Nucleic acid, composition and conjugate containing nucleic acid, and preparation method therefor and use thereof

Abstract

Provided in the present disclosure are an siRNA for inhibiting PTOR mRNA expression, and a pharmaceutical composition and conjugate containing the siRNA. The siRNA contains a sense strand and an antisense strand, and each nucleotide in the siRNA is independently a modified or unmodified nucleotide, wherein the sense strand contains nucleotide sequence I that is equal in length to a nucleotide sequence as shown in SEQ ID NO: 1 and differs therefrom by no more than three nucleotides; and the antisense strand contains nucleotide sequence II that is equal in length to a nucleotide sequence as shown in SEQ ID NO: 2 and differs therefrom by no more than three nucleotides. The siRNA, pharmaceutical composition and conjugate provided in the present disclosure can be used as mTORC1 inhibitors to effectively treat related diseases caused by mTORC1 activation, and as autophagy inducers to treat autophagy-associated diseases or symptoms.

Description

A nucleic acid, a composition and conjugate containing the nucleic acid, a method for its preparation, and its uses. Technical Field This disclosure relates to a nucleic acid capable of inhibiting RPTOR mRNA expression and a pharmaceutical composition containing the nucleic acid and an siRNA conjugate. This disclosure also relates to methods for preparing and using these nucleic acids, pharmaceutical compositions, and siRNA conjugates. Background Technology Neurodegenerative diseases are a class of diseases characterized by the progressive death of neurons and the accompanying progressive decline in cognitive function, including but not limited to Parkinson's disease (PD) and Alzheimer's disease (AD). AD and PD mainly occur in middle-aged and elderly people, and with the aging of the population, the incidence of AD and PD is increasing. Currently, drug treatment for neurodegenerative diseases mainly relies on Western medicine. However, drug treatment requires long-term medication, has significant side effects, and can easily affect the central nervous system, digestive system, respiratory system, and even lead to endocrine disorders and mood changes. The mammalian target of rapamycin (mTOR) signaling pathway is a signaling pathway that regulates protein synthesis, cell growth, and proliferation. Two distinct complexes, mTORC1 and mTORC2, exist within the cell. mTORC1 is a complex composed of RPTOR, a Ras homolog enriched in brain (RHEB), a DEP domain-containing mTOR-interacting protein (DEPTOR), a mammalian lethal factor with SEC13 protein 8 (mLST8), and a 40 kDa proline-rich AKT substrate (PRAS40). This complex is a key negative regulator of autophagy. Previous studies have shown that mTORC1 activation and mitophagy inhibition in Alzheimer's Disease (AD) patients and animal models are key factors contributing to senile plaques, neurofibrillary tangles, and cognitive decline in AD patients. Among these factors, the regulatory associated protein of mTOR, complex 1 (RPTOR), is a crucial component of mTORC1. Literature reports that inhibiting RPTOR can suppress mTORC1 activity, thereby promoting cellular and mitophagy, and ultimately reducing misfolded proteins in the brains of neurodegenerative disease patients. There is a significant need in the field to develop new drugs that regulate RPTOR mRNA expression levels, thereby modulating mTORC1 activity and subsequently treating diseases or symptoms associated with mTORC1 activation and autophagy dysfunction, particularly neurodegenerative diseases. Summary of the Invention The inventors of this disclosure unexpectedly discovered that siRNAs and their modified sequences provided in this disclosure can specifically inhibit the expression of RPTOR mRNA in cells. Pharmaceutical compositions and siRNA conjugates containing the siRNAs of this disclosure can effectively deliver the siRNAs of this disclosure to target tissues and / or cells, thereby showing high drug development potential in the treatment or prevention of diseases associated with mTORC1 activation and autophagy dysfunction, such as non-alcoholic steatohepatitis (NASH), and neurodegenerative diseases, particularly Alzheimer's disease. Therefore, the inventors made the following invention. In one aspect, this disclosure provides an siRNA capable of inhibiting RPTOR mRNA expression, the siRNA containing a sense strand and an antisense strand, each nucleotide in the siRNA being independently modified or unmodified, wherein the sense strand contains a nucleotide sequence I, the antisense strand contains a nucleotide sequence II, the nucleotide sequence I and the nucleotide sequence II forming a double-stranded region at least partially inversely complementary, wherein the nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO:1 and differs by no more than 3 nucleotides, and the nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO:2 and differs by no more than 3 nucleotides. 5'-UCCUGUCCUUCGAGACCAZ a1 -3'(SEQ ID NO:1); 5'-Z a2 UGGUCUCGAAGGACAGGA-3'(SEQ ID NO:2), Among them, Z a1 For U, Z a2 For A, the nucleotide sequence I contains a position corresponding to Z. a1 nucleotide Z a3 The nucleotide sequence II contains a position corresponding to Z. a2 nucleotide Z a4 The Z a4 It is the first nucleotide at the 5' end of the antisense strand. In another aspect, this disclosure provides a pharmaceutical composition comprising the siRNA of this disclosure and a pharmaceutically acceptable carrier. In another aspect, this disclosure provides an siRNA conjugate containing the siRNA provided in this disclosure and a conjugating group conjugated to the siRNA. In another aspect, this disclosure provides the use of the siRNA and / or pharmaceutical compositions and / or siRNA conjugates of this disclosure in the preparation of treatments and / or preventions of diseases related to RPTOR functional regulation. In another aspect, this disclosure provides a method for treating and / or preventing diseases or symptoms associated with RPTOR function regulation, such as neurodegenerative diseases or symptoms, particularly Alzheimer's disease, said method comprising administering to a subject in need an effective amount of the disclosed siRNA and / or pharmaceutical composition and / or siRNA conjugate. In another aspect, this disclosure provides a method for inhibiting RPTOR mRNA expression in cells, the method comprising contacting the cells with an effective amount of the disclosed siRNA and / or pharmaceutical composition and / or siRNA conjugate. In addition, this disclosure also provides a kit containing the siRNA and / or pharmaceutical composition and / or siRNA conjugate of this disclosure. Incorporate by reference All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually incorporated herein by reference. Beneficial effects The siRNA, pharmaceutical composition, and siRNA conjugates disclosed herein exhibit good stability and high RPTOR mRNA inhibitory activity, and can significantly treat and / or alleviate diseases or symptoms related to RPTOR function regulation. Specific details are as follows. The siRNA, pharmaceutical composition, or siRNA conjugate disclosed herein exhibits excellent RPTOR mRNA expression inhibitory activity in in vitro cell experiments. For example, in in vitro Hepa1-6 mouse hepatocellular carcinoma cells, at a low concentration of 1 μM, the siRNA disclosed herein showed an RPTOR mRNA inhibition rate of 53.1%; in HepG2 human hepatocellular carcinoma cells, at a concentration of 50 nM, the siRNA disclosed herein showed an RPTOR mRNA inhibition rate of at least 67.9%. On the other hand, the siRNA, pharmaceutical composition, or siRNA conjugate provided in this disclosure can exhibit excellent RPTOR mRNA inhibitory activity in vivo. For example, the siRNA conjugate with an N-acetylgalactosamine group disclosed in this disclosure showed an RPTOR mRNA expression inhibition rate of at least 67.1% in C57BL / 6j mice at a concentration of 3 mg / kg. As another example, at a concentration of 9 mg / kg, the siRNA conjugate showed an RPTOR mRNA expression inhibition rate of 77.21% in C57BL / 6j mice. Therefore, the siRNA conjugate disclosed in this disclosure exhibits good RPTOR mRNA inhibitory activity at different dosages, and the inhibition efficiency shows a dose-dependent effect. On the other hand, the siRNAs, pharmaceutical compositions, or siRNA conjugates provided in this disclosure can exhibit region-selective RPTOR mRNA inhibitory activity in the central nervous system. For example, conjugates of this disclosure with conjugated polypeptide ligands, administered via intracerebroventricular injection, showed good inhibition rates against RPTOR mRNA expression in different regions of the mouse brain, with an inhibition rate as high as 73.0% in the cortex. Inhibition rates in the hippocampus and medulla oblongata both exceeded 50%, reaching 50.4% and 52.2%, respectively. Furthermore, conjugates with different polypeptide ligands showed comparable inhibitory activity against RPTOR mRNA in the right cortex and right hippocampus compared to conjugates with conjugated lipophilic groups, with inhibition rates between 40% and 50%. In the right cortex, the inhibition rate of RPTOR mRNA by the conjugates with conjugated lipophilic groups was 17% higher than that of siRNAa1; in the right hippocampus, the inhibition rate of RPTOR mRNA by the conjugates with conjugated lipophilic groups was at least 14% higher than that of siRNAa1. For example, when administered via intracerebroventricular injection, the conjugates of this disclosure, conjugated with lipophilic groups, exhibited inhibition rates of over 50% against RPTOR mRNA in multiple deep brain regions, including the cortex, hippocampus, medulla oblongata, and striatum. Specifically, in the cortex, hippocampus, and medulla oblongata, the lipophilic conjugates showed inhibition rates of over 60% against RPTOR mRNA, with a particularly high inhibition rate of 69.64% in the hippocampus. For example, after intrathecal administration, the conjugates disclosed herein exhibited region-specific RPTOR mRNA inhibitory activity in the mouse central nervous system. Experimental data showed that on day 29 of administration, the lumbar spinal cord showed the highest RPTOR mRNA inhibition rate (≥60%), indicating that the drug was highly enriched locally in the spinal cord and had a long-lasting effect; the cortex showed the second highest inhibition rate (maximum inhibition rate 56.05%), while deep brain regions (such as the striatum and hippocampus) maintained an inhibition rate of at least 20% for RPTOR mRNA. Furthermore, the conjugates of this disclosure, with lipophilic groups, showed targeted delivery advantages in the striatum (46.89% inhibition rate of RPTOR mRNA) and thalamus (49.86% inhibition rate of RPTOR mRNA). This demonstrates that the siRNA, pharmaceutical composition, and siRNA conjugates provided herein can inhibit RPTOR mRNA expression, effectively treating diseases or symptoms related to RPTOR function regulation, and have promising application prospects. Other features and advantages of this disclosure will be described in detail in the following detailed description section. Detailed Implementation The following provides a detailed description of specific embodiments of this disclosure. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit this disclosure. definition In this disclosure, RPTOR mRNA refers to the sequence shown in GenBank accession number NM_020761.3. Furthermore, unless otherwise specified, the term "target gene" as used in this disclosure refers to the gene encoding the aforementioned RPTOR mRNA, and the term "target mRNA" refers to the aforementioned RPTOR mRNA. Unless otherwise specified, in the preceding and following text, uppercase letters C, G, U, and A represent the base composition of nucleotides; lowercase letter m indicates that the nucleotide adjacent to the left of letter m is a methoxy-modified nucleotide; lowercase letter f indicates that the nucleotide adjacent to the left of letter f is a fluorinated nucleotide; lowercase letter s indicates that the two nucleotides adjacent to the left and right of letter s are linked by a thiophosphate group; P1 indicates that the nucleotide adjacent to the right of letter P1 is a 5'-phosphate nucleotide or a 5'-phosphate analog nucleotide. In some embodiments, P1 represents the specific modification VP, Ps, or P, wherein the letter combination VP indicates that the nucleotide adjacent to the right of the letter combination VP is a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modified nucleotide, the letter combination Ps indicates that the nucleotide adjacent to the right of the letter combination Ps is a thiophosphate modified nucleotide, and the uppercase letter P indicates that the nucleotide adjacent to the right of letter P is a 5'-phosphate nucleotide. In the preceding and following text, "fluorinated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with fluorine, and "non-fluorinated nucleotides" refers to nucleotides or nucleotide analogs formed by replacing the 2'-hydroxyl group of the ribosome with a non-fluorinated group. "Nucleotide analogs" refer to groups that can replace nucleotides in nucleic acids but whose structure differs from adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, or thymine deoxyribonucleotides. Examples include isonucleotides, bridged nucleic acids (BNAs), or acyclic nucleotides. "Methoxylated nucleotides" refers to nucleotides formed by replacing the 2'-hydroxyl group of the ribosome with a methoxy group. In the context of this article, the terms "complementary" and "reverse complementary" are used interchangeably and have the meaning known to those skilled in the art: in a double-stranded nucleic acid molecule, each base of one strand forms a hydrogen bond with a base of the other strand in a complementary manner to achieve base pairing, forming a Watson-Crick base pair. A "base pair" refers to the two bases that form a base pair. In DNA, the purine base adenine (A) always pairs with the pyrimidine base thymine (T) (or uracil (U) in RNA); the purine base guanine (C) always pairs with the pyrimidine base cytosine (G). Each base pair consists of one purine and one pyrimidine. When adenine on one strand always pairs with thymine (or uracil) on the other strand, and guanine always pairs with cytosine, the two strands are considered complementary, and the sequence of the complementary strand can be inferred from its sequence. When bases are modified, as long as the above purine-pyrimidine pairing relationship is not affected (including but not limited to the number and strength of hydrogen bonds between bases), these modified bases are also considered to form complementary pairs. Correspondingly, "mismatch" in this field means that in double-stranded nucleic acids, the bases at corresponding positions are not paired in a complementary manner. Unless otherwise specified above and below, "substantially anticomplementary" means that there are no more than 3 base mismatches between the two nucleotide sequences involved; "substantially anticomplementary" means that there are no more than 1 base mismatch between the two nucleotide sequences; and "completely