected from a small molecule ligand group that has affinity for an asialoglycoprotein receptor on the surface of a hepatocyte cell. In some embodiments, at least one or each of the targeting groups is selected from a group consisting of a ligand group capable of binding to a surface receptor of a mammalian liver parenchymal cell. In some embodiments, each of the targeting groups is independently a ligand having affinity for an asialoglycoprotein receptor on the surface of a mammalian liver cell. In some embodiments, each of the targeting groups is independently an asialoglycoprotein or a saccharide. In some embodiments, each of the targeting groups is independently selected from one of the group consisting of D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, a-D-mannofuranose, β-D-mannofuranose, a-D-mannopyranose, β-D-mannopyranose, a-D-glucopyranose, β-D-glucopyranose, a-D-glucoruranose, β-D-glucoruranose, a-D-fructofuranose, a-D-fructopyranose, a-D-galactopyranose, β-D-galactopyranose, a-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-0-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L- pyranoglucose, 4,6-dideoxy-4-formamido-2,3-di-0-methyl-D-mannopyranose, 2-deoxy-2- sulfonamido-D-glucopyranose, N-glycolyl-a-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4-tri-0-acetyl-1-thio-6-0-trityl-a-D-glucopyranoside methyl ester, 4-thio-β-D- galactopyranose, 3,4,6,7-tetra-0-acetyl-2-deoxy-1,5-dithio-a-D-glucopyranoside ethyl ester, 2,5- anhydro-D-allosonitrile, ribose, D-ribose, D-4-thioribose, L-ribose, L-4-thioribose, and a group formed by removing one atom or group from one of the foregoing. In some embodiments, at least one or each of the targeting groups is a galactosyl group or an N-acetylgalactosamine group. In some embodiments, each of the targeting groups is an N-acetylgalactosamine group. In some embodiments, the oligonucleotide group is capable of modulating the expression level of FXI 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 linking group in the oligonucleotide conjugates of the present disclosure has a structure as shown in formula (301): wherein k is an integer from 1 to 5, represents the site of covalent attachment of the group; all L A to L C the same atom in ; or, each L A is independently attached to a different atom in C . In some embodiments, L C has the structure of -NH-C(H) n301 (CH2O-) k , wherein k is an integer from 1 to 3, n301=3-k; L B has a length of 5 to 20 atoms. In some embodiments, each L A is independently a straight chain alkylene having a length of 5 to 20 carbon atoms, wherein one or more methylene groups are optionally replaced by any one or more selected from the group consisting of C(O), NH, O, S, 1,2,3-triazolylene, butadienylene imine. In some embodiments, L A has the structure containing an amide bond as shown in formula (302), L B has the 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, represents the site of covalent attachment of the group. In some embodiments, the linking group has the structure as shown in formula (304) or formula (305): In the linking group, each L A is attached to one of the targeting groups through an ether linkage, respectively, and is attached through the oxygen atom of the hydroxyl group in the L C moiety to form an ether linkage with the L C moiety; L B is attached through the carbonyl group in formula (303) to the nitrogen atom of the amino group in the L C moiety to form an amide linkage, and is attached through the oxygen atom in formula (303) to the double stranded oligonucleotide group through an oxygen atom to form a phosphonate or thiophosphonate linkage. In some embodiments, the oligonucleotide conjugate provided by the present disclosure has a structure as shown in formula (305A): wherein Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the linking group in the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (306): wherein n 306 is an integer from 0 to 3, each p 306 is independently an integer from 1 to 6, represents a site where groups are covalently connected; the linking group is connected to the targeting group via an ether bond through the oxygen atom marked by *; at least one of the oxygen atoms marked by # in the linking group is connected to the double-stranded oligonucleotide via a phosphonate bond or a phosphorothioate bond, and the rest of the oxygen atoms marked by # are connected to hydrogen atoms to form hydroxyl groups or to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (307): wherein Nu represents an oligonucleotide group formed by a single-stranded oligonucleotide or a double-stranded oligonucleotide provided by the present disclosure. In some embodiments, the oligonucleotide conjugate of the present disclosure has a structure as shown in formula (308): wherein n 308 is an integer selected from 2 to 4; each m 308 is independently an integer selected from 2 to 5; each R 308 is independently a hydrogen atom, a methyl group or an ethyl group, or 2 R 308 on the same carbon atom together form a carbonyl group; one of the groups represented by A0, each independently, is an oligonucleotide group which is a group formed by removing one atom or group of atoms from a single-stranded oligonucleotide or a double-stranded oligonucleotide described in the present disclosure; all the remaining A0are targeting groups, each of which is the same or different, and the definition and selection range thereof are as described above. In some embodiments, each targeting group is independently selected from one of ligands having affinity to asialoglycoprotein receptor on the surface of mammalian liver parenchymal cells. each L1is independently a divalent linking group having a length of 1-70 or 3-25 atoms; the site of covalent attachment of the group. In some embodiments, each L1is independently a straight-chain alkylene of 1-70 or 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more from the group consisting of C(O), NH, O, S, CH=N, S(O)2, OP(O)2, OP(O)(S), C2-C 10 alkenylene, C2-C 10 alkynylene, C6-C 10 arylene, C3-C 18 heterocyclylene, and C5-C 10 heteroarylene; and the straight-chain alkylene can optionally have substituents of any one or more from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C5-C 10 heteroaryl, C1-C 10 haloalkyl, -OC1-C 10 alkyl, OC1-C 10 alkylphenyl, -C1-C 10 alkyl-OH, -OC1-C 10 haloalkyl, -SC1-C 10 alkyl, -SC1-C 10 alkylphenyl, -C1-C 10 alkyl-SH, -SC1-C 10 haloalkyl, halogen substituent, -OH, -SH, -NH2, -C1-C 10 alkyl-NH2, -N(C1-C 10 alkyl)(C1-C 10 alkyl), -NH(C1-C 10 alkyl), N(C1-C 10 alkyl)(C1-C 10 alkylphenyl), NH(C1-C 10 alkylphenyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 alkyl), -CON(C1-C 10 alkyl)(C1-C 10 alkyl), -CONH(C1-C 10 alkyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 alkyl)C(O)(C1-C 10 alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), C(O)C1-C10 alkyl, -C(O)C1-C 10 alkylphenyl, C(O)C1-C 10 haloalkyl, -OC(O)C1-C 10 alkyl, -SO2(C1-C 10 alkyl), -SO2(phenyl), -SO2(C1-C 10 haloalkyl), -SO2NH2, -SO2NH(C1-C 10 alkyl), -SO2NH(phenyl), -NHSO2(C1-C 10 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C 10 haloalkyl). It will be understood by the skilled person that, although for convenience L1is defined as being a linker group formed from a linear alkylene group by substitution or replacement, it can not be a linear group or an amine or alkenyl group resulting from the above-mentioned substitution and / or replacement. Unless otherwise stated, the "length" of any group in the chemical structural formulae described in the present 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 having a length of 4 atoms, whereas 1,2-cyclopentanediyl is calculated as having a length of 2 atoms. The role of L1covalently linked to A0representing a double-stranded oligonucleotide group is to enable covalent linkage of the oligonucleotide group to the targeting group, to enable entry of the oligonucleotide conjugate comprising the oligonucleotide group into a cell expressing FXI mRNA via the targeting effect of the targeting group, and not to affect the FXI mRNA level modulating effect of the oligonucleotide group once it has entered a cell expressing FXI mRNA. Thus, in some embodiments, L1covalently linked to A0representing an oligonucleotide group has a length of 3-20 atoms, or 4-15 atoms, or 5-12 atoms. In some embodiments, L1covalently linked to A0representing an oligonucleotide group is selected from one or more of the following combinations of linking groups with phosphate groups or phosphate groups having a modifying group: wherein j1is an integer from 2 to 10; represents the site of covalent linkage of the group. In some embodiments, R2is selected from a combination of at least two of A1, A2, A4, A10, and A16 linked to a phosphate group or a phosphate group having a modifying group; in some embodiments, R2is selected from a combination of at least two of A1, A2, A10 linked to a phosphate group or a phosphate group having a modifying group. In some embodiments, L1covalently linked to A0representing an oligonucleotide group has a structure as shown in formula (B1), (B2), (B3), or (B4): wherein, represents a site where a group is covalently attached, L B1 and L B2 are the same or different, independently selected from one of the following groups or any combination of linkage: -(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 1 to 20 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 10 atoms. In some embodiments, L B1 and L B2 each independently have a length of 1 to 6 atoms. L B3 is selected from one of a phosphate group, a phosphorothioate group, a phosphorodithioate 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 present disclosure is prepared by a process of solid phase synthesis, L1covalently linked to A0representing the oligonucleotide group needs to contain simultaneously a linking site to N on the nitrogen-containing backbone, a linking site to the oligonucleotide group, and a functional group capable of linking to a solid support. In some embodiments, the linking site to N on the nitrogen-containing backbone in L1covalently linked to A0representing the oligonucleotide group forms an amide bond with N, the oligonucleotide group is covalently linked via a phosphate ester bond, and the functional group capable of linking to a solid support is a hydroxyl group or an amino group. In some embodiments, R2is B5, B6, B5’, or B6’: wherein, represents a site of covalent linkage of groups. q2may be an integer from 1 to 10, and in some embodiments, q2is an integer from 1 to 5. The role of L1covalently linked to A0representing the targeting group is to place the targeting group in a suitable spatial position, so as to better bind to the receptor, so as to specifically target and enter the relevant cell or tissue. Therefore, L1covalently linked to A0representing the targeting group can be used in the present disclosure as long as it has a suitable length, and the chemical properties do not have a significant impact on delivery. In some embodiments, each L1covalently linked to A0representing the targeting group is independently a divalent linking group of 3-25 atoms in length. In some embodiments, each L1covalently linked to A0representing the targeting group is independently 4-15 atoms in length. In some embodiments, each L1covalently linked to A0representing the targeting group is 5-10 atoms in length. In some embodiments, each L1covalently linked to A0representing the targeting group is the same in length. In some embodiments, each L1covalently linked to A0representing the targeting group is the same or different, and is independently selected from the group consisting of the groups represented by formulae (L3)-(L18) and any linking combination thereof: wherein each j1is an integer from 2 to 10; each R’ is independently a hydrogen atom or a C1-C3 alkyl group, represents a site of covalent linkage of groups. For simplicity of synthesis and / or stability of chemical properties, in some embodiments, each L1covalently linked to A0representing a targeting group is independently a combination of at least 2 linking units, each linking unit independently having a structure represented by any one of formulae (L3)-(L7). In some embodiments, each linking unit independently has a structure represented by any one of formulae (L3), (L4), and (L7). For simplicity of synthesis, in some embodiments, each L1covalently linked to A0representing a targeting group includes a carbonyl group attached to the nitrogen atom represented in formula (308). In some embodiments, each L1covalently linked to A0representing a targeting group independently has a structure represented by formula (L20) or (L21): wherein j2is an integer from 4 to 9, and j3is 1 or 2. In some embodiments, j2is 5, 6, or 7, and j3is 1. In some embodiments, each L1covalently linked to A0representing a targeting group is the same. In the conjugate of the present disclosure, the number of targeting groups and the spacing between the targeting groups are such that a proper spatial configuration of multiple targeting groups is provided. To this end, n308and each m308are independently an integer selected from 2-4. In some embodiments, n308is 3 or 4, such that the number of targeting groups in the conjugate of the present disclosure is 3 or 4, which can better bind to the surface receptors of hepatocytes. In some embodiments, n308is 3, and each m308is independently 3 or 4. As understood by one skilled in the art, each R 308 is a hydrogen atom, a methyl group, or an ethyl group, without affecting the delivery effect of the oligonucleotide conjugate, and each can achieve the purpose of the present disclosure. In some embodiments, for simplicity of synthesis, each R 308 is a hydrogen atom. In the conjugates of the disclosure, each targeting group is the same or different, and is independently selected from a ligand group that binds to a cell surface receptor. In some embodiments, at least one or each targeting group is a group that is capable of targeting the liver. In some embodiments, at least one or each targeting group is one of a ligand that is capable of having affinity for a receptor on the surface of a mammalian hepatocyte. In some embodiments, at least one or each targeting group is one of a ligand group that has affinity for an asialoglycoprotein receptor (ASGPR) on the surface of a mammalian hepatocyte. In some embodiments, each targeting group is a galactose group or an N-acetylgalactosamine group formed by removing one atom or group from a galactose or N-acetylgalactosamine (GalNAc). In some embodiments, the oligonucleotide conjugates of the disclosure have a structure according to 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 