anticomplementary" means that there are no base mismatches between the two nucleotide sequences. In the preceding and following text, a "nucleotide difference" between two nucleotide sequences refers to a change in the type of bases at the same position of the nucleotides compared to the latter. For example, if a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G, or T, then a nucleotide difference is considered to exist between the two nucleotide sequences at that position. In some embodiments, replacing the nucleotide at the original position with a baseless nucleotide or its equivalent can also be considered a nucleotide difference at that position. A baseless nucleotide is a monomeric compound formed when a nucleic acid base in a nucleotide is replaced by other groups or hydrogen atoms. These other groups include, but are not limited to, substituted or unsubstituted aromatic or heteroaryl groups. In the foregoing and hereinafter, particularly in the description of methods for preparing siRNA, pharmaceutical compositions, or siRNA conjugates of this disclosure, unless otherwise specified, the nucleoside monomer refers to the modified or unmodified RNA phosphoramidites (sometimes also called nucleoside phosphoramidites) used in phosphoramidite solid-phase synthesis, depending on the type and sequence of nucleotides in the siRNA or siRNA conjugate to be prepared. Phosphoramidite solid-phase synthesis is a method known to those skilled in the art for RNA synthesis. All nucleoside monomers used in this disclosure are commercially available. Unless otherwise specified, in the preceding and following text, each letter in the polypeptide sequence represents an amino acid, where G represents glycine, A represents alanine, V represents valine, L represents leucine, I represents isoleucine, P represents proline, F represents phenylalanine, Y represents tyrosine, W represents tryptophan, S represents serine, T represents threonine, C represents cysteine, M represents methionine, N represents asparagine, Q represents glutamine, D represents aspartic acid, E represents glutamic acid, K represents lysine, R represents arginine, and H represents histidine. In the preceding and following text, a polypeptide sequence refers to a polypeptide sequence formed by the dehydration condensation reaction of multiple amino acid monomers through the carboxyl and amino positions. Unless otherwise specified, the N-terminus of a polypeptide sequence refers to the end of the polypeptide containing an unreacted amino group, and the C-terminus of a polypeptide sequence refers to the end of the polypeptide containing an unreacted carboxyl group. It is important to note that in the preceding and following text, A in a polypeptide sequence represents alanine, while A in a nucleic acid molecule represents adenine (a purine base); T in a polypeptide sequence represents threonine, while T in a nucleic acid molecule represents thymine; G in a polypeptide sequence represents glycine, while G in a nucleic acid molecule represents guanine; and C in a polypeptide sequence represents cysteine, while C in a nucleic acid molecule represents cytosine. Those skilled in the art will understand the different meanings of A, T, G, and C in polypeptide sequences and nucleic acid molecules and will not be confused by them. In the context of this disclosure, unless otherwise stated, "conjugation" refers to the covalent connection between two or more chemical parts, each having a specific function; correspondingly, "conjugated compound" refers to a compound formed by the covalent connection of these chemical parts. Further, "siRNA conjugated compound" refers to a compound formed by the covalent attachment of one or more chemical parts having a specific function to siRNA. siRNA conjugated compounds should be understood, depending on the context, as a collective term for multiple siRNA conjugated compounds or a siRNA conjugated compound represented by a specific chemical formula. In the context of this disclosure, "conjugated molecule" should be understood as a specific compound that can be reactively conjugated to siRNA to ultimately form the siRNA conjugated compounds of this disclosure. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable. As used herein, “alkyl” refers to a straight-chain or branched alkyl group having a specified number of carbon atoms, typically from 1 to 20 carbon atoms, such as from 1 to 10 carbon atoms, or from 1 to 8 or 1 to 6 carbon atoms. For example, C1-C6 alkyl groups comprise straight-chain and branched alkyl groups with 1 to 6 carbon atoms. When referring to an alkyl residue having a specific number of carbon atoms, it is intended to encompass all branched and straight-chain forms having that number of carbon atoms; thus, for example, “butyl” means including n-butyl, sec-butyl, isobutyl, and tert-butyl; “propyl” includes n-propyl and isopropyl. Alkylenes are subsets of alkyl groups, referring to divalent groups that are identical to alkyl groups but have two bonding points. As used herein, "alkenyl" refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond obtained by removing a hydrogen molecule from an adjacent carbon atom of a parent alkyl group. The group can be in either a cis or trans configuration of the double bond. Typical alkenyl groups include, but are not limited to: vinyl; propenyl, such as propyl-1-en-1-yl, propyl-1-en-2-yl, propyl-2-en-1-yl (allyl), propyl-2-en-2-yl; butenyl, such as buten-1-en-1-yl, buten-1-en-2-yl, 2-methylpropen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, buten-1,3-dien-2-yl, etc. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, while in other embodiments, it has 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Subalkenyl groups are a subset of alkenyl groups, referring to residues that are identical to alkenyl groups but have two connection points. As used herein, "alkoxy" refers to an alkyl group with a specified number of carbon atoms connected by oxygen bridges, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms connected by oxygen bridges. Various hydroxyl protecting groups may be used in this disclosure. Generally, protecting groups insensitize chemical functional groups to specific reaction conditions and can be added to and removed from the molecule without substantially impairing the rest of the molecule. Representative hydroxyl protecting groups are disclosed in Beaucage et al., Tetrahedron 1992, 48, 2223-2311, and Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, 2d ed., John Wiley & Sons, New York, 1991, all of which are incorporated herein by reference in their entirety. In some embodiments, the protecting group is stable under basic conditions but can be removed under acidic conditions. Non-exclusive examples of hydroxyl protecting groups that may be used herein include dimethoxytriphenylmethyl (DMT), monomethoxytriphenylmethyl, 9-phenyloxanthracene-9-yl (Pixyl), and 9-(p-methoxyphenyl)oxanthracene-9-yl (Mox). In some embodiments, non-exclusive examples of hydroxyl protecting groups that may be used herein include Tr (triphenylmethyl), MMTr (4-methoxytriphenylmethyl), DMTr (4,4'-dimethoxytriphenylmethyl), and TMTr (4,4',4”-trimethoxytriphenylmethyl). The term “subject” as used herein refers to any animal, such as a mammal or marsupial. Subjects of this disclosure include, but are not limited to, humans, non-human primates (e.g., rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, rabbits, sheep, rats, and any kind of poultry. As used herein, “treatment” refers to a method of achieving a beneficial or desired outcome, including but not limited to treatment benefits. A “treatment benefit” means the eradication or improvement of the underlying disorder being treated. Furthermore, a treatment benefit is achieved by eradicating or improving one or more physical symptoms associated with the underlying disorder, thereby observing improvement in the subject, even though the subject may still be suffering from the underlying disorder. The “polypeptide ligand” described in this disclosure refers to a peptide composed of a certain number of amino acids that binds to siRNA via a covalent bond or linker group. As used herein, “prevention” refers to methods for obtaining a beneficial or desired outcome, including but not limited to preventive benefits. To obtain a “preventive benefit,” the siRNA, pharmaceutical composition, or siRNA conjugate of this disclosure may be given to a subject at risk of developing a disease associated with RPTOR mRNA, or to a subject who reports one or more physiological symptoms of a disease associated with RPTOR mRNA, even if a diagnosis of the disease may not have been made. Unless otherwise specified, in the context of any application or method provided in this disclosure, referring solely to siRNA and / or siRNA conjugates, including but not limited to any siRNA and / or siRNA conjugates represented by a structural formula as described in the application or method provided in this disclosure, also refers to a pharmaceutically acceptable salt of the conjugate, depending on the context. This disclosed siRNA In one aspect, this disclosure provides a siRNA capable of inhibiting RPTOR mRNA expression. The siRNA disclosed herein contains nucleotide groups as basic structural units. As is known to those skilled in the art, the nucleotide groups contain phosphate groups, ribose groups, and bases, which will not be elaborated further here. The siRNA disclosed herein contains a sense strand and an antisense strand, the sense strand and the antisense strand being the same length or different, the sense strand being 19-23 nucleotides in length and the antisense strand being 19-26 nucleotides in length. Thus, the length ratio of the sense strand to the antisense strand of the siRNA provided in this disclosure can be 19 / 19, 19 / 20, 19 / 21, 19 / 22, 19 / 23, 19 / 24, 19 / 25, 19 / 26, 20 / 20, 20 / 21, 20 / 22, 20 / 23, 20 / 24, 20 / 25, 20 / 26, 21 / 20, 21 / 21, 21 / 22, 21 / 23, 21 / 24, 21 / 25, 21 / 26, 22 / 20, 22 / 21, 22 / 22, 22 / 23, 22 / 24, 22 / 25, 22 / 26, 23 / 20, 23 / 21, 23 / 22, 23 / 23, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, the length ratio of the siRNA's sense strand to its antisense strand is 19 / 21, 21 / 21, 21 / 23, or 23 / 25. In some embodiments, the sense strand is 19 nucleotides long and the antisense strand is 21 nucleotides long. In some embodiments, the sense strand is 21 nucleotides long and the antisense strand is 23 nucleotides long. According to this disclosure, the siRNA contains a sense strand and an antisense strand, each nucleotide in the siRNA being independently modified or unmodified, wherein the sense strand contains a nucleotide sequence I and the antisense strand contains a nucleotide sequence II, the nucleotide sequence I and the nucleotide sequence II being at least partially anticomplementary to form a double-stranded region. In some embodiments, the siRNA of this disclosure has nucleotide sequence I that is the same length as the nucleotide sequence shown in SEQ ID NO:1 and differs by no more than 3 nucleotides, and nucleotide sequence II that is the same length as the nucleotide sequence shown in SEQ ID NO:2 and differs by no more than 3 nucleotides. 5'-UCCUGUCCUUCGAGACCAZ a1 -3'(SEQ ID NO:1); 5'-Z a2 UGGUCUCGAAGGACAGGA-3'(SEQ ID NO:2), Among them, Z a1 For U, Z a2 For A, the nucleotide sequence I contains a position corresponding to Z. a1 nucleotide Z a3 The nucleotide sequence II contains a position corresponding to Z. a2 nucleotide Z a4 The Z a4 It is the first nucleotide at the 5' end of the antisense strand. In this context, "positional correspondence" means that the nucleotides are located at the same position in the nucleotide sequence, counting from the same end. For example, the position of the first nucleotide at the 3' end of nucleotide sequence I corresponds to the first nucleotide at the 3' end of SEQ ID NO:1. In some embodiments, the sense strand contains only nucleotide sequence I, and the antisense strand contains only nucleotide sequence II. In some embodiments, nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO:1 by no more than one nucleotide, and / or nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one nucleotide. In some embodiments, the nucleotide differences between nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 include Z. a4 The difference in position, and Z a4 Selected from U, C, or G. In some embodiments, Z... a3 Is with Z a4 Complementary nucleotides, or Z a3It is a reverse debase deoxynucleotide (ia). siRNAs with the above-mentioned nucleotide differences have higher RPTOR mRNA repressive ability, and these siRNAs containing nucleotide differences are also within the scope of protection of this disclosure. In some embodiments, the nucleotide sequence I and the nucleotide sequence II are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary; substantially anticomplementary means that there are no more than 3 base mismatches between the two nucleotide sequences; substantially anticomplementary means that there are no more than 1 base mismatch between the two nucleotide sequences; completely anticomplementary means that there are no base mismatches between the two nucleotide sequences. In some embodiments, the sense and antisense strands may be the same or different in length, with the sense strand being 19-23 nucleotides long and the antisense strand being 19-26 nucleotides long; and the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO:3, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO:4. 