deoxyabasic nucleotide, and the P atom shown in the above structural formula is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group of the ribose ring of the 3' terminal inverted deoxyabasic nucleotide of the sense strand of the double-stranded oligonucleotide group represented by Nu with a methylene group. In some embodiments, the P atom shown in the above structural formula (403) 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 deoxyabasic nucleotide 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 oligonucleotide group comprised in the oligonucleotide conjugate of the present disclosure can be an siRNA group formed by removing one atom or atom group from an siRNA, in which case the oligonucleotide conjugate of the present disclosure is also referred to as an siRNA conjugate. In some embodiments, the oligonucleotide group comprised in the oligonucleotide conjugate of the present disclosure is an siRNA group formed by siRNAa1, siRNAb1, siRNAb2 or siRNAb3 listed in Table 1. The siRNA conjugate comprising these siRNA groups exhibits excellent stability and high FXI mRNA inhibitory activity. In some embodiments, the oligonucleotide conjugate of the present disclosure is one of Conjugate 1 to Conjugate 7 listed in Table 2. Preparation of the oligonucleotide conjugate of the present disclosure The oligonucleotide conjugates described in the present disclosure can be prepared by various suitable methods by those skilled in the art. For example, when the nucleoside monomers are linked one by one according to the sequence and modification scheme of the single-stranded oligonucleotide or the sense strand and the antisense strand of the double-stranded oligonucleotide described in the present disclosure, respectively, by the solid-phase synthesis method, the delivery group can be introduced by the methods described in detail in the prior art to synthesize the oligonucleotide conjugates described in the present disclosure. For example, the preparation methods of various siRNA conjugates are described in detail in WO2015006740A2. In the case of a double-stranded oligonucleotide being an siRNA, the oligonucleotide conjugates of the present disclosure can also be obtained by means well known to those skilled in the art. The preparation method of the structure shown in formula (305A) is described in WO2014025805A1, and the preparation method of the structure shown in formula (307) is described in Rajeev et al., ChemBioChem 2015, 16, 903-908. The preparation method of the oligonucleotide conjugate shown in formula (308) is also disclosed in detail in Chinese patent application CN110959011A. The contents of the above documents are incorporated herein by reference in their entirety. Pharmaceutically acceptable salt In yet another aspect, the present disclosure also provides a pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure. The pharmaceutically acceptable salt is known to those skilled in the art. By forming a salt form, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure can exhibit better solubility, bioavailability, or stability than the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate itself. In the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate described in the present disclosure, the non-bridging oxygen atom or the sulfur atom in the phosphodiester bond or the phosphorothioate bond connecting between each adjacent nucleotide carries a negative charge, which can exist in the form of a hydroxyl group or a thiol group, and the hydrogen ion in the hydroxyl group or the thiol group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, an ammonium ion NH4 +one of the organic ammonium cations. Further, there can also be a salt-forming group in the delivery group. 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 is a salt or a partial salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate, the salt being one or more of a methylamine salt, a triethylamine salt, or a sodium salt. In some embodiments, the pharmaceutically acceptable salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate. Pharmaceutical composition In another aspect, the present disclosure also provides a pharmaceutical composition comprising one or more of the single-stranded oligonucleotide, the double-stranded oligonucleotide, the oligonucleotide conjugate, and the pharmaceutically acceptable salt provided by the present disclosure, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is one or more of various ingredients conventionally employed in the art, such as one or more of a solvent, a protective agent, an osmotic pressure adjusting agent, and other pharmaceutically acceptable carriers. For example, when the pharmaceutical composition is an injection solution, the pharmaceutically acceptable excipient is a solvent, such as one or more of deionized water, water for injection, physiological saline, ethanol, an aqueous ethanol solution, a pH buffer. The pH buffer can be a tris-hydroxymethyl aminomethane hydrochloride buffer having a pH value of 7.5-8.5 and / or a phosphate buffer having a pH value of 5.5-8.5, for example, can be a phosphate buffer having a pH value of 5.5-8.5. The amount of the solvent is adjusted according to the desired concentration of the solution, and the concentration of the oligonucleotide conjugate in the injection solution can be 0.01 mg / mL-20 mg / mL, 0.1 mg / mL-10 mg / mL, or 0.5 mg / mL-5 mg / mL, based on the oligonucleotide group. The protective agent can be at least one of myo-inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The content of the protective agent can be 0.01-30% 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 200-700 milliosmoles per kilogram (mOsm / kg). The content of the osmotic pressure adjusting agent can be easily determined by one skilled in the art depending on the desired osmotic pressure. In some embodiments, the dose of the pharmaceutical composition during administration is adjusted depending on the mode of administration. In some embodiments, the pharmaceutical composition can be a liquid formulation, such as an injection solution, or a lyophilized powder formulation that is mixed with a liquid excipient to prepare a liquid formulation for administration. The liquid formulation can be, but is not limited to, for subcutaneous, intramuscular, or intravenous injection, or can be, but is not limited to, for delivery of the pharmaceutical composition to the lung by inhalation, or to other organ tissues (e.g., liver) by inhalation, or by oral administration. In some embodiments, the pharmaceutical composition is administered by subcutaneous injection. The pharmaceutically acceptable other carrier can be one or more of the carriers conventionally used in the field of double-stranded oligonucleotide administration, such as, but not limited to, magnetic nanoparticles (e.g., nanoparticles based on 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 conjugate and the pharmaceutically acceptable carrier can be 1: (1-500), and in some embodiments, the above weight ratio is 1: (1-50). In some embodiments, the pharmaceutical composition can be in the form of a liposome preparation. In some embodiments, the pharmaceutically acceptable carrier used in the liposome preparation comprises an amine-containing transfection compound (hereinafter can also be referred to as an organic amine), a helper lipid, and / or a pegylated lipid. Among them, the organic amine, the helper lipid, and the pegylated lipid can be selected from one or more of the amine-containing transfection compounds or pharmaceutically acceptable salts or derivatives thereof, the helper lipids, and the pegylated lipids described in Chinese Patent Application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine can be a compound represented by formula (201) or a pharmaceutically acceptable salt thereof described in Chinese Patent Application CN103380113A: wherein: X 101 and X 102 each independently is O, S, N-A, or C-A, wherein A is hydrogen or a C1-C 20 hydrocarbon chain; Y 101 and Z 101 each independently is C=O, C=S, S=O, CH-OH, or SO2; R 101 , R 102 , R 103 , R 104 , R 105 , R 106 and R 107 each independently is hydrogen, a cyclic or acyclic, substituted or unsubstituted, branched or straight chain aliphatic group, a cyclic or acyclic, substituted or unsubstituted, branched or straight chain heteroaliphatic group, a substituted or unsubstituted, branched or straight chain acyl group, a substituted or unsubstituted, branched or straight chain aryl group, a substituted or unsubstituted, branched or straight chain heteroaryl group; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; wherein, if m=p=0, R 102 is hydrogen; and, if at least one of n or m is 2, R 103and the nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): wherein g, e, and f are each independently an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some embodiments, R 103 is a polyamine. In other embodiments, R 103 is a ketal. In some embodiments, R 101 and R 102 each independently is any substituted or unsubstituted, branched or straight chain alkyl or alkenyl group having from 3 to about 20 carbon atoms, such as from 8 to about 18 carbon atoms, and from 0 to 4 double bonds, such as from 0 to 2 double bonds. In some embodiments, if each of n and m independently has a value of 1 or 3, then R 103 may be any one of the following formula (204) - formula (213): wherein in formula (204) - formula (213), g, e, and f are each independently an integer from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * shows a possible point of attachment to a nitrogen atom in formula (201), wherein each H at any * position can be replaced to achieve attachment to a nitrogen atom in formula (201). 103 may be any one of the following formula (204) - formula (213): A person skilled in the art can obtain the compound shown in formula (201) by any reasonable method. In some embodiments, the compound shown in formula (201) can be prepared according to the description in Chinese Patent Application CN103380113A. In some embodiments, the organic amine is an organic amine as shown in formula (214) and / or an organic amine as shown in formula (215): the helper lipid is cholesterol, an analog of cholesterol, and / or a derivative of cholesterol; the pegylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio among the organic amine, the helper lipid, and the pegylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, can be (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed by the oligonucleotide or oligonucleotide conjugate of the present disclosure and the above-mentioned amine-containing transfection reagent have an average diameter of about 30 nm to about 200 nm, typically about 40 nm to about 135 nm, more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm, for example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, in the pharmaceutical composition formed 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 double-stranded oligonucleotide to the total lipids (e.g., organic amine, helper lipid, and / or PEGylated lipid) is in the range of from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10, for example, the weight ratio of the oligonucleotide of the present disclosure or the oligonucleotide conjugate to the total lipids is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, or 1:18. In some embodiments, the components of the pharmaceutical composition can exist independently at the time of sale and in the form of a liquid preparation at the time of use. In some embodiments, the pharmaceutical composition formed 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, only by replacing the existing siRNA 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 to obtain a lipid solution; the amount of alcohol is such that the total mass concentration of the obtained lipid solution is 2-25 mg / mL, for example, it can be 8-18 mg / mL. The alcohol is selected from pharmaceutically acceptable alcohols, such as alcohols that are liquid near room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, for example, it can be ethanol. The oligonucleotide or oligonucleotide conjugate provided by the present disclosure is dissolved in a buffer salt solution to obtain an aqueous solution of the oligonucleotide or oligonucleotide conjugate. The concentration of the buffer salt solution is 0.05-0.5M, for example, it can be 0.1-0.2M, the pH of the buffer salt solution is adjusted to 4.0-5.5, for example, it can be 5.0-5.2, and the amount of the buffer salt solution is used to make the concentration of the oligonucleotide or oligonucleotide conjugate not more than 0.6mg / mL, for example, it can be 0.2-0.4mg / mL. The buffer salt is selected from one or more of soluble acetate, soluble citrate, for example, it can be sodium acetate and / or potassium acetate. The lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate are mixed, and the product obtained after mixing is incubated at 40-60℃ for at least 2 minutes, for example, it can be 5-30 minutes, to obtain the liposome preparation after incubation. The volume ratio of the lipid solution and the aqueous solution of the oligonucleotide or oligonucleotide conjugate is 1:(2-5). The liposome preparation after incubation is concentrated or diluted, impurities are removed, and sterilized to obtain the pharmaceutical composition provided by the present disclosure, and the physicochemical parameters thereof are as follows: the pH value is 6.5-8, the encapsulation efficiency is not less than 80%, the particle size is 40-200nm, the polydispersity index is not higher than 0.30, and the osmotic pressure is 250-400mOsm / kg; for example, the physicochemical parameters can be as follows: the pH value is 7.2-7.6, the encapsulation efficiency is not less than 90%, the particle size is 60-100nm, the polydispersity index is not higher than 0.20, and the osmotic pressure is 300-400mOsm / kg. The concentration or dilution can be performed before, after or simultaneously with the removal of impurities. The method for removing impurities can use various existing methods, for example, a tangential flow system or a hollow fiber column can be used, and the ultrafiltration is performed under the condition of 100KDa, and the ultrafiltration exchange solution is a phosphate buffer solution (PBS) with a pH of 7.4. The method for sterilization can use various existing methods, for example, the sterilization can be performed by filtering through a 0.22μm filter. Applications of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt and pharmaceutical composition of the present disclosure The present disclosure also provides the use of the single-stranded oligonucleotide, double-stranded oligonucleotide, oligonucleotide conjugate, pharmaceutically acceptable salt or pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease or symptom related to the level of FXI mRNA. In some embodiments, the disease or symptom related to the level of FXI mRNA is a thrombotic disease and / or ischemic stroke. The present disclosure also provides a method of treating and / or preventing a disease or condition associated with FXI mRNA levels, comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. In some embodiments, the disease or condition associated with FXI mRNA levels is a thrombotic disease and / or ischemic stroke. Further, the present disclosure also provides a method of modulating the level of FXI mRNA expression in a cell, comprising contacting the cell with an effective amount of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure. The term "administering / administration" as used herein refers to the placement of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates into the subject by means or routes such that at least a portion of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates are positioned at the desired site 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 single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates to a particular site as compared to the entire body of the subject, while systemic administration results in delivery of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates 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 one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the present disclosure can be a conventional dosage in the art, which can be determined according to various parameters, especially the age, weight, and sex of the subject. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. In administering one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions of the disclosure, for example, to a male or female, 6-12 week old, 18-25 g body weight C57BL / 6J or C3H / HeNCrlVr mouse, the amount of siRNA, pharmaceutical composition, and / or siRNA in the siRNA conjugate formed by the siRNA and the pharmaceutically acceptable conjugate molecule can be 0.001-100 mg / kg body weight, in some embodiments 0.01-50 mg / kg body weight, in further embodiments 0.05-20 mg / kg body weight, in still further embodiments 0.1-15 mg / kg body weight, in yet further embodiments 0.1-10 mg / kg body weight. The above amounts can be preferred in administering the siRNA, pharmaceutical composition, and / or siRNA conjugate of the disclosure. The amount of double-stranded oligonucleotide of one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates provided to inhibit the expression of FXI mRNA in a cell provided by the methods of the disclosure is readily determined by one of skill in the art depending on the desired effect to be obtained. For example, in some embodiments, the oligonucleotide is an siRNA, the oligonucleotide conjugate is an siRNA conjugate, and the amount of siRNA in the siRNA conjugate provided is an amount sufficient to reduce the level of FXI mRNA expression and result in an extracellular concentration of 1 pM to 1 μΜ, 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. Kit The disclosure provides a kit comprising one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates provided by the disclosure. In some embodiments, the kits described herein can provide one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates in one container. In some embodiments, the kits described herein can include a container providing a pharmaceutically acceptable excipient. In some embodiments, the kits can further include other ingredients such as stabilizers or preservatives, etc. In some embodiments, the kits described herein can include at least one other therapeutic agent in a container different from the container providing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and conjugates described herein. In some embodiments, the kits can include instructions for mixing one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, pharmaceutical compositions, pharmaceutically acceptable salts, and oligonucleotide conjugates with a pharmaceutically acceptable carrier and / or excipient or other ingredients, if any. In the kits of the present disclosure, one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and / or pharmaceutically acceptable excipients can be provided in any form, such as liquid form, dry form, or lyophilized form. In some embodiments, one or more of the single-stranded oligonucleotides, double-stranded oligonucleotides, oligonucleotide conjugates, pharmaceutically acceptable salts, and pharmaceutical compositions, and optional pharmaceutically acceptable excipients are substantially pure and / or sterile. In some embodiments, sterile water can be provided in the kits of the present disclosure. The present disclosure will be further described by way of Examples, but the present disclosure is not in any way limited thereto. Without wishing to be limited, the present application is further described in detail in the following embodiments and examples of exemplary embodiments of the double-stranded oligonucleotide in the pharmaceutical composition, the oligonucleotide and / or the oligonucleotide conjugate of the present disclosure, which are the exemplary embodiments of small interfering RNA (siRNA). In this case, the double-stranded oligonucleotide, the pharmaceutical composition, the pharmaceutically acceptable salt and the oligonucleotide conjugate of the present disclosure are siRNA, the pharmaceutical composition comprising siRNA and the salt formation and the siRNA conjugate, respectively. In the context of the present disclosure, for ease of description, the siRNA, the pharmaceutical composition comprising siRNA and the salt formation and the siRNA conjugate in these embodiments are also referred to as the siRNA of the present disclosure, the pharmaceutical composition of the present disclosure and the salt formation and the siRNA conjugate of the present disclosure. This does not mean that the double-stranded oligonucleotide of the present disclosure can only be siRNA, on the contrary, the double-stranded oligonucleotide can be other variants disclosed herein or known to those skilled in the art, such as small activating RNA (saRNA) and the like. It is envisaged that, based on the detailed description of siRNA, the pharmaceutical composition comprising siRNA and the salt formation and the siRNA conjugate, other double-stranded oligonucleotides will similarly function when used alone, or when forming the pharmaceutical composition and / or the oligonucleotide conjugate described in the present disclosure. Examples Unless otherwise specified, the reagents, media used in the following examples are commercially available, and the nucleic acid electrophoresis, real-time PCR and other operations are carried out according to the methods described in Molecular Cloning (Cold Spring Harbor Laboratory Press (1989)). Preparation of siRNA conjugates 1-7 provided by the present disclosure According to the preparation method described in Preparation Example 13 of CN110959011A, the conjugates 1-7 in Table 2 were prepared, and the only difference was that the sense strand and the antisense strand of the siRNA contained in each conjugate were as shown in Table 2; for the nucleic acid sequence with the sense strand and the antisense strand sequence of the siRNA in the conjugates 1-7 in the following Table 2, the nucleoside phosphoramidite monomers were connected one by one to synthesize the sense strand and the antisense strand of the siRNA. After the synthesis was completed, the conjugates 1-5 were purified by centrifugal ultrafiltration desalting purification using 3K (MWCO) ultrafiltration tube; the conjugates 6-7 were first purified by ion exchange using a strong anion exchange filler self-packed column, and then desalted and purified by HiPrep 26 / 13 Desalting desalting pre-packed column. Conjugate 1-5 is a mixture of methylamine salt and ammonium salt of a compound having the structure shown in formula (403); conjugate 6-7 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 oxygen atom in the inverted abasic deoxynucleotide ia shown in formula (35) which is connected to the 3' end of the sense strand of the siRNA represented by Nu through a methylene group, thereby covalently linking to the sense strand of the siRNA. And the siRNA conjugate contains the siRNA having the sequence corresponding to the siRNA sequence of conjugate 1-7 in Table 2. After each siRNA conjugate was diluted to a concentration of 0.2 mg / mL (calculated as siRNA) using ultrapure water (Milli-Q ultrapure water instrument, resistivity 18.2 MΩ*cm (25℃)), the molecular weight was detected by liquid chromatography-mass spectrometry (LC-MS, Liquid Chromatography-Mass Spectrometry, purchased from Waters Company, model: LCT Premier). The theoretical molecular weight of the sense strand of conjugate 1 was 7438.37, and the measured molecular weight was 7437.98; the theoretical molecular weight of the antisense strand was 6884.63, and the measured molecular weight was 6884.27; the theoretical molecular weight of the sense strand of conjugate 2 was 7298.21, and the measured molecular weight was 7297.68; the theoretical molecular weight of the antisense strand was 7018.79, and the measured molecular weight was 7018.23; the theoretical molecular weight of the sense strand of conjugate 3 was 7298.21, and the measured molecular weight was 7297.84; the theoretical molecular weight of the antisense strand was 7018.79, and the measured molecular weight was 7018.28; the theoretical molecular weight of the sense strand of conjugate 4 was 7298.21, and the measured molecular weight was 7297.69; the theoretical molecular weight of the antisense strand was 7018.79, and the measured molecular weight was 7018.23; the theoretical molecular weight of the sense strand of conjugate 5 was 7298.21, and the measured molecular weight was 7297.50; the theoretical molecular weight of the antisense strand was 7094.78, and the measured molecular weight was 7093.90; the theoretical molecular weight of the sense strand of conjugate 6 was 7298.21, and the measured molecular weight was 7297.60; the theoretical molecular weight of the antisense strand was 7018.80, and the measured molecular weight was 7018.0; the theoretical molecular weight of the sense strand of conjugate 7 was 7298.21, and the measured molecular weight was 7297.60; the theoretical molecular weight of the antisense strand was 7094.79, and the measured molecular weight was 7094.0; the measured value is consistent with the theoretical value, indicating that the synthesized conjugates 1-7 contain the target designed double-stranded nucleic acid sequence. Table 2 siRNA sequence in siRNA conjugate wherein the capital letters C, G, U, A and T represent the base composition of the nucleotides; the lower case letter m represents that the nucleotide represented by the capital letter adjacent to the left of the letter m is a 2'-methoxy modified nucleotide; the lower case letter f represents that the nucleotide represented by the capital letter adjacent to the left of the letter f is a 2'-fluoro modified nucleotide; the letter combination VP represents that the nucleotide represented by the capital letter to the right of the letter combination is a 5'-vinylphosphonate modified nucleotide; the lower case letter s represents that the nucleotides represented by the two capital letters adjacent to the left and right of the letter s are connected by a phosphorothioate group; the lower case letter d represents that the nucleotide represented by the capital letter to the right of the letter d is a deoxyribonucleotide; and ia represents an inverted abasic deoxyribonucleotide. Synthesis of Comparative Preparation Example 1 Reference Conjugate NC Reference Conjugate NC was synthesized according to the procedure of Preparation Example 1. The sense strand and the antisense strand of the siRNA contained in Reference Conjugate NC are shown in Table 2, respectively. Reference Conjugate NC is a mixture of methylamine salt and amine salt of a compound having the structure shown in Formula (403), wherein the conjugate group is linked to the ribose 3' position of the 3' terminal nucleotide of the sense strand of the siRNA represented by Nu. Experimental Example 1 Inhibitory activity of Conjugates 1-4 in HepG2 human hepatoma cells in vitro This experimental example investigated the inhibitory activity of Conjugates 1-4 and Reference Conjugate NC on FXI mRNA in HepG2 human hepatoma cells in vitro. The specific steps are as follows: [1] Cell culture HepG2 human hepatoma cells (purchased from Nanjing KeyGen Biotech Co., Ltd.) were cultured at 37°C in a culture box containing 5% CO2 / 95% air using DMEM complete medium (purchased from MACGENE Co., Ltd.) added with 10% fetal bovine serum (FBS, purchased from GIBCO Co., Ltd.). HepG2 cells were seeded at 0.5x10 5 The cells were seeded at 0.5x10 [2] Transfection For each siRNA conjugate to be tested, a conjugate working solution was prepared in PBS at a concentration of 20 μM (calculated based on the amount of siRNA in the conjugate). The siRNA conjugates to be tested used were Conjugates 1-4 and Reference Conjugate NC, respectively. 5A solutions were prepared, each containing 1.5 μL of the conjugate working solution and 48.5 μL of Opti-MEM medium. Prepare 5B solution, each 5B solution contains 1 μL Lipofectamine TM 2000 (Invitrogen) and 49 μL Opti-MEM medium. For each conjugate, mix one portion of 5A solution and one portion of 5B solution to obtain transfection complex 5X1. In the culture wells, add transfection complex 5X1 of each siRNA conjugate, mix evenly, and add 100 μL / well to obtain transfection mixture containing siRNA conjugate at a concentration of 50 nM (calculated by the amount of siRNA). Transfect 2 culture wells with transfection complex 5X1 of each siRNA conjugate respectively to obtain transfection mixture containing siRNA conjugate, which is denoted as test group. For reference conjugate NC, mix one portion of 5A solution and one portion of 5B solution to obtain transfection complex 5X'. In the culture wells, add transfection complex 5X' of reference conjugate NC, mix evenly, and add 100 μL / well to obtain negative control transfection mixture at a concentration of 50 nM (calculated by the amount of siRNA). Transfect 2 culture wells with transfection complex 5X' of reference conjugate NC respectively to obtain transfection mixture containing reference conjugate NC, which is denoted as negative control group. In another 2 culture wells, add Opti-MEM medium, and add 100 μL / well to obtain control without siRNA conjugate, which is denoted as blank control group. Place the well plate in a 5% CO2 incubator for 6 h, add 500 μL / well of DMEM medium containing 20% FBS, and place the well plate in a 5% CO2 incubator for 24 h. [3] Detection Use TRIZOL reagent (purchased from Sigma, item number: T9424-200 mL) to extract total RNA in each well according to the method recorded in the instruction book. For each well of cells, take 1 μg of total RNA, and use the reagents provided by the reverse transcription kit Revers Transcription System (purchased from Promega, item number A3500), and select Oligo(dT) 15As primers, the reverse transcription reaction system 20 μL was configured according to the reverse transcription operation steps in the kit instructions, wherein the reaction system A 10.5 μL (1 μg total RNA) and the reaction system B 9.5 μL (reverse transcription reagent components) were contained, and the total RNA of each well of cells was reverse transcribed. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the reverse transcription reaction system A was incubated at 70°C for 10 min, then the reaction system B was added and incubated at 42°C for 30 min, and finally 95°C for 5 min. After the reaction was completed, 80 μL of RNase-free water was added to the reverse transcription reaction system to obtain a cDNA-containing solution. For each reverse transcription reaction system, 5 μL of the above cDNA-containing solution was taken as a template, and a qPCR reaction system 20 μL was configured using the reagents provided by the SYBR Select Master Mix kit (purchased from Applied Biosystems, item number 4472908), wherein the PCR primer sequences for amplifying the target gene FXI and the internal reference gene GAPDH were as shown in Table 3, and the final concentration of each primer was 0.25 μM. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and a three-step amplification was performed, and the amplification program was as follows: 95°C pre-denaturation for 10 min, then 95°C denaturation for 30 s, 60°C annealing for 30 s, 72°C extension for 30 s, and the above denaturation, annealing and extension processes were repeated for 40 times, and then a product W1 containing the amplified target gene FXI and internal reference gene GAPDH was obtained. The product W1 was then subjected to 95°C for 15 s, 60°C for 1 min, gradient heating to 95°C and collecting fluorescence signal every 0.3°C, 95°C for 15 s, and the real-time fluorescence quantitative PCR instrument collected the melting curves of the target gene and the internal reference gene GAPDH in the product W1, respectively, to obtain the Ct values of the target gene FXI and the internal reference gene GAPDH. Table 3 primer information The comparative Ct (ΔΔCt) method was used to relatively quantify the expression level of the target gene FXI mRNA in each test group, 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 ΔCt (control group) of two culture holes of the blank control group respectively. Thus, each culture hole of the test group and the control group corresponds to a ΔΔCt value. The expression level of the test group FXI mRNA is normalized based on the average value of the blank control group, and the average value of the blank control group FXI mRNA expression level is defined as 100%. Test group FXI mRNA relative expression level = 2- ΔΔCt(测试组) × 100% Test group FXI mRNA inhibition rate = (1-test group FXI mRNA relative expression level) × 100% The inhibition rate of each conjugate to FXI mRNA is shown in Table 4 below: Table 4 Inhibition rate of each conjugate to target gene FXI mRNA Table 4 shows that the siRNA conjugate provided by the present disclosure can achieve an inhibition rate of 83.3% to the target gene FXI mRNA in HepG2 cells in vitro at a concentration of 50nM, and has good in vitro inhibition activity. Experimental Example 2: In vitro target sequence inhibition activity of the conjugate of the present disclosure HEK293A cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were cultured at 37°C in a culture box containing 5% CO2 / 95% air with DMEM complete medium (purchased from MACGENE Co., Ltd.) containing 10% fetal bovine serum (FBS, purchased from GIBCO Co., Ltd.). According to the method described in Kumico Ui-Tei et. al., Functional dissection of siRNA sequence by systematic DNA substitution: modified siRNA with a DNA seed arm is a powerful tool for mammalian gene silencing with significantly reduced off-target effect. Nucleic Acids Research, 2008. 36(7), 2136-2151, a detection plasmid was constructed, the conjugate 1 to be evaluated was transfected into HEK293A cells, and the inhibition activity of the conjugate 1 was reflected by the expression level of the dual luciferase reporter gene. The specific steps are as follows: [1] Construction of detection plasmid The psiCHECK™-2 (Promega™) plasmid was used to construct the detection plasmid, which contains a target sequence, i.e., the siRNA target sequence. For the siRNA to be tested, the target sequence is: 5'-GAGTACGTGGACTGGATTCTG-3' (SEQ ID NO: 21) The target sequence was cloned into the Xho I / Not I site of the psiCHECK™-2 plasmid. [2] Transfection HEK293A cells were seeded in a 96-well plate at a density of 8 x 10 3 After 16 h, when the cell density reached 70-80%, the DMEM complete medium in the culture wells was aspirated, and 80 μL of Opti-MEM medium (GIBCO) was added to each well for 1.5 h of incubation. The above detection plasmid was diluted with RNase-free Water to a working solution of 200 ng / μL; the conjugate to be tested was prepared into a working solution with a concentration of 10 nM and 3 nM (based on the amount of siRNA in the conjugate). 1A1 solution was prepared, each containing 1 μL of siRNA working solution with a concentration of 10 nM, 0.05 μL of detection plasmid working solution (containing 10 ng of detection plasmid), and 8.95 μL of Opti-MEM medium. 1A2 solution was prepared, each containing 1 μL of siRNA working solution with a concentration of 3 nM, 0.05 μL of detection plasmid working solution (containing 10 ng of detection plasmid), and 8.95 μL of Opti-MEM medium. 1B solution was prepared, each containing 0.2 μL of Lipofectamine TM 2000 and 9.8 μL of Opti-MEM medium. 1C solution was prepared, each containing 0.05 μL of detection plasmid working solution (containing 10 ng of detection plasmid) and 9.95 μL of Opti-MEM medium. One portion of 1B solution was mixed with one portion of 1A1 solution or one portion of 1A2 solution, respectively, and incubated at room temperature for 20 min to obtain transfection complexes 1X1 and 1X2, respectively; one portion of 1B solution was mixed with one portion of 1C solution, and incubated at room temperature for 20 min to obtain transfection complex 1X3. In three culture wells, transfection complex 1X1 was added, mixed evenly, and the amount added was 20 μL / well to obtain a co-transfection mixture with a final siRNA concentration of about 0.1 nM, which was recorded as test group 1. In another three culture wells, respectively add transfection complex 1X2, mix evenly, the amount of addition is 20 μL / well, to obtain the co-transfection mixture with siRNA final concentration of about 0.03 nM, recorded as test group 2. In another three culture wells, respectively add transfection complex 1X3, to obtain the transfection mixture without siRNA, the amount of addition is 20 μL / well, recorded as control group. After co-transfecting the co-transfection mixture containing siRNA and the transfection mixture without siRNA in the culture wells for 4 h, add 100 μL of DMEM complete medium containing 20% FBS to each well. Place the 96-well plate in a 5% CO2 incubator for continuous culture for 24 h. [3] Detection Remove the culture medium in the culture wells, and add 150 μL of Mix the luciferase reagent with DMEM at a volume ratio of 1:1, incubate at room temperature for 10 min, then transfer 120 μL of the mixture to a 96-well enzyme-labeled plate, and use a Synergy H1 multifunctional enzyme-labeled instrument (BioTek) to read the Firefly chemiluminescence value (Fir); then add 60 μL of Stop & Glow® Buffer and Stop & Glow® Substrate at a volume ratio of 100:1, mix thoroughly, incubate at room temperature for 10 min, and then use the enzyme-labeled instrument to read the Renilla chemiluminescence value (Ren) according to the arrangement for reading Fir. Calculate the luminescence ratio Ratio = Ren / Fir for each well, and the luminescence ratio Ratio (control) of the control group is the average of the ratios of the three culture wells; normalize the luminescence ratios of each test group based on the average of the luminescence ratios of the control group, to obtain the ratio R of Ratio (test) / Ratio (control), which represents the expression level of the Renilla reporter gene, i.e. the residual activity. The inhibition rate of siRNA = (1-R) x 100%. The inhibition activity results of the conjugate to be tested at different concentrations on the target sequence are shown in Table 5. The inhibition activity of the reference conjugate NC in the psiCHECK system was also investigated according to the above method, the only difference being that the conjugate to be tested was the reference conjugate NC. The results are shown in Table 5. Table 5: Inhibition rate of target sequence As can be seen from the results of Table 5, the conjugate 1 provided by the present disclosure has good in vitro inhibitory activity on the target sequence at each concentration, and shows concentration-dependent inhibitory activity. At a siRNA concentration of 0.1 nM, the inhibition rate on the target sequence in HEK293A cells is 58.51%, showing a good effect of inhibiting FXI mRNA. Inhibitory activity of conjugates in monkey liver primary cells in experimental example 3 This experimental example investigates the inhibitory activity of conjugates 1-4 and reference conjugate NC on FXI gene in monkey liver primary cells. The specific steps are as follows: [1] Cell culture The monkey liver primary cells (purchased from Mysun Biotech Co., Ltd.) were cultured at 37°C in a culture box containing 5% CO2 / 95% air using a rhesus monkey liver cell culture medium kit (purchased from Mysun Biotech Co., Ltd., product number HCTPM-R-001) containing coating medium, resuscitation medium, plating medium and maintenance medium. The monkey liver primary cells were inoculated in the 24-well plate at a concentration of 1x10 5 The cells were inoculated in the 24-well plate at a concentration of 1x10 [2] Transfection For each siRNA conjugate to be tested, a conjugate working solution was prepared using PBS at a concentration of 20 μM (calculated based on the amount of siRNA in the conjugate). The siRNA conjugates to be tested were conjugates 1-4 and reference conjugate NC. A 3A solution was prepared, and each 3A solution contained 3 μL of the conjugate working solution and 97 μL of the cell maintenance medium. A 3B solution was prepared, and each 3B solution contained 2 μL of Lipofectamine TM 2000 (Invitrogen) and 98 μL of Opti-MEM medium. For each conjugate, one 3A solution and one 3B solution were mixed to obtain a transfection complex 3X1. In the culture wells, the transfection complex 3X1 of each siRNA conjugate was added, and the mixture was uniformly mixed, and the amount added was 200 μL / well, to obtain a transfection mixture with a concentration of 50 nM (calculated based on the amount of siRNA). The transfection complex 3X1 of each siRNA conjugate was used to transfect 2 culture wells to obtain a transfection mixture containing the siRNA conjugate, which was recorded as the test group. For the reference conjugate NC, one portion of the 3A solution and one portion of the 3B solution were mixed to obtain the transfection complex 3X'. In the culture wells, the transfection complex 3X' of the reference conjugate NC was added, mixed evenly, and the amount added was 200 μL / well to obtain a negative control transfection mixture with a concentration of 50 nM (calculated by the amount of siRNA). The transfection complex 3X' of the reference conjugate NC was used to transfect 2 culture wells to obtain a transfection mixture containing the reference conjugate NC, which was recorded as the negative control group. One portion of 100 μL Opti-MEM medium was mixed with 100 μL cell maintenance medium to obtain a blank transfection mixture 3X2. In another 2 culture wells, the blank transfection mixture 3X2 was added, and the amount added was 200 μL / well to obtain a transfection mixture without siRNA conjugate, which was recorded as the blank control group. The 24-well plate was placed in a CO2incubator for continuous culture for 24 hours. [3] Detection The [3] detection process in Experimental Example 1 was followed, except that the primers used were as shown in Table 6A. Table 6A Primer Information The expression level of the target gene FXI mRNA in each test group was relatively quantitatively calculated according to the method of Experimental Example 1, and the inhibition rate of each conjugate on FXI mRNA was as shown in Table 6B: Table 6B Inhibition rate of each conjugate on target gene FXI mRNA The results of Table 6B show that in the monkey liver primary cells, the inhibition rate of the siRNA conjugate provided by the present disclosure on the target gene FXI mRNA can reach more than 72.2% at a concentration of 50 nM, and the inhibition rate of conjugate 2 and conjugate 3 with the same siRNA sequence and different modification methods on FXI mRNA can reach more than 97.9%, which has good in vitro inhibition activity. Experimental Example 4 Inhibition activity of conjugates in monkey liver primary cells This experimental example investigated the inhibition activity of conjugates 2-4 and the reference conjugate NC on FXI mRNA in monkey liver primary cells, and the same method as in Experimental Example 3 was used, except that the concentration of the transfection mixture was 5 nM (calculated by the amount of siRNA). The expression level of the target gene FXI mRNA in each test group was relatively quantitatively calculated according to the method of Experimental Example 3, and the inhibition rate of each conjugate on FXI mRNA was as shown in Table 7: Table 7 Inhibition rate of each conjugate on target gene FXI mRNA As shown in Table 7, the siRNA conjugate provided by the present disclosure still has an inhibition rate of 94.5% or more on the target gene FXI mRNA at a concentration of 5 nM in monkey liver primary cells, and in particular, the conjugate 3 has an inhibition rate of 97.2% on FXI mRNA, which has good in vitro inhibition activity. Experimental Example 5: Inhibition activity of the conjugate of the present disclosure on FXI mRNA expression in vivo in mice C57BL / 6N mice were randomly divided (all female), 5 mice in each group, and numbered respectively. The test conjugate 1 was administered to each group of mice at different doses of 3 mg / kg and 9 mg / kg (all in terms of siRNA) by subcutaneous injection. The siRNA conjugate was provided in the form of 0.9% sodium chloride aqueous solution of siRNA conjugate at 0.5 mg / mL and 1.5 mg / mL, and the administration volume was 6 mL / kg. One group of mice was administered with 1xPBS, and the administration volume was 6 mL / kg, as a control group. The animals were sacrificed on the 7th day after administration, and the liver tissues of each mouse were collected and preserved with RNA later (purchased from Sigma Aldrich Company); the liver tissues were homogenized with a tissue homogenizer, and total RNA was extracted using Trizol (purchased from Sigma Company) according to the operation steps described in the instruction manual. For each homogenized tissue, 1 μg of total RNA was taken, and the reagents provided by the reverse transcription kit Revers Transcription System (purchased from Promega Company, item number A3500) were used, in which Oligo(dT) 15 As a primer, the reverse transcription reaction system 20 μL was configured according to the reverse transcription operation steps in the instruction manual, which contained reaction system A 10.5 μL (1 μg of total RNA) and reaction system B 9.5 μL (reverse transcription reagent components), and the total RNA of each well of cells was subjected to reverse transcription. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the reverse transcription reaction system A was incubated at 70°C for 10 min, then the reaction system B was added and incubated at 42°C for 30 min, and finally incubated at 95°C for 5 min, after the reaction was completed, 80 μL of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above cDNA-containing solution was taken as a template to configure a qPCR reaction system of 20 μL using reagents provided by a fluorescent quantitative PCR kit SYBR Select Master Mix (purchased from Applied Biosystems, item number 4472908), wherein the PCR primer sequences for amplifying the target gene FXI and the internal reference gene mGAPDH are shown in Table 8, and the final concentration of each primer is 0.25 μM. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and amplification was performed using a three-step method, and the amplification program was 95°C pre-denaturation for 10 min, then 95°C denaturation for 30 s, 60°C annealing for 30 s, 72°C extension for 30 s, and the above denaturation, annealing and extension process was repeated for 40 times, and then the product W containing the amplified target gene FXI and internal reference gene mGAPDH was obtained. The product W was then subjected to 95°C for 15 s, 60°C for 1 min, gradient heating to 95°C and collecting fluorescence signal every 0.3°C, 95°C for 15 s of incubation, and the real-time fluorescence quantitative PCR instrument collected the melting curve of the target gene FXI and the internal reference gene mGAPDH in the product W, and the Ct value of the target gene FXI and the internal reference gene mGAPDH was obtained. In the calculation of the FXI mRNA expression level and the inhibition rate, the control group was the control group of mice administered with PBS in the experiment, and the test group was the administration group of mice administered with different dosages of conjugate 1. The FXI mRNA expression level of the control group was recorded as 100%, and the FXI mRNA expression level inhibition rate was recorded as 0%. The test results were standardized with the FXI mRNA expression level of the control group, and the calculation process was shown in Experimental Example 1, and the results were shown in Table 9. Table 8: Sequences of detection primers Table 9: FXI mRNA inhibition rate of conjugates at different concentrations As can be seen from the results in Table 9, the conjugate provided by the present disclosure can show an FXI mRNA inhibition rate of 56.0% at an siRNA administration dosage of 3 mg / kg; at an siRNA concentration of 9 mg / kg, the FXI mRNA inhibition rate is as high as 77.0%, showing a good FXI mRNA inhibition effect. Experimental Example 6 Inhibition of FXI mRNA expression in mice by conjugates 1-4 In this experimental example, the inhibition efficiency of conjugates 1-4 on the expression amount of FXI mRNA in hFXI transgenic mice (Jiangsu Jizhu Yaoke Biotechnology Co., Ltd.) was investigated. First, the hFXI transgenic mice (SPF level, all male, 6-8 weeks old) were randomly divided into groups, 5 mice in each group, and numbered respectively, and a phosphate buffer (PBS) control group was added. All animals were calculated according to the weight of the drug, single dose (subcutaneous administration), respectively, 3 mg / kg dose of conjugate 1-4. Conjugate 1-4 was provided in the form of 0.9% sodium chloride aqueous solution of 0.6 mg / mL of conjugate, and the administration volume was 5 mL / kg. The animals were sacrificed on the 7th day after administration, and the liver was collected, and the inhibition activity of FXI mRNA was determined and calculated according to the operation process of Experimental Example 5, except that the primer sequences used in this experimental example are shown in Table 10: Table 10: Sequences of detection primers The inhibition rate of each conjugate on FXI mRNA is shown in Table 11 below: Table 11: Inhibition rate of each conjugate on target gene FXI mRNA From the results of Table 11, it can be seen that the conjugates provided by the present disclosure can all show excellent FXI mRNA inhibition effect at a siRNA administration dose of 3 mg / kg, with an inhibition rate of at least 77.5%, and in particular, conjugate 4 can achieve an FXI mRNA inhibition rate of 94.9%. Experimental Example 7 Inhibition of FXI mRNA expression in mice by conjugate In this experimental example, the inhibition efficiency of conjugate 6 on the expression amount of FXI mRNA in hFXI transgenic mice (provided by Jiangsu Jizhu Yaoke Biotechnology Co., Ltd.) was investigated. First, the hFXI transgenic mice (SPF level, all female, 6-8 weeks old) were randomly divided into groups, 6 mice in each group, and numbered respectively, and a phosphate buffer (PBS) control group was added. All animals were calculated according to the weight of the drug, single dose (subcutaneous administration), respectively, 3 mg / kg dose of conjugate 6 as test group, including test group one and test group two. Conjugate 6 was provided in the form of 0.9% sodium chloride aqueous solution of 0.6 mg / mL of conjugate, and the administration volume was 5 mL / kg. On the 15th day (D15) after administration, 6 mice in each of test group one and control group were sacrificed, and on the 29th day (D29) after administration, 6 mice in each of test group two and control group were sacrificed, and the livers of the mice in each group were collected, and the inhibition activity of FXI mRNA was determined and calculated according to the operation process of Experimental Example 5, except that the primer sequences used in this experimental example are shown in Table 10. In the experimental example, the conjugate 6 provided by the present disclosure continuously showed a high FXI mRNA inhibition rate at a drug administration dose of 3 mg / kg within a 29-day drug administration cycle, and the FXI mRNA inhibition rate reached as high as 80.4% on the 15th day after drug administration, and the FXI mRNA inhibition rate could still reach 54.5% on the 29th day after drug administration, showing a good FXI mRNA inhibition effect and long-acting property. Experimental Example 8 Inhibition of FXI mRNA expression in vivo by conjugate in mice In the experimental example, the inhibition efficiency of the conjugate 7 on the expression amount of FXI mRNA in hFXI transgenic mice (provided by Jiangsu Jicui Yekang Biotechnology Co., Ltd.) was investigated. Firstly, the hFXI transgenic mice (SPF level, all female, 6-8 weeks old) were randomly divided into groups, 6 mice in each group, and were numbered respectively, and a phosphate buffer (PBS) control group was added. All animals were calculated for drug amount according to body weight, and were administered once (subcutaneous administration), and the conjugate 7 was administered at a dose of 3 mg / kg as a test group, including test group one, test group two and test group three. In each test group, the conjugate 7 was provided in the form of 0.9% sodium chloride aqueous solution of the conjugate at 0.6 mg / mL, and the administration volume of each mouse was 5 mL / kg of mouse body weight. On the 15th day (D15) after administration, 6 mice in the test group one and the control group were sacrificed respectively, on the 29th day (D29) after administration, 6 mice in the test group two and the control group were sacrificed respectively, and on the 43rd day (D43) after administration, 6 mice in the test group three and the control group were sacrificed respectively, and the livers of the mice in each group were collected, and the FXI mRNA inhibition activity was determined and calculated according to the operation process of experimental example 5, except that the primer sequences used in the experimental example were as shown in Table 10. In the experimental example, the conjugate 7 provided by the present disclosure could all show a high FXI mRNA inhibition rate at a drug administration dose of 3 mg / kg within a 43-day drug administration cycle, and the FXI mRNA inhibition rate reached as high as 88.3% on the 15th day after drug administration, the FXI mRNA inhibition rate was still as high as 80.4% on the 29th day after drug administration, and the FXI mRNA inhibition rate could still reach 51.4% on the 43rd day after drug administration, showing a good FXI mRNA inhibition effect and long-acting property. Experimental Example 9 Determination of prolongation multiples of activated partial thromboplastin time at different time points of drug administration in mice In the experimental example, the prolongation multiples of the activated partial thromboplastin time ratio (APTT ratio) at different time points of drug administration in vivo by the conjugate 6 and the conjugate 7 in hFXI transgenic mice (provided by Jiangsu Jicui Yekang Biotechnology Co., Ltd.) were investigated. Firstly, the hFXI transgenic mice were randomly divided into groups (SPF level, all female, 6-8 weeks old), 6 mice in each group, and numbered respectively, and a phosphate buffer (PBS) control group was added. All animals were calculated according to the weight of the drug, and a single dose (subcutaneous administration) was given to the conjugate 6 and the conjugate 7 as the test group at a dose of 3 mg / kg, and the test group included test group one, test group two, test group three, test group four, test group five and test group six, wherein test group one, test group two and test group three were given conjugate 6, and test group four, test group five and test group six were given conjugate 7. The conjugate 6 and the conjugate 7 were both provided in the form of 0.9% sodium chloride aqueous solution of 0.6 mg / mL of the conjugate, and the administration volume was 5 mL / kg of mouse body weight per mouse. On the 15th day after administration (D15), 6 mice in test group one, test group four and the control group were sacrificed respectively, on the 29th day after administration (D29), 6 mice in test group two, test group five and the control group were sacrificed respectively, and on the 43rd day after administration (D43), 6 mice in test group three, test group six and the control group were sacrificed respectively, and the plasma of each group of mice was collected. The anticoagulant was added to the plasma at a volume ratio of 1:9 (v / v), and 3.2 wt% (0.109 mol / L) sodium citrate dihydrate aqueous solution was used to prevent blood clotting, and the plasma was separated by centrifugation. The APTT value of the plasma of each mouse was determined by turbidimetry using the APTT kit (Rayto Company, batch number 20190402M) on a semi-automatic coagulation instrument (Rayto Company, model RT-2202), and the specific determination method was carried out according to the method described in the instruction manual of the APTT kit. The APTT value was compared with the control group, and the APTT multiple of each mouse was (test group APTT detection average) / (control group APTT detection average). The determination results are shown in Table 12. In Table 12, the average APTT multiple is the average value of the APTT multiple of 6 mice in this group after corresponding days of administration of the corresponding siRNA conjugate. Table 12 Average APTT multiple of siRNA conjugate at different time points after single administration As can be seen from the results in Table 12, after administration of the siRNA conjugate of the present disclosure, the mice showed significant prolongation of APTT multiple within 43 days of administration, and the highest average APTT multiple reached 1.61, and the average APTT multiple was still as high as 1.08 on the 43rd day after administration. It can be seen that the siRNA conjugate of the present disclosure can effectively prolong the coagulation time of mice, indicating that it has excellent application prospect for treating and / or preventing thrombotic diseases and ischemic stroke. Further, the FXI protein content in the plasma obtained from the mice in each of the above test groups and the control group was tested using a Human Coagulation Factor XI ELISA Kit (Sigma, Lot No. 0926F2350, Cat No. RAB1385-1KT). The sample diluent in the ELISA Kit was diluted 5-fold with deionized water (Item E2 in the Kit) to obtain a diluted sample diluent. For the plasma of the mice in the test group administered with Conjugate 6 and Conjugate 7, 108 μL of the diluted sample diluent was added to 12 μL of the plasma to obtain a sample solution to be tested, which was reserved for later use. For the plasma of the mice in the control group administered with PBS, 108 μL of the diluted sample diluent was added to 12 μL of the plasma to obtain a 10-fold diluted plasma. To 5 μL of the 10-fold diluted plasma, 45 μL of the diluted sample diluent was added to obtain a 100-fold diluted plasma; and to 12 μL of the 100-fold diluted plasma, 108 μL of the diluted sample diluent