5'-UCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:3); 5'-Z a4 UGGUCUCGAAGGACAGGA-3' (SEQ ID NO:4), Among them, Z a3 Selected from A, U, G, or C, Z a4 Is with Z a3 Complementary nucleotides, or Z a3 It is a reverse debased deoxynucleotide (ia). In some implementations, Z a3 For U or ia, Z a4 The answer is A. In some embodiments, the sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV, wherein nucleotide sequence III and nucleotide sequence IV are each 1 to 4 nucleotides in length; nucleotide sequence III and nucleotide sequence IV are of equal length and are substantially anticomplementary or completely anticomplementary; nucleotide sequence III is attached to the 5' end of nucleotide sequence I, and nucleotide sequence IV is attached to the 3' end of nucleotide sequence II. In some embodiments, the nucleotide sequence IV is substantially anticomplementary or completely anticomplementary to the second nucleotide sequence, which is a nucleotide sequence in RPTOR mRNA that is adjacent to the 5' end of the nucleotide sequence represented by SEQ ID NO:1 and has the same length as the nucleotide sequence IV. In some embodiments, nucleotide sequences III and IV are both 1 nucleotide in length along the 5'-3' direction, with bases A for nucleotide sequence III and U for nucleotide sequence IV; in this case, the length ratio of the sense strand to the antisense strand is 20 / 20. Alternatively, nucleotide sequences III and IV are both 2 nucleotides in length, with bases UA for nucleotide sequence III and UA for nucleotide sequence IV along the 5'-3' direction; in this case, the length ratio of the sense strand to the antisense strand is 21 / 21. Alternatively, nucleotide sequences III and IV are both 3 nucleotides in length, with bases AUA for nucleotide sequence III and UAU for nucleotide sequence IV along the 5'-3' direction; in this case, the length ratio of the sense strand to the antisense strand is 22 / 22. Alternatively, nucleotide sequences III and IV are both 4 nucleotides in length, with bases CAUA for nucleotide sequence III and UAUG for nucleotide sequence IV along the 5'-3' direction; in this case, the length ratio of the sense strand to the antisense strand is 23 / 23. In some implementations, nucleotide sequence III and nucleotide sequence IV are completely inversely complementary; therefore, given the bases of nucleotide sequence III, the bases of nucleotide sequence IV are determined. In some embodiments, the sense strand and the antisense strand have different lengths, and the antisense strand further contains a nucleotide sequence V, which is 1 to 3 nucleotides in length, attached to the 3' end of the antisense strand to form the 3' overhang of the antisense strand. In some embodiments, the positive strand further contains a nucleotide sequence VI, which is 1 to 3 nucleotides in length, attached to the 3' end of the positive strand to form a 3' overhang of the positive strand. In some embodiments, the siRNA provided in this disclosure includes nucleotide sequence V but excludes nucleotide sequence VI. Therefore, the length ratio of the sense and antisense strands of the siRNA provided in this disclosure can be 19 / 20, 19 / 21, 19 / 22, 20 / 21, 20 / 22, 20 / 23, 21 / 22, 21 / 23, 21 / 24, 22 / 23, 22 / 24, 22 / 25, 23 / 24, 23 / 25, or 23 / 26. In some embodiments, the siRNA provided in this disclosure includes nucleotide sequences V and VI. In some embodiments, the length of nucleotide sequence V is the same as or different from the length of nucleotide sequence VI. Therefore, the length ratio of the sense and antisense strands of the siRNA provided in this disclosure can be (19-26):(19-26). In some embodiments, the length of the nucleotide sequence V and / or VI is 2 nucleotides, thereby the length ratio of the sense strand to the antisense strand of the siRNA provided in this disclosure can be 19 / 21, 21 / 21, 21 / 23, 23 / 23, 23 / 25 or 25 / 25. Each nucleotide in the nucleotide sequence V can be any nucleotide. For ease of synthesis and cost savings, in some embodiments, the nucleotide sequence V is two consecutive thymine deoxyribonucleotides (dTdT) or two consecutive uracil ribonucleotides (UU); or, to improve the affinity of the siRNA antisense strand to RPTOR mRNA, the nucleotide sequence V is complementary to the nucleotides at the corresponding positions of the RPTOR mRNA. Therefore, in some embodiments, the ratio of the sense strand to the antisense strand length of the siRNA disclosed herein is 19 / 21 or 21 / 23, in which case the siRNA disclosed herein exhibits better mRNA silencing activity. Each nucleotide in the nucleotide sequence VI can be any nucleotide. To facilitate synthesis and reduce synthesis costs, in some embodiments, the nucleotide sequence VI is two consecutive thymine deoxyribonucleotides (dTdT) or two consecutive uracil ribonucleotides (UU); or, to improve the affinity of the siRNA's sense and antisense strands, the nucleotide sequence VI is identical to the corresponding nucleotide in the RPTOR mRNA. Therefore, in some embodiments, the siRNA of this disclosure comprises nucleotide sequences V and VI, and the length ratio of the siRNA's sense and antisense strands is 21 / 21 or 23 / 23. In this case, the siRNA of this disclosure has better mRMA silencing activity. The nucleotide at the corresponding position of RPTOR mRNA refers to the nucleotide or nucleotide sequence adjacent to the 5' end of a nucleotide sequence of RPTOR mRNA. This nucleotide sequence of RPTOR mRNA is substantially anticomplementary or completely anticomplementary to nucleotide sequence II, or substantially anticomplementary or completely anticomplementary to the nucleotide sequence formed by nucleotide sequences II and IV. In some embodiments, the sense strand of the siRNA contains the nucleotide sequence shown in SEQ ID NO:5, and the antisense strand contains the nucleotide sequence shown in SEQ ID NO:6. 5'-UCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:5); 5'-Z a4 UGGUCUCGAAGGACAGGUAA-3' (SEQ ID NO: 6); Wherein, the Z a4 It is the first nucleotide at the 5' end of the antisense strand, Z a3 Choose from ia, A, U, G, or C, and Z a3 When it is not ia, Z a4 Is with Z a3 Complementary nucleotides; Alternatively, the sense strand of the siRNA contains a nucleotide sequence as shown in SEQ ID NO:7, and the antisense strand of the siRNA contains a nucleotide sequence as shown in SEQ ID NO:8. 5'-UAUCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:7); 5'-Z a4 UGGUCUCGAAGGACAGGAUAUG-3' (SEQ ID NO: 8); Wherein, the Z a4 It is the first nucleotide at the 5' end of the antisense strand, Z a3 Choose from ia, A, U, G, or C, and Z a3 When it is not ia, Z a4 Is with Z a3 Complementary nucleotides. In some embodiments, the siRNA described in this disclosure is siRPTORa1, siRPTORa2 and siRPTORa3 listed in Table 1. As previously stated, the nucleotides in the siRNA of this disclosure are each independently modified or unmodified nucleotides. In some embodiments, the nucleotides in the siRNA of this disclosure are unmodified nucleotides; in some embodiments, some or all of the nucleotides in the siRNA of this disclosure are modified nucleotides, and these modifications on the nucleotide groups do not cause a significant weakening or loss of the function of the siRNA of this disclosure in inhibiting RPTOR mRNA expression. In some embodiments, the siRNA of this disclosure contains at least one modified nucleotide. In the context of this disclosure, the term "modified nucleotide" refers to a nucleotide or nucleotide analog formed by replacing the 2' hydroxyl group of the ribosyl group with another group, or a nucleotide whose bases are modified. The modified nucleotide does not cause a significant reduction or loss of the siRNA's ability to inhibit RPTOR mRNA expression. For example, the modified nucleotide disclosed in JK Watts, G.F. Deleavey, and MJ Damha, Chemically Modified siRNA: Tools and Applications. Drug Discov Today, 2008, 13(19-20):842-55, may be selected. In some embodiments, at least one nucleotide in the sense strand or the antisense strand of the siRNA provided in this disclosure is a modified nucleotide, and / or at least one phosphate ester group is a phosphate ester group with a modifying group; in other words, at least a portion of the phosphate ester group and / or ribosome in the phosphate-sugar backbone of at least one single strand of the sense strand and the antisense strand is a phosphate ester group with a modifying group and / or a ribosome with a modifying group. In some embodiments, all nucleotides in the sense strand and / or the antisense strand are modified nucleotides. In some embodiments, each nucleotide in the sense strand and the antisense strand of the siRNA provided in this disclosure is independently a fluorinated or non-fluorinated nucleotide. The inventors of this disclosure were surprised to find that the siRNA provided in this disclosure achieved a high balance between plasma stability and RPTOR mRNA silencing efficiency in animal experiments. In some embodiments, the fluorinated nucleotides are located in nucleotide sequence I and nucleotide sequence II, wherein there are no more than 5 fluorinated nucleotides in nucleotide sequence I, and the nucleotides at positions 7, 8, and 9 of nucleotide sequence I are fluorinated nucleotides in the direction from the 5' end to the 3' end; and there are no more than 7 fluorinated nucleotides in nucleotide sequence II, and the nucleotides at positions 2, 6, 14, and 16 of nucleotide sequence II are fluorinated nucleotides. In some embodiments, in the positive strand, the nucleotides at positions 7, 8, and 9, or positions 5, 7, 8, and 9 of nucleotide sequence I are fluorinated nucleotides, and the remaining nucleotides in the positive strand are non-fluorinated nucleotides, following the direction from the 5' end to the 3' end; in the negative strand, the nucleotides at positions 2, 6, 14, and 16, or positions 2, 6, 8, 9, 14, and 16 of nucleotide sequence II are fluorinated nucleotides, and the remaining nucleotides in the negative strand are non-fluorinated nucleotides. In the context of this disclosure, a "fluorinated nucleotide" refers to a nucleotide formed by replacing the hydroxyl group at the 2' position of the ribosyl group with fluorine, having the structure shown in formula (7). A "non-fluorinated nucleotide" refers to a nucleotide or nucleotide analog formed by replacing the hydroxyl group at the 2' position of the ribosyl group with a non-fluorinated group. In some embodiments, each non-fluorinated nucleotide is independently selected from one of the nucleotides or nucleotide analogs formed by replacing the hydroxyl group at the 2' position of the ribosyl group with a non-fluorinated group. The nucleotides formed by replacing the hydroxyl group at the 2' position of the ribosyl group with a non-fluorinated group are well known to those skilled in the art, and these nucleotides may be selected from one of the following: 2'-alkoxy modified nucleotides, 2'-substituted alkoxy modified nucleotides, 2'-alkyl modified nucleotides, 2'-substituted alkyl modified nucleotides, 2'-amino modified nucleotides, 2'-substituted amino modified nucleotides, and 2'-deoxynucleotides. In some embodiments, the 2'-alkoxy-modified nucleotide is a 2'-methoxy-modified nucleotide (2'-OMe), as shown in formula (8). In some embodiments, the 2'-substituted alkoxy-modified nucleotide may be, for example, a 2'-O-methoxyethyl-modified nucleotide (2'-MOE), as shown in formula (9). In some embodiments, the 2'-amino-modified nucleotide (2'-NH2) is shown in formula (10). In some embodiments, the 2'-deoxynucleotide (DNA) is shown in formula (11). Here, Base represents a nucleic acid base, such as A, U, G, C, or T. Nucleotide analogs are groups that can replace nucleotides in nucleic acids, but whose structure differs from that of adenine ribonucleotides, guanine ribonucleotides, cytosine ribonucleotides, uracil ribonucleotides, or thymine deoxyribonucleotides. In some embodiments, nucleotide analogs can be isonucleotides, bridged nucleic acids (BNAs), or acyclic nucleotides. BNA refers to a restricted or inaccessible nucleotide. A BNA can contain a bridging structure with a "fixed" C3'-endoglucan condensation, such as a five-membered, six-membered, or seven-membered ring. This bridge is typically incorporated into the 2'-, 4'-position of the ribose to provide a 2',4'-BNA nucleotide. In some embodiments, the BNA can be LNA, ENA, cET BNA, etc., where LNA is shown in formula (12), ENA in formula (13), and cET BNA in formula (14), where Base represents a nucleic acid base, such as A, U, G, C, or T: Acyclic nucleotides are a class of nucleotides formed by opening the sugar ring of a nucleotide. In some embodiments, acyclic nucleotides can be unblocking nucleic acids (UNA) or glycerol nucleic acids (GNA), wherein UNA is shown in formula (15) and GNA is shown in formula (16): In formulas (15) and (16) above, R is selected from H, OH or alkoxy (O-alkyl), and Base represents a nucleic acid base, such as A, U, G, C or T. Isonucleotides are compounds formed by altering the position of a base on the ribose ring in a nucleotide. In some embodiments, an isonucleotide can be a compound formed by moving a base from the 1'-position to the 2'-position or 3'-position on the ribose ring, as shown in formula (17) or (18). In the compounds of formulas (17)-(18) above, Base represents a nucleic acid base, such as A, U, G, C or T; R is selected from H, OH, F or non-fluorine groups as described above. In some embodiments, the nucleotide analogue is selected from one of the following: isonucleotides, LNA, ENA, cET, UNA, and GNA. In some embodiments, each non-fluorinated nucleotide is an alkoxy-modified nucleotide, and each alkoxy-modified nucleotide is independently a methoxy-modified nucleotide. In the foregoing and hereinafter, the methoxy-modified nucleotide refers to a nucleotide formed by replacing the 2'-hydroxyl group of the ribosome with a methoxy group. An inverted abasic deoxyribonucleotide (abbreviated as invab or ia, having a structure as shown in formula (35)). In some embodiments, the first nucleotide of the positive strand is an alkoxy-modified nucleotide or an inverted abasic deoxyribonucleotide, with the 3' end to the 5' end in the direction. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the penultimate nucleotide at the 3' end of the positive strand. In some embodiments, the oxygen atom directly attached to the ribose ring as shown in formula (35) may be attached to the 3' phosphate group of the 3' terminal nucleotide of the positive strand, and the oxygen atom attached to the ribose ring via a methylene group as shown in formula (35) may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand. In some embodiments, the oxygen atom of formula (35) connected to the ribose ring via a methylene group may be attached to the 5' phosphate group of the penultimate nucleotide at the 5' end of the positive strand, and the oxygen atom of formula (35) directly attached to the ribose ring may be attached to a hydrogen atom, a hydroxyl protecting group, or a delivery group as described below. In the preceding and following text, “fluorinated nucleotide” refers to a compound having the structure shown in formula (7) formed by replacing the 2'-hydroxyl group of a nucleotide with fluorine; “methoxylated nucleotide” refers to a compound having the structure shown in formula (8) formed by replacing the 2'-hydroxyl group of the ribose group of a nucleotide with a methoxyl group. In some embodiments, the siRNA of this disclosure is an siRNA with the following modifications: in the positive strand, the nucleotides at positions 7, 8, and 9, or positions 5, 7, 8, and 9 of nucleotide sequence I are fluorinated nucleotides, and the nucleotides at the remaining positions in the positive strand are methoxylated nucleotides; in the negative strand, the nucleotides at positions 2, 6, 14, and 16, or positions 2, 6, 8, 9, 14, and 16 of nucleotide sequence II are fluorinated nucleotides, and the nucleotides at the remaining positions in the negative strand are methoxylated nucleotides. In some embodiments, the siRNA of this disclosure is an siRNA with the following modifications: nucleotides at positions 5, 7, 8, and 9 of nucleotide sequence I in the sense strand of the siRNA are fluorinated nucleotides, and nucleotides at the remaining positions of the sense strand of the siRNA are methoxylated nucleotides; and nucleotides at positions 2, 6, 8, 9, 14, and 16 of nucleotide sequence II in the antisense strand of the siRNA are fluorinated nucleotides, and nucleotides at the remaining positions of the antisense strand of the siRNA are methoxylated nucleotides. Alternatively, in the direction from the 5' end to the 3' end, the nucleotides at positions 5, 7, 8, and 9 of nucleotide sequence I in the sense strand of the siRNA are fluorinated nucleotides, and the nucleotides at the remaining positions of the sense strand of the siRNA are methoxylated nucleotides; and in the direction from the 5' end to the 3' end, the nucleotides at positions 2, 6, 14, and 16 of nucleotide sequence II in the antisense strand of the siRNA are fluorinated nucleotides, and the nucleotides at the remaining positions of the antisense strand of the siRNA are methoxylated nucleotides. Alternatively, in the direction from the 5' end to the 3' end, the nucleotides at positions 7, 8, and 9 of nucleotide sequence I in the sense strand of the siRNA are fluorinated nucleotides, and the nucleotides at the remaining positions of the sense strand of the siRNA are methoxylated nucleotides. Furthermore, in the direction from the 5' end to the 3' end, the nucleotides at positions 2, 6, 14, and 16 of nucleotide sequence II in the antisense strand of the siRNA are fluorinated nucleotides, and the nucleotides at the remaining positions of the antisense strand of the siRNA are methoxylated nucleotides. In some embodiments, the siRNA provided in this disclosure is arbitrarily selected from one of the following siRNAs: siRPTORa1-M1, siRPTORa1-M2, siRPTORa1-M3, siRPTORa2-M1, siRPTORa2-M2, siRPTORa2-M3, siRPTORa3-M1, siRPTORa3-M2, siSRPTORa3-M3. The modified siRNAs are not only low-cost, but also make it more difficult for ribonucleases in the blood to cleave nucleic acids, thereby increasing the stability of nucleic acids and making them more resistant to nuclease hydrolysis. Simultaneously, the modified siRNAs exhibit high activity in inhibiting RPTOR mRNA. In some embodiments, at least a portion of the phosphate ester groups in the phosphate-sugar backbone of at least one single strand of the sense and antisense strands of the siRNA provided in this disclosure are phosphate ester groups with modifying groups. In some embodiments, the phosphate ester group with modifying groups is a thiophosphate ester group formed by replacing at least one oxygen atom in the phosphodiester bond of the phosphate ester group with a sulfur atom; in some embodiments, the phosphate ester group with modifying groups is a thiophosphate ester group having the structure shown in formula (1): This modification stabilizes the double-stranded structure of siRNA, maintaining high specificity and high affinity for base pairing. In some embodiments, the siRNA provided in this disclosure has a thiophosphate group linker present at least one of the following positions: between the first and second nucleotides at either end of the sense or antisense strand; between the second and third nucleotides at either end of the sense or antisense strand; or any combination thereof. In some embodiments, the thiophosphate group linker is present at all of the above positions except for the 5' end of the sense strand. In some embodiments, the thiophosphate group linker is present at all of the above positions except for the 3' end of the sense strand. In some embodiments, the thiophosphate group linker is present at at least one of the following positions: Between the first and second nucleotides at the 5' end of the positive strand; Between the second and third nucleotides at the 5' end of the positive strand; Between the first and second nucleotides at the 3' end of the positive strand; Between the second and third nucleotides at the 3' end of the positive strand; Between the first and second nucleotides at the 5' end of the antisense strand; Between the second and third nucleotides at the 5' end of the antisense strand; Between the first and second nucleotides at the 3' end of the antisense strand; and between the second and third nucleotides at the 3' end of the antisense strand. In some embodiments, the siRNA provided in this disclosure is arbitrarily selected from one of the following siRNAs: siRPTORa1-M1S, siRPTORa1-M1X, siRPTORa1-M2S, siRPTORa1-M2X, siRPTORa1-M3S, siRPTORa1-M3X, siRPTORa2-M1S, siRPTORa2-M1X, siRPTORa2-M2S, siRPTORa2-M2X, siRPTORa2-M3S, siRPTORa2-M3X, siRPTORa3-M1S, siRPTORa3-M1X, siRPTORa3-M2S, siRPTORa3-M2X, siRPTORa3-M3S, and siRPTORa3-M3X. In some embodiments, the 5' terminal nucleotide of the siRNA antisense strand is a 5'-phosphate nucleotide or a nucleotide modified with a 5'-phosphate analogue. Commonly used 5'-phosphate nucleotides or 5'-phosphate analogues modified nucleotides are well known to those skilled in the art. For example, 5'-phosphate nucleotides may have the following structures: For example, Anastasia Khvorova and Jonathan K. Watts, The chemical evolution of oligonucleotide therapies of clinical utility. Nature Biotechnology, 2017, 35(3):238-48, discloses the following four 5'-phosphate analog-modified nucleotides: In this context, R is selected from H, OH, methoxy, and fluorine; Base represents a nucleic acid base, selected from A, U, C, G, or T. In some embodiments, the 5'-phosphate nucleotide is a nucleotide containing 5'-phosphate modification as shown in formula (2), the 5'-phosphate analog modified nucleotide is a nucleotide containing vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modification as shown in formula (3), or a nucleotide modified with thiophosphate as shown in formula (5). In some embodiments, the siRNA provided in this disclosure is arbitrarily selected from one of the following groups: siRPTORa1-M1P1, siRPTORa1-M2P1, siRPTORa1-M3P1, siRPTORa2-M1P1, siRPTORa2-M2P1, siRPTORa2-M3P1, siRPTORa3-M1P1, siRPTORa3-M2P1, siRPTORa3-M3P1, siRPTORa1-M1SP1, siRPTORa1-M2SP1, siRPTORa1-M3SP1, siRPTORa2-M1 SP1, siRPTORa2-M2SP1, siRPTORa2-M3SP1, siRPTORa3-M1SP1, siRPTORa3-M2SP1, siRPTORa3-M3SP1, siRPTORa1-M1XP1, siRPTORa1-M2XP1, siRPTORa1-M3XP1, siRPTORa2-M1XP1, siRPTORa2-M2XP1, siRPTORa2-M3XP1, siRPTORa3-M1XP1, siRPTORa3-M2XP1 and siRPTORa3-M3XP1. The inventors of this disclosure unexpectedly discovered that the siRNA provided in this disclosure not only has significantly enhanced plasma and lysosomal stability, but also retains high RPTOR mRNA inhibitory activity. The siRNA provided in this disclosure can be obtained using conventional siRNA preparation methods in the art (e.g., solid-phase synthesis and liquid-phase synthesis). Solid-phase synthesis is already available as a commercially available custom service. Modified nucleotide groups can be introduced into the siRNA described in this disclosure using appropriately modified nucleoside monomers. Methods for preparing appropriately modified nucleoside monomers and for introducing modified nucleotide groups into siRNA are also well known to those skilled in the art. Pharmaceutical Composition In one aspect, this disclosure provides a pharmaceutical composition comprising siRNA as an active ingredient and a pharmaceutically acceptable carrier as described above. The pharmaceutically acceptable carrier can be a carrier conventionally used in the field of siRNA delivery, such as, but not limited to, magnetic nanoparticles (e.g., Fe3O4 or Fe2O3-based nanoparticles), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&L-lactic / glycolic acid) copolymer (PLGA), and poly(2-aminoethyl ethylene phosphate). One or more of the following: phosphate), PPEEA, and poly(2-dimethylaminoethyl methacrylate), PDMAEMA, and their derivatives. In some embodiments, there are no particular requirements for the content of siRNA and pharmaceutically acceptable carrier in the pharmaceutical composition. In some embodiments, the weight ratio of siRNA to pharmaceutically acceptable carrier can be 1:(1-500), and in some embodiments, the weight ratio is 1:(1-50). In some embodiments, the pharmaceutical composition may also contain other pharmaceutically acceptable excipients, which may be one or more of a variety of formulations or compounds conventionally used in the art. For example, the other pharmaceutically acceptable excipients may include at least one of pH buffers, protectants, and osmotic pressure regulators. The pH buffer solution can be a tris(hydroxymethyl)aminomethane hydrochloride buffer with a pH of 7.5-8.5 and / or a phosphate buffer with a pH of 5.5-8.5, for example, a phosphate buffer with a pH of 5.5-8.5. The protective agent may be at least one selected from inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. Based on the total weight of the pharmaceutical composition, the content of the protective agent may be 0.01-30% by weight. The osmotic pressure regulator may be, for example, sodium chloride and / or potassium chloride. The content of the osmotic pressure regulator results in an osmotic pressure of 200-700 milliosm / kg (mOsm / kg) for the pharmaceutical composition. The content of the osmotic pressure regulator can be readily determined by those skilled in the art based on the desired osmotic pressure. In some embodiments, the dosage of the formulation made from the pharmaceutical composition may be adjusted during administration depending on the route of administration. In some embodiments, the pharmaceutical composition may be a liquid formulation, such as an injection; or it may be a lyophilized powder for injection, which is mixed with liquid excipients to form a liquid formulation for administration. The liquid formulation may be used, but is not limited to, subcutaneous, intramuscular, intraventricular, or intrathecal injection, and may also be delivered via, but is not limited to, nasal administration, oropharyngeal inhalation, or aerosol administration. In some embodiments, the pharmaceutical composition is delivered via intrathecal injection. In some embodiments, intrathecal injection of the pharmaceutical composition into the cerebrospinal fluid may be performed via a bolus injection or via a micropump implanted under the skin to provide regular and constant delivery of siRNA into the cerebrospinal fluid. In some embodiments, intrathecal administration is performed via a surgically implanted osmotic pump. In some embodiments, an osmotic pump is implanted in the subarachnoid space of the spinal canal to facilitate intrathecal administration. Further details regarding this intrathecal delivery system can be found in PCT / US2015 / 013253, filed January 28, 2015, the entire contents of which are incorporated herein by reference. In some embodiments, the pharmaceutical composition may be in the form of a liposomal formulation. In some embodiments, the pharmaceutically acceptable carrier used in the liposomal formulation comprises an amine-containing transfection compound (hereinafter also referred to as an organic amine), a cofactor lipid, and / or a polyethylene glycol-modified lipid. The organic amine, cofactor lipid, and polyethylene glycol-modified lipid may be selected from one or more of the amine-containing transfection compounds or their pharmaceutically acceptable salts or derivatives, cofactor lipids, and polyethylene glycol-modified lipids described in Chinese patent application CN103380113A (which is incorporated herein by reference in its entirety). In some embodiments, the organic amine may be a compound of formula (201) as described in Chinese patent application CN103380113A, or a pharmaceutically acceptable salt thereof: in: X 101 and X 102 Each can be independently O, S, NA, or CA, where A is hydrogen or C1-C. 20 hydrocarbon chain; Y 101 and Z 101 Each can be independently C=O, C=S, S=O, CH-OH, or SO2; R 101 R 102 R 103 R 104 R 105 R 106 and R 107 Each is independently hydrogen, cyclic or acyclic, substituted or unsubstituted, branched or straight aliphatic group, cyclic or acyclic, substituted or unsubstituted, branched or straight heteroaliphatic group, substituted or unsubstituted, branched or straight acyl group, substituted or unsubstituted, branched or straight aryl group, substituted or unsubstituted, branched or straight heteroaryl group; x is an integer from 1 to 10; n is an integer from 1 to 3, m is an integer from 0 to 20, and p is 0 or 1; where, if m = p = 0, then R 102 It is hydrogen; Furthermore, if at least one of n or m is 2, then R 103 The nitrogen in formula (201) forms a structure as shown in formula (202) or formula (203): In this context, g, e, and f are each an integer from 1 to 6, "HCC" represents a hydrocarbon chain, and each *N represents a nitrogen atom in formula (201). In some implementations, R 103It is a polyamine. In other embodiments, R 103 It is a ketal. In some embodiments, R in formula (201) 101 and R 102 Each of them is independently an arbitrary substituted or unsubstituted, branched or straight-chain alkyl or alkenyl group having 3 to 20 carbon atoms, such as 8 to 18 carbon atoms, and 0 to 4 double bonds, such as 0 to 2 double bonds. In some implementations, if each of n and m independently has a value of 1 or 3, then R 103 It can be any one of the following equations (204)-(213): In equations (204)-(213), g, e, and f are each independent integers from 1 to 6, each "HCC" represents a hydrocarbon chain, and each * indicates R. 103 Possible connection points with nitrogen atoms in equation (201), wherein each H at any * position can be replaced to achieve connection with nitrogen atoms in equation (201). The compound shown in formula (201) can be prepared according to the description in Chinese patent application CN103380113A. In some embodiments, the organic amine is an organic amine as shown in formula (214) and / or an organic amine as shown in formula (215): The auxiliary lipid is cholesterol, cholesterol analogues and / or cholesterol derivatives; The PEGylated lipid is 1,2-dipalmitoyl-sn-glycerol-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)]-2000. In some embodiments, the molar ratio of the organic amine, the auxiliary lipid, and the polyethylene glycol-modified lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50), for example, (50-70):(20-40):(3-20). In some embodiments, the pharmaceutical composition particles formed from the siRNA of this 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, and more typically, the average diameter of the liposome particles is about 50 nm to about 120 nm, about 50 nm to about 100 nm, about 60 nm to about 90 nm, or about 70 nm to about 90 nm. For example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150, or 160 nm. In some embodiments, in the pharmaceutical composition formed from the siRNA of this disclosure and the above-mentioned amine-containing transfection reagent, the weight ratio (weight / weight ratio) of siRNA to all lipids (e.g., organic amines, auxiliary lipids and / or polyethylene glycol-modified lipids) is in the range of about 1:1 to about 1:50, about 1:1 to about 1:30, about 1:3 to about 1:20, about 1:4 to about 1:18, about 1:5 to about 1:17, about 1:5 to about 1:15, about 1:5 to about 1:12, about 1:6 to about 1:12 or about 1:6 to about 1:10. For example, the weight ratio of siRNA to all lipids of this disclosure is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17 or 1:18. In some embodiments, the components of the pharmaceutical composition may exist independently when sold, and may be in liquid form when used. In some embodiments, the pharmaceutical composition formed by the siRNA provided in this disclosure and the pharmaceutically acceptable carrier described above can be prepared according to various known methods, simply by replacing existing siRNAs with the siRNA provided in this disclosure; in some embodiments, it can be prepared according to the following method: An organic amine, auxiliary lipid, and polyethylene glycol-modified lipid are suspended in an alcohol at the above molar ratio