was added to obtain a sample solution diluted by 1000-fold, which was reserved for later use as a sample solution to be tested. The FXI detection antibody (Item F in the Kit) was dissolved in 100 μL of the diluted sample diluent to obtain an antibody sample, and then 75 μL of the antibody sample was added to 5925 μL of the diluted sample diluent to obtain a detection antibody solution. The streptavidin concentrate (Item G in the Kit) was diluted 250-fold with the diluted sample diluent to obtain a streptavidin diluent. The washing buffer (Item B in the Kit) was diluted 20-fold with deionized water to obtain a diluted washing buffer. Eight standard concentration gradient solutions were provided, one of which was the diluted sample diluent (which was regarded as a standard solution with a concentration of 0 pg / mL), and the other seven of which were obtained by sequentially diluting the standards (Item C in the Kit) in the Kit with the diluted sample diluent obtained above to obtain standard solutions with concentrations of 2500 pg / mL, 1000 pg / mL, 400 pg / mL, 160 pg / mL, 64 pg / mL, 25.6 pg / mL and 10.24 pg / mL, i.e., seven concentration values. ELISA detection The Human Coagulation Factor XI ELISA Kit (SIGMA, item number RAB1385-1KT) was used to set up standard wells and sample wells according to the instructions, and different concentrations of standard concentration gradient solutions or each sample liquid to be tested were added to each well, 100 μL of solution was added to each well, and incubated at room temperature for 2.5 hours. Discard the liquid, add 300 μL of dilution washing solution to each well and wash for 1 min, then discard the washing solution. Add 100 μL of detection antibody solution to each well, and incubate at room temperature for 1 hour. Discard the liquid, add 300 μL of dilution washing solution to each well and wash for 1 min, then discard the washing solution. Repeat the above steps for 3 times (a total of 4 times). Add 100 μL of streptomycin dilution solution to each well, and incubate at room temperature for 45 minutes. Discard the liquid, add 300 μL of dilution washing solution to each well and wash for 1 min, then discard the washing solution. Repeat the above steps for 3 times (a total of 4 times). Add 100 μL of TMB (labeled as Item H in the kit) to each well, and incubate for 30 minutes. Add 50 μL of stop solution (provided in the kit) to each well to terminate the reaction, and immediately read the wavelength at 450 nm using a full-automatic enzyme label instrument (BioTek, Biotck SYNERGY MX). Each test group of a specific concentration was treated with saline as a control. According to the activity results measured for the standard concentration gradient solutions, the GraphPad Prism 6 software log(inhibitor) vs.response—Variable slope function was used to fit the dose-effect standard curve, and the protein concentration value in the plasma to be tested was calculated according to the dose-effect curve. The obtained dose-effect curve was fitted according to the following calculation formula: In the formula: Y is the corresponding optical density value read at 450 nm, X is the logarithmic value of the concentration (μg / mL) in the standard curve, Bot is the Y value at the bottom of the steady state, Top is the Y value at the top of the steady state, X' is the X value obtained by fitting when Y is halfway between the bottom and the top, and HillSlope is the slope of the curve at X', The concentration of each sample was obtained by substituting the optical density value of each plasma sample into the standard curve, and the logarithmic value X of the concentration of each sample was obtained. The plasma FXI protein concentration value of the sample administered with conjugate 6 and conjugate 7 was calculated as 10^X (μg / mL). According to the plasma FXI protein concentration value, the protein concentration relative to the control group was calculated, and the FXI protein inhibition rate was calculated as (control group protein concentration-test group protein concentration) / control group protein concentration x 100%. The obtained inhibition rate data is shown in Table 13. In Table 13, the FXI protein inhibition rate is the arithmetic mean of the FXI protein inhibition rate of a group of mice administered with conjugate 6 or conjugate 7. Table 13 Relative inhibition rate of conjugate to plasma protein As can be seen from the results in Table 13, the conjugates of the present disclosure all showed good effects in inhibiting the expression of human FXI protein in the plasma of hFXI transgenic mice during the 43-day administration period, and in particular, conjugate 7 had a relative inhibition rate of FXI protein as high as 94.2% on the 15th day of administration, and still reached 56.3% on the 43rd day of administration. Experimental Example 10 Inhibition activity of conjugate in cynomolgus monkeys Eighteen non-naive cynomolgus monkeys (purchased from Hainan Jintang Biotechnology Co., Ltd.) weighing 2.0 kg-5.0 kg and aged 2-5 years were selected, of which 9 were male cynomolgus monkeys and 9 were female cynomolgus monkeys. The drug amount was calculated according to the body weight of the cynomolgus monkeys, and a single administration method was used to subcutaneously inject conjugate 6 solution. Specifically, test group one included 3 male cynomolgus monkeys and 3 female cynomolgus monkeys, which were all subcutaneously injected with 0.5 mL / kg of conjugate 6 solution with a concentration of 2 mg / mL (calculated as siRNA), and the administration dose was 1 mg / kg; test group two included 3 male cynomolgus monkeys and 3 female cynomolgus monkeys, which were all subcutaneously injected with 0.5 mL / kg of conjugate 6 solution with a concentration of 6 mg / mL (calculated as siRNA), and the administration dose was 3 mg / kg; test group three included 3 male cynomolgus monkeys and 3 female cynomolgus monkeys, which were all subcutaneously injected with 0.5 mL / kg of conjugate 6 solution with a concentration of 18 mg / mL (calculated as siRNA), and the administration dose was 9 mg / kg. The first day of administration was recorded as D1, and plasma was collected before administration, on D7, D14, D28, D42, D56, D70, and D84 for detection of the FXI protein inhibition rate, wherein 2 mL of plasma was collected from the peripheral blood vessels of the restrained cynomolgus monkeys in a conscious state each time. The FXI protein inhibition rate in the plasma of the cynomolgus monkeys in different test groups was determined according to the operation process of Example 9, wherein the FXI protein inhibition rate was calculated relative to the protein concentration in the plasma before administration as (protein concentration before administration-protein concentration in the test group) / protein concentration before administration x 100%. The results are shown in Table 14. Table 14 Relative inhibition rate of different doses of conjugate 6 to plasma protein in cynomolgus monkeys As can be seen from the results of Table 14, the conjugates provided by the present disclosure show good inhibitory effects on the expression of human FXI protein in cynomolgus monkey plasma at different dosages within the 84-day administration cycle. When the administration dosage is 9 mg / kg, the relative inhibition rate of FXI protein in cynomolgus monkey plasma can reach as high as 88.53% on D28, and still reach 65.30% on D84. Even at a lower administration dosage of 1 mg / kg, the relative inhibition rate of FXI protein can still reach 51.88% on D42. Therefore, the conjugates provided by the present disclosure can effectively inhibit the expression of FXI protein in plasma, and have long-acting properties, indicating that they have excellent application prospects for treating and / or preventing thrombotic diseases and ischemic stroke. Experimental Example 11 Inhibitory activity of conjugates in monkey liver primary cells This experimental example investigates the inhibitory activity of conjugate 4 and conjugate 5 on FXI mRNA in monkey liver primary cells. The monkey liver primary cells (purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd., product code: CCH-100CYS-PQ, batch number: CCH-100CY-V10188) were cultured in a 37°C incubator containing 5% CO2 / 95% air in a liver cell maintenance medium (purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd., product code: HCTPM-R-002) at a density of 1x105cells / well. 5 The cells were seeded in a 24-well plate at 250 μL per well. For each conjugate to be tested, a working solution of the conjugate was prepared in PBS at a concentration of 20 μM (calculated based on the amount of siRNA in the conjugate). The conjugates to be tested used were conjugate 4 and conjugate 5. The working solution of the conjugate was then gradient-diluted with the liver cell maintenance medium to prepare dilutions at 20 μM, 2 μM, 0.2 μM, 0.02 μM, 0.002 μM, 0.0002 μM, 0.00002 μM, 0.000002 μM, 0.0000002 μM, and 0.0000002 μM, respectively. To the cell plate, 250 μL of the gradient-diluted solution at different concentrations was added to each well, with two replicates for each concentration, to obtain mixtures at final concentrations of 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0.0001 μM, 0.00001 μM, 0.000001 μM, 0.0000001 μM, and 0.0000001 μM, respectively. The components added with conjugate 4 and conjugate 5 were recorded as the test group. To another two culture wells, 250 μL of the liver cell maintenance medium was added, which was recorded as the blank control group. The test group and the blank control group were incubated at 37°C in a 5% CO2 / 95% air incubator for 72 hours. The total RNA in each well of cells was extracted using TRI Reagent (purchased from SIGMA, item number: T9424-200ML) according to the method recorded in the instruction book. For each well of cells, 1 μg of total RNA was taken respectively, and cDNA was obtained by reverse transcription using a reverse transcription kit (purchased from Promega Company, item number A3500) according to the operation method of its instruction book. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the reverse transcription reaction system was incubated at 70 °C for 10 min, then at 42 °C for 30 min, and finally at 95 °C for 5 min. After the reaction was completed, 80 μL of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. For each reverse transcription reaction system, 5 μL of the above-mentioned cDNA-containing solution was taken as a template to configure a qPCR reaction system 20 μL using the reagents provided by SYBR select Master Mix (purchased from Applied Biosystems, item number: 4472908), wherein the PCR primer sequences for amplifying the target gene FXI and the internal reference gene GAPDH were as shown in Table 6A above, and the final concentration of each primer was 10 μM. Each qPCR reaction system was placed on a real-time fluorescent quantitative PCR instrument (purchased from Thermo, model StepOnePlus), and amplification was performed using a three-step method. The amplification program was as follows: pre-denaturation at 95 °C for 10 min, then denaturation at 95 °C for 30 s, annealing at 60 °C for 30 s, extension at 72 °C for 30 s, and repeating the above denaturation, annealing and extension processes for 40 times, to obtain product W1 containing the products of the amplified target gene FXI and the internal reference gene GAPDH. Product W1 was then subjected to 95 °C for 15 s, 60 °C for 1 min, gradient heating to 95 °C with fluorescence signal collection every 0.3 °C, 95 °C for 15 s, and the melting curve of the target gene and the internal reference gene GAPDH in product W1 was collected by the real-time fluorescent quantitative PCR instrument, to obtain the Ct values of the target gene FXI and the internal reference gene GAPDH. The expression levels of the target gene FXI mRNA in each test group were relatively quantitatively calculated according to the calculation method of Example 1, to obtain the inhibition rate of the test group at different concentrations on FXI mRNA. According to the activity results measured by the test group at different concentrations, the dose-effect curve was fitted using the GraphPad Prism 8.0 software log(inhibitor) vs. response-Variable slope function, and the IC 50 value of the test conjugate in monkey liver primary cells was calculated according to the dose-effect curve, and the calculation method was as follows, In the formula: Y is the expression level of residual mRNA, X is the logarithm of the transfection conjugate concentration. Bot is the Y value at the bottom of the steady-state period. Top is the Y value at the peak of the steady-state period. The X value is half of the LogIC50 value, while HillSlope is the slope of the curve. The IC50 values ​​of conjugates 4 and 5 in primary monkey liver cells were calculated based on the dose-response curves. 50 The IC50 of conjugate 4 in primary monkey liver cells was obtained. 50 The value was 0.011 μM, and the IC50 of conjugate 5 in primary monkey liver cells was [value missing]. 50 The value was 0.003 μM, indicating that the conjugate provided in this disclosure has a strong inhibitory effect on the expression of FXI mRNA. Inhibitory activity of conjugate in human primary liver cells in Experiment Example 12 This experiment investigated the inhibitory activity of conjugates 4 and 5 on FXI mRNA in primary human liver cells. Human primary liver cells (purchased from Huizhiheyuan Biotechnology (Suzhou) Co., Ltd., catalog number: 085A12.22, batch number: 24A076) were cultured in hepatocyte maintenance medium (purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd., catalog number: HCTPM-R-002) at 37°C in an incubator containing 5% CO2 / 95% air. The density of the human primary liver cells was adjusted to 1x10⁻⁶. 5 Cell suspensions were seeded in 24-well plates. Following the solution preparation, transfection, detection, and data analysis procedures described in Example 11, the IC50 of conjugate 4 in primary human liver cells was calculated. 50 The value was 0.0014 μM, and the IC50 of conjugate 5 in human primary liver cells was [value missing]. 50 The values ​​were all 0.0003 μM, and all had lower IC50 values ​​than in primary monkey liver cells. 50 The value indicates that the conjugate provided in this disclosure has a strong inhibitory effect on the expression of FXI mRNA. Some embodiments of this disclosure have been described in detail above. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure. It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately. Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.