and mixed to obtain a lipid solution. The amount of alcohol used is such that the total mass concentration of the resulting lipid solution is 2-25 mg / mL, for example, 8-18 mg / mL. The alcohol is selected from pharmaceutically acceptable alcohols, such as alcohols that are liquid near room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400, for example, ethanol. The siRNA provided in this disclosure is dissolved in a buffer salt solution to obtain an aqueous siRNA solution. The concentration of the buffer salt solution is 0.05-0.5M, for example, 0.1-0.2M. The pH of the buffer salt solution is adjusted to 4.0-5.5, for example, 5.0-5.2. The amount of buffer salt solution used is such that the concentration of siRNA does not exceed 0.6 mg / mL, for example, 0.2-0.4 mg / mL. The buffer salt is selected from one or more of soluble acetate and soluble citrate, for example, sodium acetate and / or potassium acetate. The lipid solution and siRNA aqueous solution are mixed, and the resulting product is incubated at 40-60°C for at least 2 minutes, for example, 5-30 minutes, to obtain the incubated liposome formulation. The volume ratio of lipid solution to siRNA aqueous solution is 1:(2-5). The incubated liposome formulation is concentrated or diluted, impurities are removed, and sterilization is performed to obtain the pharmaceutical composition provided in this disclosure. Its physicochemical parameters are: pH value of 6.5-8, encapsulation efficiency of not less than 80%, particle size of 40-200 nm, polydispersity index of not more than 0.30, and osmotic pressure of 250-400 mOsm / kg; for example, the physicochemical parameters can be: pH value of 7.2-7.6, encapsulation efficiency of not less than 90%, particle size of 60-100 nm, polydispersity index of not more than 0.20, and osmotic pressure of 300-400 mOsm / kg. Concentration or dilution can be performed before, after, or simultaneously with impurity removal. Impurity removal can be achieved using various existing methods, such as ultrafiltration at 100 kDa using a tangential flow system, hollow fiber column, and phosphate-buffered saline (PBS) at pH 7.4. Sterilization can be achieved using various existing methods, such as filtration sterilization through a 0.22 μm filter. The siRNA conjugates disclosed herein In another aspect, this disclosure provides an siRNA conjugate comprising the aforementioned siRNA and a conjugating group conjugated to the siRNA. In some embodiments, the conjugating group comprises a linker and a pharmaceutically acceptable targeting group and / or a delivery aid group, and the siRNA, the linker, and the targeting group or the delivery aid group are sequentially covalently or non-covalently linked, each targeting group being selected from ligands capable of binding to cell surface receptors, and each delivery aid group being selected from groups capable of increasing the biocompatibility of the siRNA conjugate in the target organ or tissue. In the context of this disclosure, unless otherwise stated, "conjugation" refers to the covalent connection between two or more chemical parts, each having a specific function; correspondingly, "conjugated compound" refers to a compound formed by the covalent connection of these chemical parts. Further, "siRNA conjugated compound" refers to a compound formed by the covalent attachment of one or more chemical parts having a specific function to siRNA. siRNA conjugated compounds should be understood, depending on the context, as a collective term for multiple siRNA conjugated compounds or a siRNA conjugated compound represented by a specific chemical formula. In the context of this disclosure, "conjugated molecule" should be understood as a specific compound that can be reactively conjugated to siRNA to ultimately form the siRNA conjugated compounds of this disclosure. Generally, the conjugation group comprises at least one pharmaceutically acceptable target group and / or delivery aid group. In some embodiments, the conjugation group further comprises a linker, and the linker and / or the target group or the delivery aid group are sequentially linked. In some embodiments, there are 1-6 target groups. In some embodiments, there are 2-4 target groups. The siRNA molecule can be non-covalently or covalently conjugated to the conjugation group, for example, it can be covalently conjugated to the conjugation group. The conjugation site of the siRNA and the conjugation group can be at the 3' or 5' end of the siRNA's sense strand, at the 5' end of the antisense strand, or within the siRNA's internal sequence. In some embodiments, the conjugation site of the siRNA and the conjugation group is at the 3' end of the siRNA's sense strand. In some embodiments, the conjugation group can be attached to any position of a nucleotide, such as a phosphate group, a 2'-, 3'-, or 5'-hydroxyl group of a ribose, or a base. In some embodiments, the conjugate group may also be attached to a 3'-hydroxyl group, in which case the nucleotides are linked by a 2'-5' phosphodiester bond. When the conjugate group is attached to the end of the siRNA chain, it is usually attached to a phosphate group of the nucleotide; when the conjugate group is attached to the inner sequence of the siRNA, it is usually attached to a ribose ring or a base. Various connection methods can be found in the reference: 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. In some embodiments, the siRNA and the conjugate group are linked by acid-labile or reducible chemical bonds. These bonds can degrade in the acidic environment of the endosomes, thus freeing the siRNA. For non-degradable conjugates, the conjugate group can be attached to the positive and negative strands of the siRNA to minimize the impact of the conjugate on the siRNA's activity. The targeting group can be linked to the siRNA molecule via a suitable adapter. Those skilled in the art can select an appropriate adapter based on the specific type of the targeting group. For example, when the targeting group is a group that targets receptors on the surface of hepatocytes, the types of adapters, the types of targeting groups, and the way they are linked to the siRNA can be found in the disclosure of WO2015006740A2, the entire contents of which are incorporated herein by reference. In some embodiments, the pharmaceutically acceptable targeting group may be a ligand conventionally used in the field of siRNA delivery, such as the various ligands described in WO2009082607A2, the entire disclosure of which is incorporated herein by reference. In some embodiments, each ligand is independently selected from a ligand capable of binding to a cell surface receptor. In some embodiments, at least one targeting ligand targets a receptor mediated by delivery to the central nervous system (CNS) tissue. In some embodiments, at least one or each of the targeting groups is selected from a ligand capable of binding to the mammalian hepatocyte surface receptor (ASGPR). The types of these ligands are well known to those skilled in the art, and their function is to bind to specific receptors on the surface of target cells, mediating the delivery of ligand-linked siRNA to the target cells. In some embodiments, at least one of the targeting groups is selected from a ligand capable of binding to a cell surface receptor expressing RPTOR. In some embodiments, each of the targeting groups is selected from a ligand capable of binding to a cell surface receptor expressing RPTOR. In some embodiments, at least one targeting group is a ligand targeting a receptor on the surface of hepatocytes. In some embodiments, at least one or each targeting group is a ligand that targets the desialyl glycoprotein receptor on the surface of hepatocytes. In some embodiments, each of the target groups is independently a desialylated glycoprotein or a sugar. In some embodiments, each of the target groups is independently a desialylated glycoprotein, such as asialostromococcus (ASOR) or asialofetuin (ASF). In some embodiments, each of the target groups is independently selected from D-mannopyranoside, L-mannopyranoside, D-arabinose, D-xylfuranose, L-xylfuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannopyranoside, β-D-mannopyranoside, α-D-mannopyranoside, β-D-mannopyranoside, α-D-glucose pyranopyranoside, β-D-glucose pyranopyranoside, α-D-glucose pyranopyranoside, β-D-glucose pyranopyranoside, α- D-Furfuranose, β-D-Furfuranose, α-D-Fructose, α-D-Fructose, α-D-Galactopyranose, β-D-Galactopyranose, α-D-Galactopyranose, β-D-Galactopyranose, Glucosamine, Sialic acid, Galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-Amino-3-O -[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-carboxamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfonamido-D-glucopyranose, N-ethanolyl-α-neuraminic acid, 5-thio-β-D-glucopyranose, 2,3,4-tri-O-acetyl-1- One of the following groups: thio-6-O-triphenylmethyl-α-D-glucopyranoside methyl ester, 4-thio-β-D-galactopyranose, 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucopyranoside ethyl ester, 2,5-dehydrated-D-alosulfonyl, ribose, D-ribose, D-4-thioribose, L-ribose, and L-4-thioribose. In some embodiments, at least one or each of the target groups is a galactose group or an N-acetylgalactosamine group. In some embodiments, each of the target groups is an N-acetylgalactosamine group. In some embodiments, the target groups are capable of regulating the expression level of RPTOR mRNA in hepatocytes. In some embodiments, the linker in the siRNA conjugate of this disclosure has a structure as shown in formula (301): Where k is an integer from 1 to 3; L A Having a structure containing amide bonds as shown in formula (302), L BHaving a structure containing N-acylpyrrolidine as shown in formula (303), containing a carbonyl group and an oxygen atom, L C It is a linking group based on hydroxymethylaminomethane, dihydroxymethylaminomethane, or trihydroxymethylaminomethane; Where, n 302 q 302 and p 302 Each is an independent integer from 2 to 6; optionally, n 302 q 302 and p 302 Each can be 2 or 3 independently; n 303 n is an integer between 4 and 16, optionally n 303 For integers between 8 and 12, This indicates the site where the group is covalently linked. In the aforementioned connector, each L A Each of the target groups is connected via an ether bond and via L C The oxygen atom of the hydroxyl group in some of the middle groups is related to L. C Partially linked by ether bonds; L B Through the carbonyl group in formula (303) and L C The nitrogen atom of the amino group in the middle is linked by an amide bond, and is linked to the siRNA by an oxygen atom in formula (303) through a phosphate ester bond or a thiophosphate ester bond. In some embodiments, the siRNA conjugates provided in this disclosure have a structure as shown in formula (305): Nu represents the siRNA provided in this disclosure. In some embodiments, the linker in the siRNA conjugate of this disclosure has the structure shown in formula (306): Where, n 306 For each p, the integer is between 0 and 3. 306 Independently, integers from 1 to 6. The site indicates a covalently linked group; the linking group is connected to the target group by an ether bond formed by an oxygen atom marked with *; the linking group is connected to the siRNA by at least one of the oxygen atoms marked with # forming a phosphate ester bond or a thiophosphate ester bond, and the remaining oxygen atoms marked with # are connected to hydrogen atoms to form hydroxyl groups, or connected to C1-C3 alkyl groups to form C1-C3 alkoxy groups; In some embodiments, the siRNA conjugates of this disclosure have a structure as shown in formula (307): Nu represents the siRNA group provided in this disclosure. In some embodiments, the siRNA conjugates of this disclosure have the structure shown in formula (308): in, n1 is an integer selected from 1 to 3, and n3 is an integer selected from 0 to 4; Each m1, m2, or m3 is an independent integer selected from 2 to 10; R 10 R 11 R 12 R 13 R 14 Or R 15 Each is independently H, or selected from the group consisting of C1-C. 10 Alkyl, C1-C 10 Halogenated alkyl groups and C1-C 10 Alkoxy; R3 has the structure shown in Equation A59: Wherein, E1 is OH, SH or BH2, and Nu represents the siRNA group provided in this disclosure; R2 is a straight-chain alkylene group with a length of 1-20 carbon atoms, wherein one or more carbon atoms are optionally replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, CH=N, S(O)2, C2-C 10 alkenyl, C2-C 10 Ethyne group, C6-C 10 aryl, C3-C 18 Heterocyclic groups and C5-C 10 Heteroaryl; and wherein R2 may optionally have any one or more substituents 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 Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10Alkyl) (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), -CON (C1-C) 10 Alkyl) (C1-C 10 alkylphenyl), -CONH(C1-C 10 alkylphenyl), -CONH2, -NHC(O)(C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 Alkyl)C(O)(C1-C 10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), -C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, -C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (halogenated alkyl); Each L1 is independently a straight-chain alkylene group with a length of 1-70 carbon atoms, wherein one or more carbon atoms may optionally be replaced by any one or more groups selected from the group consisting of: C(O), NH, O, S, CH=N, S(O)2, C2-C 10 alkenyl, C2-C 10 Ethyne group, C6-C 10 Aromatic, C3-C 18 Heterocyclic groups and C5-C 10 A heteroaryl group; and wherein L1 optionally has any one or more substituents from the group consisting of: C1-C 10 Alkyl, C6-C10 Aryl, C5-C 10 heteroaryl, C1-C 10 Halogenated alkyl, -OC1-C 10 Alkyl, -OC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-OH, -OC1-C 10 Halogenated alkyl, -SC1-C 10 Alkyl, -SC1-C 10 Alkylphenyl, -C1-C 10 Alkyl-SH, -SC1-C 10 Halogenated alkyl groups, halogenated substituents, -OH, -SH, -NH2, -C1-C 10 Alkyl-NH2,-N(C1-C) 10 Alkyl) (C1-C 10 alkyl), -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl) (C1-C 10 alkylphenyl), -NH(C1-C 10 Alkylphenyl), cyano, nitro, -CO2H, -C(O)O(C1-C 10 Alkyl), -CON (C1-C) 10 Alkyl) (C1-C 10 Alkyl), -CONH (C1-C) 10 Alkyl group), -CONH2, -NHC(O) (C1-C 10 alkyl), -NHC(O)(phenyl), -N(C1-C 10 Alkyl)C(O)(C1-C 10 Alkyl), -N(C1-C 10 alkyl)C(O)(phenyl), -C(O)C1-C 10 Alkyl, -C(O)C1-C 10 Alkylphenyl, -C(O)C1-C 10 Haloalkyl, -OC(O)Cl-C 10 Alkyl group, -SO2 (C1-C) 10 alkyl), -SO2 (phenyl), -SO2 (C1-C 10 Halogenated alkyl groups), -SO2NH2, -SO2NH (C1-C 10 alkyl), -SO2NH (phenyl), -NHSO2 (C1-C 10 Alkyl), -NHSO2 (phenyl) and -NHSO2 (C1-C) 10 (halogenated alkyl); Indicates the site where groups are covalently linked; M1 represents a targeting group, the definition of which and the range of possible selections are the same as described above. In some embodiments, each M1 is independently selected from a group of ligands that have affinity for desialylate glycoprotein receptors on the surface of mammalian liver cells. Those skilled in the art will understand that, although L1 is defined as a linear alkylene group for convenience, it may not be a linear group or may have a different name, such as an amine or alkenyl group resulting from the above substitutions and / or replacements. For the purposes of this disclosure, the length of L1 is the number of atoms in the chain connecting the two attachment points. For this purpose, a ring (such as a heterocyclic or heteroaryl group) obtained by replacing a carbon atom of the linear alkylene group is counted as one atom. When M1 is a ligand with affinity for the desialyl glycoprotein receptor on the surface of mammalian liver cells, in some embodiments, n1 can be an integer from 1 to 3, and n3 can be an integer from 0 to 4, ensuring that the number of M1 ligands in the conjugate is at least 2; in some embodiments, n1 + n3 ≥ 2, which ensures that the number of M1 ligands is at least 3, making it easier for the M1 ligand to bind to the desialyl glycoprotein receptor on the liver surface, thereby promoting the conjugate's entry into the cell via endocytosis. Experiments show that when the number of M1 ligands is greater than 3, the ease of binding of the M1 ligand to the desialyl glycoprotein receptor on the liver surface does not increase significantly. Therefore, considering factors such as ease of synthesis, structural / process cost, and delivery efficiency, in some embodiments, n1 is an integer from 1 to 2, n3 is an integer from 0 to 1, and n1 + n3 = 2 - 3. In some embodiments, when m1, m2, and m3 are independently selected from integers of 2 to 10, the spatial positions between the multiple M1 ligands can be adapted to the binding of the M1 ligand to the liver surface desialylate glycoprotein receptor. In order to make the conjugates provided in this disclosure simpler, easier to synthesize, and / or reduce costs, in some embodiments, m1, m2, and m3 are each independently an integer of 2 to 5, and in some embodiments, m1 = m2 = m3. Those skilled in the art will understand that when R 10 R 11 R 12 R 13 R 14 and R 15 Each is independently selected from H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl groups and C1-C 10 Using one of the alkoxy groups will not change the properties of the conjugates disclosed herein, and the objectives of this disclosure can still be achieved. In some embodiments, R 10 R 11 R 12R 13 R 14 and R 15 Each is independently selected from H, methyl, and ethyl. In some embodiments, R 10 R 11 R 12 R 13 R 14 and R 15 All are H. According to the siRNA conjugate provided in this disclosure, R3 is a group with the structure shown in Formula A59, wherein E1 is OH, SH or BH2. Based on the consideration of the availability of raw materials, in some embodiments, E1 is OH or SH. In some implementations, R2 is chosen to enable the connection between the N atom on the nitrogen-containing framework and A59. In the context of this disclosure, a "nitrogen-containing framework" refers to a framework with R... 10 R 11 R 12 R 13 R 14 and R 15 The structure consists of a chain-like structure in which carbon atoms and nitrogen atoms are interconnected. Therefore, R2 can be any linking group capable of connecting the A59 group to the nitrogen-containing backbone in a suitable manner. In some embodiments, when the siRNA conjugates of this disclosure are prepared by solid-phase synthesis, the R2 group needs to contain both a linking site connecting to the nitrogen-containing backbone and a linking site connecting to the p atom in R3. In some embodiments, the site in R2 connecting to the nitrogen-containing backbone forms an amide bond with the nitrogen atom, and the site connecting to the p atom in R3 forms a phosphate ester bond with the p atom. In some embodiments, the length of R2 is 2-20 atoms, or 4-15 atoms. In some embodiments, R2 is B5, B6, B5', or B6'. in, This indicates the site where a group is covalently bonded. The value of q2 can be an integer from 1 to 10. In some implementations, q2 is an integer from 1 to 5. The function of L1 is to link the M1 ligand to the N on the nitrogen-containing backbone, providing targeting functionality for the siRNA conjugate of this disclosure. In some embodiments, L1 is selected from one or more linkage combinations of groups of formulas A1-A26. In some embodiments, L1 is selected from one or more linkage combinations of A1, A4, A5, A6, A8, A10, A11, and A13; in some embodiments, L1 is selected from a linkage combination of at least two of A1, A4, A8, A10, and A11; in some embodiments, L1 is selected from a linkage combination of at least two of A1, A8, and A10. In some embodiments, the length of L1 can be 3-25 atoms, 3-20 atoms, 4-15 atoms, or 5-12 atoms. In some embodiments, the length of L1 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, or 60 atoms. In some embodiments, j1 is an integer from 2 to 10, and in some embodiments, j1 is an integer from 3 to 5. In some embodiments, j2 is an integer from 2 to 10, and in some embodiments, j2 is an integer from 3 to 5. R' is a C1-C4 alkyl group, and in some embodiments, R' is one of methyl, ethyl, and isopropyl. Ra is one of A27, A28, A29, A30, and A31, and in some embodiments, Ra is A27 or A28. Rb is a C1-C5 alkyl group, and in some embodiments, Rb is one of methyl, ethyl, isopropyl, and butyl. In some embodiments, j1, j2, R', Ra, and Rb in formulas A1-A26 are selected respectively to achieve N-linking of the M1 ligand to the nitrogen-containing backbone and to make the spatial positions between the M1 ligands more suitable for the binding of the M1 ligand to the liver surface desialyl glycoprotein receptor. In some embodiments, the siRNA conjugates of this disclosure have structures shown in formulas (403), (404), (405), (406), (407), (408), (409), (410), (411), (412), (413), (414), (415), (416), (417), (418), (419), (420), (421), or (422): Wherein, Nu represents the siRNA group of this disclosure, such as the siRNA group formed by the siRNA provided in this disclosure. In some embodiments, the siRNA group is a double-stranded siRNA group, and the P atom shown in the above structural formula is covalently linked to the 3' terminal nucleotide of the positive strand of the siRNA group. In some embodiments, the P atom shown in formulas (403)-(422) is covalently linked to the oxygen atom remaining at the 3' position of the ribose hydroxyl group of the positive strand of the siRNA group represented by Nu, after removing one hydrogen atom. In some embodiments, the P atom in Formula A59 can be attached to any possible position in the siRNA sequence; for example, the P atom in Formula A59 can be attached to any nucleotide of the siRNA's sense or antisense strand. In some embodiments, the P atom in Formula A59 is attached to any nucleotide of the siRNA's sense strand. In some embodiments, the P atom in Formula A59 is attached to the end of the siRNA's sense or antisense strand; in some embodiments, the P atom in Formula A59 is attached to the end of the siRNA's sense strand. The end refers to the first four nucleotides of the sense or antisense strand counted from one end. In some embodiments, the P atom in Formula A59 is attached to the end of the siRNA's sense or antisense strand; in some embodiments, the P atom in Formula A59 is attached to the 3' end of the siRNA's sense strand. When attached to the above-described positions on the sense strand of the siRNA, the conjugate provided in this disclosure, upon entering the cell and unwinding, can release the individual siRNA antisense strand to inhibit RPTOR mRNA expression via the RNAi mechanism. The P atom in Formula A59 can be attached to any possible position on the nucleotide in the siRNA, such as the 5' position, 2' position, 3' position, or base of the nucleotide. In some embodiments, the P atom in Formula A59 can be attached to the 2', 3', or 5' position of the nucleotide in the siRNA by forming a phosphodiester bond. In some embodiments, the P atom in Formula A59 is attached to the oxygen atom formed after the dehydrogenation of the 3'-hydroxyl group of the 3'-terminal nucleotide of the siRNA positive strand, or the P atom in Formula A59 is attached to the nucleotide by substituting a hydrogen atom in the 2'-hydroxyl group of a nucleotide in the siRNA positive strand, or the P atom in Formula A59 is attached to the nucleotide by substituting a hydrogen atom in the 5'-hydroxyl group of the 5'-terminal nucleotide of the siRNA positive strand. In some embodiments, at least one targeting group is a ligand of a receptor on the surface of a target cell targeting the CNS. In some embodiments, each targeting group is a ligand of a receptor on the surface of a target cell targeting the CNS. In some embodiments, the ligand may be conjugated to siRNA to achieve specific CNS tissue delivery. In some embodiments, at least one targeting group is a peptide ligand. In some embodiments, each targeting group is a peptide ligand. In some embodiments, the targeting ligand is selected from the group consisting of: angiotensin-2, lipoprotein receptor-associated protein (LRP) ligand, bEnd.3 cell-binding ligand, transferrin receptor (TfR) ligand, mannose receptor ligand, glucose transporter, and LDL receptor ligand. For example, various targeting groups described in CN112400018A (such as...)

[0856] The ligands described in the paragraph are incorporated herein by reference in their entirety. In some embodiments, there are 1-6 polypeptide ligands. In some embodiments, there are 2-4 polypeptide ligands. In some embodiments, each polypeptide ligand is linked to the siRNA via its N-terminus; that is, during the synthesis of the siRNA conjugate, the polypeptide is conjugated via the amino group at its N-terminus and the linking group (see WO2023185946 for details on the linking of polypeptide ligands to double-stranded functional oligonucleotides). Common conjugation methods include chemical reactions known to those skilled in the art, such as dehydration condensation reactions and click chemistry reactions. In some embodiments, each of the polypeptide ligands is linked to either the sense or antisense strand of the siRNA. In some embodiments, a portion of the polypeptide ligands are linked to the sense strand of the siRNA, and a portion of the polypeptide ligands are linked to the antisense strand of the siRNA. In some embodiments, all polypeptide ligands are linked to the antisense strand of the siRNA. In some embodiments, all polypeptide ligands are linked to the sense strand. In some embodiments, at least one of the polypeptide ligands is linked to the first nucleotide at the 3' or 5' end of the sense or antisense strand. In some embodiments, at least two of the polypeptide ligands are linked to the first nucleotide at the 3' or 5' end of the antisense strand, respectively. To obtain better pharmaceutical activity, in some embodiments, at least one of the polypeptide ligands is linked to the 3' end of the sense strand, and at least one polypeptide ligand is linked to the 5' end of the sense strand. In some embodiments, each polypeptide ligand is a polypeptide ligand containing the sequence shown in SEQ ID NO:134 or SEQ ID NO:135. HAIYPRH (SEQ ID NO:134); HRPYIAH (SEQ ID NO:135). In some embodiments, each polypeptide ligand is a polypeptide ligand as shown in SEQ ID NO:134 or SEQ ID NO:135. In some embodiments, for ease of synthesis, each polypeptide ligand in the siRNA conjugate is a polypeptide ligand as shown in SEQ ID NO:134; or, each polypeptide ligand is a polypeptide ligand as shown in SEQ ID NO:135. To obtain higher pharmaceutical activity of the siRNA conjugate, in some embodiments, at least one amino acid in the polypeptide ligand is a modified amino acid. In some embodiments, at least 50% of the amino acids in the polypeptide ligand are modified amino acids. In some embodiments, all amino acids in the polypeptide ligand are modified amino acids. In the foregoing and hereinafter of this disclosure, the term "modified amino acid" includes constructing the polypeptide ligand of this disclosure by replacing a natural L-amino acid with a D-amino acid; or by substituting a natural L-amino acid with an amino acid mimic, which includes structural analogs of the amino acid, such as salts or esters of a natural amino acid. Furthermore, the C-terminus of the polypeptide may be a carboxyl group or an amide group obtained by amidation of a carboxyl group, or other substances generated by incorporating one of the aforementioned amino acid mimics. Additionally, one or more natural peptide bonds in the aforementioned peptide may be substituted by any one of the following groups, including but not limited to: sulfonamides, reverse amides, aminooxyl-containing bonds, esters, alkyl ketones, α,α-difluoroketones, α-fluoroketones, and peptide-like bonds (N-alkylated glycine amide bonds). Furthermore, the side chains of the natural amino acids in the polypeptide ligands may be substituted amino acids, for example, substituted by one of 4-fluorophenylalanine, 4-phenyl-lysine, 3-aminoproline, 2-nitrotyrosine, or N-alkylhistidine; or β-branched amino acids or β-branched amino acid mimics having a chirality opposite to that of the natural amino acid at the β-side chain carbon atom, such as allothreonine, alloleucine, and their derivatives. Representative modified amino acids are disclosed in Baran et al., Biochemistry, 2017, 56(30):3863-3873, and Mehta et al., Tetrahedron Letters, 2017, 58(14):1357-1372, which are incorporated herein by reference in their entirety. In some embodiments, the pharmaceutically acceptable delivery aid group may be a lipophilic group, comprising an aliphatic compound or an alicyclic compound. In some embodiments, the lipophilic group comprises a straight-chain aliphatic hydrocarbon, a branched-chain aliphatic hydrocarbon, or a steroid. In some embodiments, the lipophilic group contains a saturated or unsaturated C4-C30 hydrocarbon chain. In some embodiments, the lipophilic group contains a saturated or unsaturated C6-C18 hydrocarbon chain (e.g., a straight-chain C6-C18 alkyl or alkenyl group). In some embodiments, the lipophilic group contains a saturated or unsaturated C16 hydrocarbon chain (e.g., a straight-chain C16 alkyl or alkenyl group). In some embodiments, the lipophilic group is a C6-C30 aliphatic acyl group, where the C6-C30 aliphatic acyl group refers to the atomic group remaining after removing the hydroxyl group from a C6-C30 fatty acid. In some embodiments, the lipophilic group is conjugated to siRNA in a non-covalent or covalent manner. In some embodiments, the conjugation site of the lipophilic group to siRNA is at the 3' or 5' end of the siRNA's sense strand. In some embodiments, the conjugation site of the lipophilic group to siRNA is at the 5' end of the antisense strand. In some embodiments, the conjugation site of the lipophilic group to siRNA may also be within the internal sequence of the siRNA. In some implementations, the lipophilic group is attached to the phosphate group, ribose ring, or base of the nucleotide.In some embodiments, when the lipophilic group is conjugated to a nucleotide base, the preferred position is one that does not interfere with the hydrogen bonding interactions required for base pairing. In some embodiments, the lipophilic group is attached to a phosphate group, a 2'-hydroxyl group, or a base of the nucleotide. In some embodiments, the lipophilic group may be conjugated to a ribose ring via a 2'-hydroxyl group. Various methods for attaching the delivery auxiliary group to siRNA are well known to those skilled in the art, such as the various preparation methods described in CN112400018A (e.g.).