Claims

1. A single-stranded oligonucleotide of 16-30 nucleotides in length having sufficient complementarity to FXI 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 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, in the direction from the 5' end to the 3' end, if the 14th nucleotide of the single-stranded oligonucleotide is a nucleotide X, and all the nucleotides after the 15th nucleotide of the single-stranded oligonucleotide are modified nucleotides, then the 13th nucleotide of the single-stranded oligonucleotide is selected from one of an alkoxy-modified nucleotide, an alkyl-modified nucleotide, a substituted alkyl-modified nucleotide, an amine-modified nucleotide, a thermally unstable nucleotide and a BNA; each nucleotide X is a deoxynucleotide or an unmodified nucleotide.

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

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

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

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

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

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

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

9. The single stranded oligonucleotide of claim 8, wherein, 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 in the single-stranded oligonucleotide in the direction from the 5' end to the 3' end.

10. The single stranded oligonucleotide of claim 9, wherein, Each modified nucleotide in the single-stranded oligonucleotide, except for the fluorine-modified nucleotides and the nucleotide X, 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, There is no thermally unstable nucleotide in the single-stranded oligonucleotide, or the number of thermally unstable nucleotides is 1 or 2; or each modified nucleotide in the single-stranded oligonucleotide, except for the fluorine-modified nucleotides, the nucleotide X and the thermally unstable nucleotide, is selected from an alkoxy-modified nucleotide or a substituted alkoxy-modified nucleotide.

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

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

14. The single stranded oligonucleotide of any one of claims 10-13, wherein, each alkoxy-modified nucleotide 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. 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 phosphates having a modifying group.

16. The single stranded oligonucleotide of claim 15, wherein, 1-4 of the linking groups between adjacent nucleotides in the first 1-5 nucleotides from the 5' end and / or 1-4 of the linking groups between adjacent nucleotides in the first 1-5 nucleotides from the 3' end of the single-stranded oligonucleotide are independently phosphates having a modifying group; and / or If there are unmodified nucleotides in the single-stranded oligonucleotide, each of the unmodified nucleotides is independently flanked by 1 or both of the 2 linking groups between adjacent nucleotides. 2-6, or 4, of the linking groups between adjacent nucleotides in the single-stranded oligonucleotide are independently phosphates having a modifying group.

17. The single stranded oligonucleotide of claim 15 or 16, wherein, 1-4 of the linking groups between adjacent nucleotides in the first 1-3 nucleotides from the 5' end and / or 1-4 of the linking groups between adjacent nucleotides in the first 1-3 nucleotides from the 3' end of the single-stranded oligonucleotide are independently phosphates having a modifying group; and / or If there are unmodified nucleotides in the single-stranded oligonucleotide, each of the unmodified nucleotides is independently flanked by 1 or both of the 2 linking groups between adjacent nucleotides.

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.

20. The single stranded oligonucleotide of any one of claims 1-19, wherein, The single-stranded oligonucleotide has a length of 21 nucleotides, and in the direction from the 5' end to the 3' end, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th, and 16th nucleotides are fluorinated nucleotides, or the 2nd, 7th, 12th, 16th, and 19th nucleotides are fluorinated nucleotides, or the 2nd, 6th, 12th, 16th, and 19th nucleotides are fluorinated 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 groups between any two adjacent nucleotides in the first 1st to 3rd nucleotides from the 5' end and the linking groups between any two adjacent nucleotides in the first 1st to 3rd nucleotides from the 3' end are phosphorothioate groups; the 5' terminal nucleotide is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinylphosphonate modified nucleotide represented by formula (31).

21. The single stranded oligonucleotide of any one of claims 1-20, wherein, The single-stranded oligonucleotide is substantially, substantially, or completely reverse complementary to the FXI mRNA 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 In the direction from the 5' end to the 3' end, the nucleotide sequence of the single-stranded oligonucleotide is completely reverse complementary to the FXI mRNA except for the 1st nucleotide; or, the entire nucleotide sequence of the single-stranded oligonucleotide is completely reverse complementary to the FXI mRNA.

22. The single stranded oligonucleotide of any one of claims 1-21, wherein, The single-stranded oligonucleotide contains a nucleotide sequence II, which is one selected from the following i)-iii): i) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 2, and differs in no more than 3 bases: 5'-Z2AGAAUCCAGUCCACGUAC-3' (SEQ ID NO: 2), wherein Z2 is C or U, the nucleotide sequence II contains a nucleotide Z4 at a position corresponding to Z2, and Z4 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; ii) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 29, and differs in no more than 3 bases: 5'-Z6GAAAGAAUACCCAGAAAU-3' (SEQ ID NO: 29), wherein Z6 is U, the nucleotide sequence II contains a nucleotide Z8 at a position corresponding to Z6, and Z8 is the first nucleotide at the 5' end of the single-stranded oligonucleotide sequence; iii) the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 31, and differs in no more than 3 bases: 5'-Z 10 GAGUUUUCUCCAGAAUCC-3' (SEQ ID NO: 31), wherein Z 10 is U, the nucleotide sequence II comprises a nucleotide Z 10 corresponding to Z 12 , said Z 12 being the first nucleotide of the 5' end of the single-stranded oligonucleotide sequence.

23. The single stranded oligonucleotide of claim 21, wherein, the nucleotide sequence II differs in no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 2; or the nucleotide sequence II differs in no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 29; or the nucleotide sequence II differs in no more than 1 base from the nucleotide sequence set forth in SEQ ID NO: 31; or the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 2; or the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO: 29; or the nucleotide sequence II is identical to the nucleotide sequence set forth in SEQ ID NO:

31.

24. The single stranded oligonucleotide of claim 22 or 23, wherein, The single-stranded oligonucleotide further contains 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 FXI mRNA, and 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; or the nucleotide sequence IV has a length of 2 nucleotides.

25. The single stranded oligonucleotide of claim 25 or 24, wherein, the single-stranded oligonucleotide further comprises a nucleotide sequence V, each nucleotide of the nucleotide sequence V is independently a non-fluoro-modified nucleotide, the nucleotide sequence V has a length of 1 to 3 nucleotides, is linked to the 3' end of the nucleotide sequence IV or the nucleotide sequence II, and forms a 3' overhang of the antisense strand of the double-stranded oligonucleotide after forming the double-stranded oligonucleotide; or the nucleotide sequence V has a length of 2 nucleotides, and in the direction from the 5' end to the 3' end, the nucleotide sequence V is two consecutive thymine deoxynucleotides, two consecutive uracil nucleotides, or fully reverse-complementary to the FXI mRNA; or the single-stranded oligonucleotide is the antisense strand of any one of siRNAa1, siRNAb1, siRNAb2, or siRNAb3 listed in Table 1. or the single-stranded oligonucleotide is the antisense strand of any one of Conjugate 1-Conjugate 7 listed in Table 2.