[1053] ~

[1065] The preparation method described in the paragraph is incorporated herein by reference in its entirety. In some embodiments, the lipophilic group is conjugated to the siRNA via one or more linkers. In some embodiments, for ease of synthesis, the lipophilic group is a saturated straight-chain hexadecyl (C16) alkyl group. In some embodiments, to simplify the synthetic process, the lipophilic group is linked to the siRNA by substituting a hydrogen atom in the 2' hydroxyl group of the ribose ring in the nucleotide. The inventors of this disclosure have unexpectedly discovered that the siRNA conjugates of this disclosure exhibit significantly improved stability in plasma and also demonstrate higher RPTOR mRNA silencing activity. In some embodiments, the siRNA of this disclosure can be one of the siRNAs shown in Table 1. Using these siRNAs, the siRNA conjugates of this disclosure exhibit even higher RPTOR mRNA silencing activity. Table 1. siRNA disclosed herein In this context, uppercase letters C, G, U, and A represent the base composition of the nucleotide; lowercase letter m indicates that the nucleotide adjacent to the left of m is methoxylated; lowercase letter f indicates that the nucleotide adjacent to the left of f is fluorinated; lowercase letter s indicates that the two nucleotides to the left and right of s are linked by a thiophosphate group; P1 indicates that the nucleotide adjacent to the right of P1 is a 5'-phosphate nucleotide or a 5'-phosphate analog. In some embodiments, P1 represents a specific modification VP, Ps, or P, where the letter combination VP indicates that the nucleotide adjacent to the right of VP is a vinyl phosphate (5'-(E)-vinylphosphonate, E-VP) modified nucleotide, the letter combination Ps indicates that the nucleotide adjacent to the right of Ps is a thiophosphate modified nucleotide, and the uppercase letter P indicates that the nucleotide adjacent to the right of P is a 5'-phosphate nucleotide. In the siRNA, pharmaceutical composition, or siRNA conjugate described in this disclosure, each adjacent nucleotide is linked by a phosphodiester bond or a phosphothiodiester bond. The non-bridging oxygen or sulfur atom in the phosphodiester bond or phosphothiodiester bond carries a negative charge and can exist in the form of a hydroxyl or mercapto group. The hydrogen ion in the hydroxyl or mercapto group can also be partially or completely replaced by a cation. The cation can be any cation, such as a metal cation, ammonium ion (NH4+), etc. + The siRNA is one of the organic ammonium cations. Further, the conjugated group may also contain groups capable of forming salts, such as phosphate groups. For the purpose of improving solubility and / or bioavailability, in one embodiment, the pharmaceutically acceptable salt is a partial or complete water-soluble salt of the siRNA or the siRNA conjugate. In some embodiments, the water-soluble salt may be an amine salt, an alkali metal salt, or an alkaline earth metal salt. In some embodiments, the amine salt is selected from one or more of ammonium salts, methylamine salts, tertiary amine salts, and quaternary ammonium salts; the alkali metal salt is selected from potassium or sodium salts; and the alkaline earth metal salt is selected from calcium or magnesium salts. In some embodiments, the tertiary amine salt is triethylamine salt, triisopropylamine salt, or N,N-diisopropylethylamine salt. Therefore, the siRNA or siRNA conjugate of this disclosure may exist at least partially in the form of a salt. In one embodiment, the non-bridging oxygen or sulfur atom in the phosphodiester bond or thiophosphodiester bond is at least partially bonded to a sodium ion, and the siRNA or siRNA conjugate described herein exists in the form of a sodium salt or a partially sodium salt. In some embodiments, a pharmaceutically acceptable salt of the siRNA or siRNA conjugate is a mixture of a methylamine salt and an ammonium salt of the siRNA or siRNA conjugate. The synthesis of the siRNA conjugates disclosed herein is well known to those skilled in the art. Modified nucleotide groups can be introduced into the siRNAs described herein using appropriately modified nucleoside monomers. Methods for preparing appropriately modified nucleoside monomers and for introducing modified nucleotide groups into siRNAs are also well known to those skilled in the art. All modified nucleoside monomers are commercially available or prepared using known methods. The siRNA conjugates disclosed herein can be prepared using any reasonable synthetic route. For example, for a conjugate molecule containing a targeting group and an active reactive group that can react with phosphorus amide to form a covalently linked group, the active group in the conjugate molecule can first be protected with a protecting agent and then linked to a solid-phase support. Subsequently, using a phosphorus amide solid-phase synthesis method, nucleoside monomers are linked one by one in the 3' to 5' direction according to the nucleotide types and sequence of the siRNA's sense and antisense strands. The linking of each nucleoside monomer includes four steps: deprotection, coupling, capping, oxidation, or sulfidation. The sense and antisense strands of the siRNA are then separated and annealed to obtain the siRNA conjugates disclosed herein. In some embodiments, the targeting group is a polypeptide ligand group. The siRNA conjugate of this disclosure is prepared by annealing a single-chain conjugate containing a polypeptide ligand group with another single chain of the siRNA conjugate of this disclosure to form a double-chain siRNA conjugate, and then separating to obtain the siRNA conjugate of this disclosure. In some embodiments, the single-chain conjugate containing a polypeptide ligand group can be prepared by contacting a compound with a thiol exchange group as shown in formula (106) and a polypeptide ligand with a structure as shown in formula (107) in a solvent under thiol-disulfide bond exchange reaction conditions, and then separating to obtain the single-chain conjugate containing the polypeptide ligand group. Where Nu' represents the sense or antisense strand of the siRNA, and R 106 It is a thiol exchanger residue. In some embodiments, R 106 C7-C 12 Aryl or heteroaryl. In some embodiments, R 106 It is 2-pyridyl. m 106 It is an integer from 1 to 10; in some implementations, m 106 It is an integer between 3 and 6. In some implementations, m 106 It can be 4 or 6. Among them, R 107 It is -NH2 or -OH, n 107 PP is an integer from 1 to 10, representing the polypeptide ligand. In some embodiments, n 107 It is an integer from 1 to 6. In some implementations, n 107 It can be 4 or 6. The solvent and reaction conditions for the mercapto-disulfide bond exchange reaction are commonly used solvents and reaction conditions in the art for mercapto-disulfide bond exchange reactions, such as reacting for 2-10 hours, for example, 4-8 hours, in the presence of a 0.05-1M ammonium acetate aqueous solution at room temperature and pressure. The ratio of the solvent to the compound of formula (106) can be 100:1-2000:1 L / mol; the molar ratio of the compound of formula (107) to the compound of formula (106) can be 1:1-15:1, for example, 4:1-10:1. The single-chain conjugate containing the polypeptide ligand group can be separated from the reaction mixture using any suitable separation method. In some embodiments, the solvent can be removed by evaporation, followed by separation by chromatography. For example, separation can be performed using a C18 reverse-phase column as the stationary phase and a gradient elution using a solvent of 100 mM TEAA (pH = 7.0-7.3):acetonitrile at a ratio of 5%-75% (v / v). In some embodiments, the solvent can be directly removed to obtain a crude product of the single-chain conjugate containing the polypeptide ligand group, which can be directly used in subsequent reactions. The polypeptide ligand represented by formula (107) can be prepared by methods well known to those skilled in the art. In some embodiments, the polypeptide ligand represented by formula (107) can be readily obtained through commercial customization. Those skilled in the art can obtain the compound represented by formula (106) by various methods. In some embodiments, the compound represented by formula (106) can be prepared by contacting the compound represented by formula (108) with the mercapto-disulfide bond exchanger represented by formula (111) in a solvent under mercapto-disulfide bond exchange reaction conditions, and then separating the compound represented by formula (106). Where, m 106 Nu', R 106 The definition and selection range are the same as those described above. The selection of the solvent and the conditions for the mercapto-disulfide bond exchange reaction are the same as described above. The molar ratio of compound (111) to compound (108) is in large excess, for example, it can be 10:1-1000:1, and in some embodiments it is 50:1-200:1. Compound (106) can be separated from the reaction mixture using any suitable separation method. In some embodiments, compound (106) can be separated by evaporation to remove the solvent, followed by chromatographic separation, for example, under the following conditions: gel desalting purification in a purifier using a 20% (v / v) aqueous ethanol solution as the mobile phase, and collecting the product eluent at a wavelength of 280 nm. In some embodiments, the solvent can be removed directly by filtration to obtain a crude product of compound (106), which can be used directly in subsequent reactions. The mercapto-disulfide bond exchange reagent represented by formula (111) can be prepared by methods well known to those skilled in the art. In some embodiments, the compound represented by formula (111) is 2-2'-dithiopyridine, which is commercially available. Those skilled in the art can obtain compounds of formula (108) by various methods. In some embodiments, compounds of formula (108) can be prepared by contacting a compound of formula (109) with a reducing agent in an aqueous solution of a reducing agent under reduction reaction conditions, and then separating the compound of formula (108). In some embodiments, the reducing agent is a reducing agent that reduces disulfide bonds to thiol groups. In some embodiments, the reducing agent is TCEP. The reduction reaction is carried out at room temperature and pressure in an aqueous solution of TCEP. Those skilled in the art can obtain the thiol-containing polypeptide ligand of formula (107) by various methods. In some embodiments, the thiol-containing polypeptide ligand of formula (107) is prepared by contacting the polypeptide ligand with a natural or modified cysteine ​​or cysteine ​​analogue having the structure shown in formula (110) under the reaction conditions of amino acid dehydration condensation, and then isolating to obtain the thiol-containing polypeptide ligand of formula (107). In some embodiments, the N-terminus or C-terminus of the polypeptide ligand of formula (107) is connected to a thiol-containing group, thereby the prepared single-chain conjugate containing the polypeptide ligand is connected to the N-terminus or C-terminus of the polypeptide ligand. In some embodiments, the preparation method includes protecting the N-terminal amino group or C-terminal carboxyl group of the polypeptide ligand to prepare a reaction in which only the N-terminus or C-terminus is connected to the thiol group. Methods for protecting and deprotecting amino or carboxyl groups are known to those skilled in the art. Among them, R 107 and n 107 The definition is the same as that mentioned above. The reaction conditions for the amino acid dehydration condensation are those commonly used in the art. Furthermore, the methods for synthesizing the polypeptide ligand itself, i.e., methods for synthesizing polypeptides containing specific amino acid sequences, including methods for synthesizing polypeptide ligands containing modified amino acids, are well-known to those skilled in the art, and mature, publicly available commercial customization services are currently available. In some embodiments, single-chain conjugates containing polypeptide ligand groups can be prepared by contacting a compound containing a single-chain oligonucleotide as shown in formula (106A) with a polypeptide ligand as shown in formula (107A) in a solvent under mercapto-disulfide bond exchange reaction conditions, and then separating to obtain single-chain conjugates containing polypeptide ligand groups. Where Nu' represents the group formed by the sense or antisense strand of the siRNA, m 106 It is an integer from 1 to 10; in some implementations, m 106It is an integer between 3 and 6. In some implementations, m 106 It can be 4 or 6. Among them, R 107 It is -NH2 or -OH, n 107 The integers are 1-10, PP represents the polypeptide ligand group, and R... 106 It is a thiol exchanger residue. In some embodiments, R 106 C7-C 12 Aryl or heteroaryl. In some embodiments, R 106 It is 2-pyridyl. In some embodiments, n 107 It is an integer from 1 to 6. In some implementations, n 107 The value is 4 or 6. The solvent and thiol-disulfide bond exchange reaction conditions are those commonly used in the art for thiol-disulfide bond exchange reactions. In some embodiments, the lipophilic group is covalently linked to a nucleotide in the siRNA. In some embodiments, the lipophilic group is linked to the 2' position of the nucleotide ribose ring, and the siRNA conjugate can be obtained by linking nucleoside monomers one-time according to the nucleotide sequence in the siRNA single strand under the same phosphoramidite solid-phase synthesis conditions as described above, wherein at least one nucleoside monomer is a phosphoramidite monomer with the lipophilic group linked to the 2' position of the sugar ring. In some embodiments, the lipophilic group is a saturated or unsaturated, straight-chain or branched hydrocarbon group with a length of 15-25 carbon atoms. Those skilled in the art can obtain the lipophilic group in various ways; in some embodiments, the lipophilic group is commercially available. Those skilled in the art can activate the lipophilic group in various ways; in some embodiments, a haloalkane can be used as the lipophilic group containing the activating group. The phosphorus amide monomer with the lipophilic group attached is readily available to those skilled in the art. In some embodiments, the phosphorus amide monomer is synthesized using the method disclosed in Preparation Example 1 of WO2020257194Al. In some embodiments, the targeting group is a group formed from a compound of formula (403), and the preparation of the siRNA conjugate can also be performed with reference to the disclosures in existing literature. For example, WO2019010274A1 describes a method for sequentially linking a linker group with a specific structure and a targeting ligand to siRNA via a reaction in Example 1. The entire contents of WO2019010274A1 are incorporated herein by reference. The present disclosure includes siRNA, pharmaceutical compositions containing siRNA, and applications of siRNA conjugates. In some embodiments, this disclosure provides the use of one or more of the siRNA, pharmaceutical compositions, and siRNA conjugates of this disclosure in the preparation of a medicament for treating diseases or symptoms associated with RPTOR function regulation. In some embodiments, the diseases or symptoms associated with RPTOR function regulation are diseases associated with mTORC1 activation and abnormal autophagy function. In some embodiments, the neurodegenerative diseases or symptoms are Alzheimer's disease and / or Parkinson's disease, preferably Alzheimer's disease. In some embodiments, the disease associated with abnormal autophagy function is non-alcoholic steatohepatitis. In some embodiments, this disclosure provides a method for preventing and / or treating diseases or symptoms related to RPTOR function regulation, the method comprising administering an effective amount of the disclosed siRNA and / or pharmaceutical composition and / or siRNA conjugate to a subject in need. By administering the siRNA active ingredient of this disclosure to a subject in need, the purpose of preventing and / or treating the induced disease can be achieved through the mechanism of RNA interference. Therefore, one or more of the siRNA, pharmaceutical composition, and siRNA conjugate of this disclosure may be used for the prevention and / or treatment of diseases or symptoms related to RPTOR function regulation, or for the preparation of medicaments for the prevention and / or treatment of diseases or symptoms related to RPTOR function regulation. As used herein, the term "administration" refers to the placement of one or more of the siRNA, pharmaceutical composition, and siRNA conjugate of this disclosure into a subject by means of a method or route that at least partially targets one or more of the siRNA, pharmaceutical composition, and siRNA conjugate of this disclosure at a desired site to produce a desired effect. Routes of administration suitable for the methods of this disclosure include local administration and systemic administration. Generally, local administration results in the delivery of one or more of the siRNA, pharmaceutical composition, and siRNA conjugate to a specific site compared to the systemic circulation of the subject; while systemic administration results in the delivery of one or more of the siRNA, pharmaceutical composition, and siRNA conjugate of this disclosure to the basic systemic circulation of the subject. Given that this disclosure aims to provide means of preventing and / or treating neurodegenerative diseases, some embodiments employ a method of administration that delivers the drug to tissues of the central nervous system. Some embodiments employ a method of administration that delivers the drug intrathecally. Some embodiments employ a method of administration that injects the drug into the cerebrospinal fluid. The drug can be administered to the subject via any suitable route known in the art, including but not limited to: oral or parenteral routes, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, airway administration (aerosol), intraventricular administration, intrathecal administration, nasal administration, rectal administration, and local administration (including oral and sublingual administration). Dosage frequency can be once or more daily, weekly, bi-weekly, tri-weekly, monthly, or annually. The dosage of the siRNA, pharmaceutical composition, or siRNA conjugate described in this disclosure can be a conventional dosage in the art, determined based on various parameters, particularly the subject's age, weight, and sex. Toxicity and efficacy can be determined in cell culture or laboratory animals using standard pharmaceutical procedures, such as determining LD50. 