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

27. The double-stranded oligonucleotide of claim 26, wherein, The sense strand has a length of 19-23 nucleotides. or the sense strand and the antisense strand have the same length, and each has a length of 19, 20, or 21 nucleotides; or the sense strand has a length of 19 nucleotides and the antisense strand has a length of 20-24 nucleotides; or the sense strand has a length of 20 nucleotides and the antisense strand has a length of 21-24 nucleotides; or the sense strand has a length of 21 nucleotides and the antisense strand has a length of 22-24 nucleotides. or the sense strand has a length of 19 nucleotides and the antisense strand has a length of 21 nucleotides; or the sense strand has a length of 21 nucleotides and the antisense strand has a length of 23 nucleotides.

28. The double-stranded oligonucleotide of any one of claims 26-27, wherein, In the direction from the 3' end to the 5' end, 2-3 of the 11th-13th nucleotides of the sense strand are fluoro-modified nucleotides, the 1st nucleotide and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are non-fluoro-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 direction from the 3' end to the 5' end, the 11th and 13th nucleotides, or the 11th-13th nucleotides of the sense strand are fluoro-modified nucleotides, the 1st nucleotide and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted abasic deoxynucleotide, and the nucleotides at the remaining positions of the sense strand are alkoxy-modified nucleotides.

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

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

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

33. The double-stranded oligonucleotide of any one of claims 26-32, wherein, the sense strand comprises 19-21 nucleotides, and the antisense strand comprises 21-23 nucleotides; in the sense strand, the 11th and 13th nucleotides, or the 11th-13th nucleotides, are fluorine-modified nucleotides, the 1st nucleotide and / or the last nucleotide is an alkoxy-modified nucleotide or an inverted deoxyabasic nucleotide, and the nucleotides at the remaining positions are all alkoxy-modified nucleotides; each of 1-4 of the linking groups between adjacent nucleotides of the 1st to 5th nucleotides from the 5' end of the sense strand, and / or 1-4 of the linking groups between adjacent nucleotides of the 1st to 5th nucleotides from the 3' end of the sense strand, is independently a phosphate group with a modification group; or, each phosphate group with a modification group is a phosphorothioate group having a structure as shown in formula (28).

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

35. The double-stranded oligonucleotide of claim 34, wherein, The sense strand comprises 19 nucleotides, and the antisense strand comprises 21 nucleotides; In the sense strand, in the 3' end to 5' end direction, the 11th and 13th nucleotides are fluorine-modified nucleotides, the 1st nucleotide is an inverted dealkylated deoxynucleotide, and the nucleotides at the remaining positions are methoxy-modified nucleotides; the linking groups between adjacent nucleotides in the 1st-3rd nucleotides at the 5' end of the sense strand are phosphorothioate groups; In the antisense strand, the 14th nucleotide is a deoxynucleotide, the 2nd, 5th, 7th, 12th and 16th nucleotides are fluorine-modified nucleotides, or the 2nd, 7th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, or the 2nd, 6th, 12th, 16th and 19th nucleotides are fluorine-modified nucleotides, and each of the remaining nucleotides in the antisense strand is a methoxy-modified nucleotide; the linking group between two adjacent nucleotides at the 1st-3rd nucleotides at the 5' end of the antisense strand and the linking group between two adjacent nucleotides at the 1st-3rd nucleotides at the 3' end of the antisense strand are phosphorothioate groups; and the 5' end nucleotide of the antisense strand is a 5'-hydroxyl nucleotide represented by formula (29) or a 5'-vinyl phosphate-modified nucleotide represented by formula (31).

36. The double-stranded oligonucleotide of any one of claims 26-35, wherein, The double-stranded region formed by the sense strand and the antisense strand 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 reverse complementary 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 FXI mRNA is not more than 3, or not more than 2, or not more than 1; or, there is no base difference between the sense strand and the FXI mRNA.

37. The double-stranded oligonucleotide of claim 36, wherein, The double-stranded oligonucleotide is an siRNA; Or, the sense strand contains a nucleotide sequence I, and the antisense strand contains a nucleotide sequence II, the nucleotide sequence I is equal in length to the nucleotide sequence represented by SEQ ID NO: 1 and has 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 and has no more than 3 base differences: 5'-GUACGUGGACUGGAUUCUZ1-3' (SEQ ID NO: 1) 5'-Z2AGAAUCCAGUCCACGUAC-3' (SEQ ID NO: 2); wherein Z1 is G, A or ia, ia represents an inverted abasic deoxynucleotide, Z2 is C or U, the nucleotide sequence I comprises a nucleotide Z3 at a position corresponding to Z1, the nucleotide sequence II comprises a nucleotide Z4 at a position corresponding to Z2, and Z4 is the first nucleotide at the 5' end of the antisense strand; Or, the nucleotide sequence I is equal in length to the nucleotide sequence represented by SEQ ID NO: 28 and has no more than 3 base differences, and the nucleotide sequence II is equal in length to the nucleotide sequence represented by SEQ ID NO: 29 and has no more than 3 base differences: 5'-AUUUCUGGGUAUUCUUUCZ5-3' (SEQ ID NO: 28) 5'-Z6GAAAGAAUACCCAGAAAU-3' (SEQ ID NO: 29); wherein Z5 is A or ia, ia represents a reverse deoxy nucleotide, Z6 is U, the nucleotide sequence I comprises a nucleotide Z7 at a position corresponding to Z5, the nucleotide sequence II comprises a nucleotide Z8 at a position corresponding to Z6, and Z8 is the first nucleotide at the 5' end of the antisense strand of the antisense strand; or, the nucleotide sequence I is equal in length to the nucleotide sequence set forth in SEQ ID NO: 30 and differs from the nucleotide sequence set forth in SEQ ID NO: 30 by no more than 3 bases, and the nucleotide sequence II is equal in length to the nucleotide sequence set forth in SEQ ID NO: 31 and differs from the nucleotide sequence set forth in SEQ ID NO: 31 by no more than 3 bases: 5'-GGAUUCUGGAGAAAACUCZ9-3' (SEQ ID NO: 30) 5'-Z 10 GAGUUUUCUCCAGAAUCC-3' (SEQ ID NO: 31); wherein Z9 is A or ia, ia representing an inverted abasic deoxynucleotide, Z 10 is U, said nucleotide sequence I comprising a nucleotide Z 11 at a position corresponding to Z9, said nucleotide sequence II comprising a nucleotide Z 10 at a position corresponding to Z 12 , said Z 12 being the first nucleotide of the 5' end of said antisense strand.

38. The double-stranded oligonucleotide of claim 37, wherein, the nucleotide sequence I differs from the nucleotide sequence set forth in SEQ ID NO: 1, 28 or 30 by no more than 1 base, and the nucleotide sequence II differs from the nucleotide sequence set forth in SEQ ID NO: 2, 29 or 31 by no more than 1 base.

39. The double-stranded oligonucleotide of claim 38, wherein, the double-stranded oligonucleotide is siRNAa1, siRNAb1, siRNAb2 or siRNAb3.

40. An oligonucleotide conjugate comprising an oligonucleotide group and a delivery group conjugated to the oligonucleotide group, the oligonucleotide group independently being a group formed by removing one or more atoms or atom groups from the single-stranded oligonucleotide of any one of claims 1-25 or the double-stranded oligonucleotide of any one of claims 26-39.

41. The oligonucleotide conjugate of claim 40, wherein, the delivery group comprises a linker group and a pharmaceutically acceptable targeting group, and the oligonucleotide group, the linker group and the targeting group are covalently or non-covalently linked in sequence, each of the targeting groups being selected from a ligand capable of binding to a receptor on the surface of a hepatocyte; or, the oligonucleotide conjugate comprises a double-stranded oligonucleotide group that is an siRNA group formed by siRNAa1, siRNAb1, siRNAb2 or siRNAb3 listed in Table 1; Alternatively, the oligonucleotide conjugate has the structure shown in Formula (403) in formula (403), Nu is an oligonucleotide group; or, the oligonucleotide group is a double-stranded oligonucleotide group, and the P atom is covalently linked to the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group; or, the 3' terminal nucleotide of the sense strand of the double-stranded oligonucleotide group is a reverse deoxy-dealkylated nucleotide, and the P atom is covalently linked to the double-stranded oligonucleotide group by replacing the hydrogen atom in the hydroxyl group via a methylene linkage to the ribose ring in the 3' terminal reverse deoxy-dealkylated nucleotide of the sense strand of the double-stranded oligonucleotide group; or, the oligonucleotide conjugate is one of conjugates 1-7 listed in Table 2.

42. A pharmaceutically acceptable salt of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-39 or the oligonucleotide conjugate of claim 40 or 41; or, the pharmaceutically acceptable salt is a water-soluble salt of part or all of the single-stranded oligonucleotide, the double-stranded oligonucleotide or the oligonucleotide conjugate. Alternatively, the water-soluble salt is one or more of an amine salt, an alkali metal salt, or an alkaline earth metal salt; Alternatively, the amine salt is selected from one or more of an ammonium salt, a methylamine salt, a tertiary amine salt, or 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; Alternatively, the tertiary amine salt is a triethylamine salt, a triisopropylamine salt, or a N,N-diisopropylethylamine salt. Alternatively, the pharmaceutically acceptable salt is a sodium salt or a partial sodium salt of the single-stranded oligonucleotide, the double-stranded oligonucleotide, or the oligonucleotide conjugate.

43. A pharmaceutical composition comprising one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-39, the oligonucleotide conjugate of claim 40 or 41, and the pharmaceutically acceptable salt of claim 42, and a pharmaceutically acceptable excipient. Alternatively, the pharmaceutically acceptable excipient is one or more of a solvent, a protective agent, an osmotic pressure regulator, and other pharmaceutically acceptable carriers. Alternatively, the solvent is one of deionized water, water for injection, a pH buffer, physiological saline, ethanol, or an aqueous ethanol solution.

44. Use of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43 in the manufacture of a medicament for treating and / or preventing a disease or condition associated with FXI mRNA levels.

45. The use of claim 44, wherein, The disease or condition associated with FXI mRNA levels is a thrombotic disease and / or an ischemic stroke.

46. A method of treating and / or preventing a disease or condition associated with FXI mRNA levels, the method comprising administering to a subject in need thereof an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

47. The method of claim 46, wherein, The disease or condition associated with FXI mRNA levels is a thrombotic disease and / or an ischemic stroke.

48. A method of modulating the expression level of FXI mRNA in a cell, the method comprising contacting the cell with an effective amount of one or more of the single-stranded oligonucleotide of any one of claims 1-25, the double-stranded oligonucleotide of any one of claims 26-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

49. One or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-39, 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.

50. A cell expressing APOC3 mRNA, the cell comprising one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-39, the oligonucleotide conjugate of claim 40 or 41, the pharmaceutically acceptable salt of claim 42, and the pharmaceutical composition of claim 43.

51. A kit comprising one or more of the single stranded oligonucleotide of any one of claims 1-25, the double stranded oligonucleotide of any one of claims 26-39, 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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