50 (Lethal dose that causes 50% mortality in the population) and ED 50 (In quantitative responses, this refers to the dose that elicits 50% of the maximum response intensity; in qualitative responses, it refers to the dose that elicits a positive response in 50% of the subjects.) The range of human dosages can be determined based on data obtained from cell culture analysis and animal studies. In some embodiments, the dosage of one or more formulations made from the siRNA, pharmaceutical composition, and siRNA conjugate is adjusted during administration depending on the route of administration. When administering one or more of the siRNA, pharmaceutical compositions, and siRNA conjugates described herein, for example, to male or female, 6-12 week old, 18-25 g C57BL / 6J or 30-45 g ob / ob mice, the amount of siRNA may be: (i) for the siRNA conjugate, the amount of siRNA may be 0.001-100 mg / kg body weight, in some embodiments 0.01-50 mg / kg body weight, in some embodiments 0.05-20 mg / kg body weight, in other embodiments 0.1-15 mg / kg body weight, and in other embodiments 0.1-10 mg / kg body weight; (ii) for the pharmaceutical composition formed by siRNA and a pharmaceutically acceptable carrier, the amount of siRNA may be 0.001-50 mg / kg body weight, in some embodiments 0.01-10 mg / kg body weight, in some embodiments 0.05-5 mg / kg body weight, and in some embodiments 0.1-3 mg / kg body weight. In some embodiments, this disclosure provides a method for inhibiting RPTOR mRNA expression in cells, the method comprising contacting the cells with an effective amount of the disclosed siRNA and / or pharmaceutical composition and / or siRNA conjugate, introducing the disclosed siRNA and / or pharmaceutical composition and / or siRNA conjugate into the cells, thereby inhibiting RPTOR mRNA expression in cells through an RNA interference mechanism. The method disclosed herein inhibits RPTOR mRNA expression in cells. The amount of siRNA in the provided modified siRNA, pharmaceutical composition, and / or siRNA conjugate is generally sufficient to reduce RPTOR mRNA expression and result in an extracellular concentration of 1 pM to 1 μM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM, or 0.05 nM to approximately 5 nM at the target cell surface. The amount required to achieve this local concentration will vary depending on various factors, including the delivery method, delivery site, number of cell layers between the delivery site and the target cell or tissue, and delivery route (local or systemic). The concentration at the delivery site can be significantly higher than the concentration at the surface of the target cell or tissue. Reagent test kit In one aspect, this disclosure provides a kit comprising an effective amount of one or more of the siRNA, pharmaceutical composition, and siRNA conjugate of this disclosure. In some embodiments, the kit described herein may provide one or more of siRNA, pharmaceutical compositions, and siRNA conjugates in a single container. In some embodiments, the kit described herein may include a container providing pharmaceutically acceptable excipients. In some embodiments, the kit may also contain other components, such as stabilizers or preservatives. In some embodiments, the kit described herein may contain at least one other therapeutic agent in a container other than the container providing one or more of the siRNA, pharmaceutical compositions, and siRNA conjugates described herein. In some embodiments, the kit may include instructions for mixing one or more of siRNA, pharmaceutical compositions, and siRNA conjugates with a pharmaceutically acceptable carrier and / or excipients or other ingredients (if any). In the kits disclosed herein, one or more of the siRNA, pharmaceutical composition, and siRNA conjugate, along with pharmaceutically acceptable carriers and / or excipients, may be provided in any form, such as liquid, dry, or lyophilized. In some embodiments, one or more of the siRNA, pharmaceutical composition, and siRNA conjugate, along with pharmaceutically acceptable carriers and / or excipients, are substantially pure and / or sterile. In some embodiments, sterile water may be provided in the kits disclosed herein. In the context of this disclosure, for ease of description, the siRNA, pharmaceutical composition containing siRNA, and siRNA conjugate in the embodiments are also referred to as the siRNA of this disclosure, the pharmaceutical composition of this disclosure, and the siRNA conjugate of this disclosure. The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited thereto. Example Unless otherwise specified, the reagents and culture media used in the following examples are all commercially available products, and the nucleic acid electrophoresis, real-time PCR and other operations used are all performed in accordance with the methods described in Molecular Cloning (Cold Spring Harbor LBboratory Press (1989)). Unless otherwise specified, all reagent ratios provided below are calculated on a volume basis (v / v). Data analysis was performed using Graphpad Prism 8.0 statistical analysis software. Unless otherwise specified, the reagents and culture media used in the following examples are all commercially available products, and the nucleic acid electrophoresis, real-time PCR and other operations used are all performed in accordance with the methods described in Molecular Cloning (Cold Spring Harbor Laboratory Press (1989)). Preparation Example 1: Synthesis of siRNA provided in this disclosure The sense and antisense strands of the siRNA sequences listed in Table 2 were synthesized using the solid-phase synthesis method disclosed in Example 13 of CN110959011A. Equimolar amounts of complementary sense and antisense strands from Table 2 were dissolved in DEPC water, followed by annealing to obtain siRNAa2 or siRNAa1 provided in this disclosure. The only difference is that the sense and antisense strands of the siRNA contained in the siRNA are shown in Table 2. For nucleic acid sequences containing the sense and antisense strand sequences of siRNA numbered siRNAa2 or siRNAa1 in Table 2 below, nucleoside phosphoramide monomers were ligated one by one to synthesize the sense and antisense strands of the siRNA. After synthesis, the siRNA was purified by centrifugation and ultrafiltration using a 3K (MWCO) ultrafiltration tube. Each siRNA was diluted to a concentration of 0.2 g / mL using ultrapure water (Milli-Q ultrapure water system, resistivity 18.2 MΩ*cm (25℃)). Molecular weight was then determined using liquid chromatography-mass spectrometry (LC-MS, Waters Corporation, model: LCT Premier). Theoretical value for the sense strand of siRNAa2: 6907.5, measured value: 6906.5; theoretical value for the antisense strand: 7109.8, measured value: 7108.9. Theoretical value for the sense strand of siRNAa1: 6229.22, measured value: 6228.45; theoretical value for the antisense strand: 7109.8, measured value: 7108.9. The measured values ​​were consistent with the theoretical values, indicating that the synthesized siRNA was the designed double-stranded nucleic acid sequence. Table 2 siRNA sequences In this context, uppercase letters C, G, U, and A represent the base composition of nucleotides; lowercase letter m indicates that the nucleotide adjacent to the left of letter m is a methoxy-modified nucleotide; lowercase letter f indicates that the nucleotide adjacent to the left of letter f is a fluorinated nucleotide; lowercase letter s indicates that the two nucleotides to the left and right of letter s are linked by a thiophosphate group; and uppercase letter P indicates that the nucleotide adjacent to the right of letter P is a 5'-phosphate nucleotide. After the preparation of the siRNA or reference siRNA disclosed above is completed, it is lyophilized into a solid powder for later use. Preparation Example 2: Synthesis of Conjugate 1 and Reference Conjugate NC (Comparative Preparation Example 1) Conjugate 1 and reference conjugate NC of this disclosure were obtained according to the method described in Example 1 of WO2019 / 105437A1, with the only difference being that the sense and antisense strands of the siRNA conjugates are as shown in Table 1 (siRPTORa1-M1S) and Table 2 (reference conjugate NC), respectively. For the nucleic acid sequences, according to the sense and antisense strand sequences of the siRNA in Table 1 (siRPTORa1-M1S) and Table 2 (reference conjugate NC), nucleoside phosphoramide monomers were sequentially linked to synthesize the sense and antisense strands of the siRNA conjugates. After synthesis, the conjugates were purified by centrifugation and ultrafiltration using a 3K (MWCO) ultrafiltration tube. Conjugate 1 and reference conjugate NC were diluted to a concentration of 0.2 mg / mL (as siRNA) using ultrapure water (Milli-Q ultrapure water system, resistivity 18.2 MΩ*cm (25℃)). Molecular weight was then determined by liquid chromatography-mass spectrometry (LC-MS). The results showed that the theoretical value of the sense strand of conjugate 1 was 7445.3, and the measured value was 7444.6; the theoretical value of the antisense strand was 7109.7, and the measured value was 7108.7. The measured values ​​were consistent with the theoretical values, thus confirming that the synthesized conjugate 1 is the target-designed double-stranded nucleic acid sequence containing the group shown in formula (403). The structure of conjugate 1 is shown in formula (403). In equation (403), Nu is either siRPTORa1-M1S in Table 1 or NC in Table 2 of this disclosure: siRPTORa1-M1S UmsCmsCmUmGmUmCfCfUfUmCmGmAmGmAmCmCmAmUm (SEQ ID NO:33) AmsUfsGmGmUmCfUmCmGmAmAmGmGmAfCmAfGmGmAmsUmsAm (SEQ ID NO:34), Furthermore, Nu is connected to the P atom in formula (403) via the oxygen atom at the 3' position of the ribose of the 3' terminal nucleotide of the siRNA positive strand, and conjugate 1 is a mixture of methylamine salt and ammonium salt of a compound having the structure shown in formula (403). NC is the siRNA conjugate used as a negative control, and its sense and antisense strands are not sequence homologous to RPTOR mRNA. The reference conjugate NC is a mixture of methylamine and ammonium salts having the structure shown in formula (403), wherein the conjugate group is attached to the 3' position of the ribose of the 3' terminal nucleotide of the sense strand of the siRNA represented by Nu. Preparation Example 3: Synthesis of Conjugate 2 (3-1) Preparation of compound S1 containing the positive chain of conjugate 2 Following the method described in Preparation Example 1 of WO2019105418A1, the sequence of the siRNA sense strand in conjugate 2 was synthesized by solid-phase synthesis. The sense and antisense strands of conjugate 2 are the sense and antisense strands of siRNAa1 in Table 2 of this disclosure. UmsCmsCmUmGmUmCfCfUfUmCmGmAmGmAmCmCmsAmsUm (SEQ ID NO:35) AmsUfsGmGmUmCfUmCmGmAmAmGmGmAfCmAfGmGmAmsUmsAm (SEQ ID NO:36), The difference lies only in that, during solid-phase synthesis, before linking the first nucleoside monomer at the 3' end and after linking the last nucleoside monomer at the 5' end, an additional phosphoramidite monomer containing the HO(CH2)6-SS-(CH2)6- group (purchased from Hongene Biotech) is linked. The positive-chain single strand is then cleaved from the solid-phase support to obtain compound S1 (43.55 mg, 6.61 μmol) containing conjugate 2, as shown in formula (3-1-1). Equation (3-1-1); In the formula, This represents a sequence as shown in SEQ ID NO:35. (3-2) Synthesis of compound S2 containing the positive chain of conjugate 2: Dissolve S1 (43.55 mg, 6.61 μmol) prepared in (3-1) in 5.00 mL of purified water. Then, add TCEP aqueous solution (67.50 mg, 0.24 mmol, purchased from Bidex Pharmaceuticals, batch number: BD155793) to the resulting solution at a weight ratio of TCEP (CAS: 51805-45-9) to S1 of 1.5:1. Mix well and react at room temperature for 2 hours. Dilute the reaction solution with 10 mL of purified water and filter to obtain 14 mL of reaction solution. Transfer the reaction solution to a 15 mL 3K ultrafiltration tube and centrifuge at 3900 rpm for 30 min. The ultrafiltration and centrifugation steps were repeated until the conductivity of the ultrafiltration liquid was measured to be below 100 S. The product in the filter membrane was collected to obtain compound S2 (42.30 mg, 6.42 μmol, yield: 97.10%) containing the positive chain of conjugate 2 (molecular weight: 6589.50, measured: 6588.62). (3-3) Preparation of the compound of formula (3-3-1) containing the positive chain of conjugate 2: in, Representing the sequence shown in SEQ ID NO:35, T7 contains a polypeptide ligand group as shown in SEQ ID NO:134, arranged from the N-terminus to the C-terminus. All amino acids in the sequence shown are in the L-configuration. HAIYPRH (SEQ ID NO:134). The positive chain S2 (40 mg, 1.0 eq) was dissolved in 4 mL of 0.1 M ammonium acetate aqueous solution to obtain the positive chain S2 solution. The peptide T7 (69 mg, 4.0 eq) was dissolved in 4 mL of DMF solution. The obtained peptide T7 solution was added to the positive chain S2 solution, mixed, and reacted at room temperature for 2 hours. After filtering the reaction solution through a 0.22 μm microporous membrane, the reaction solution was purified using a semi-preparative reverse-phase purification method. The fraction containing the product was collected, concentrated, and the solvent was removed to obtain 26 mg of the compound with the formula (3-3-1). (3-4) Synthesis of Conjugate 2 The antisense chain in conjugate 2 was prepared according to the method described in Preparation Example 13 of WO2019105418A1, except that the nucleoside monomers were sequentially linked according to the sequence shown in SEQ ID NO: 36 to obtain the antisense chain sequence. The compound of formula (3-3-1) prepared in step (3-3) and the antisense chain prepared above were dissolved in DEPC water in equimolar amounts and annealed to obtain conjugate 2. Conjugate 2 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected and concentrated under reduced pressure to obtain a mixture of triethylamine, methylamine salt and ammonium salt of conjugate 2 as shown in formula (3-3-2). After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value for the sense strand was 8659.89, and the measured value was 8658.66. The theoretical value for the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 2. in, This refers to siRNAa1 in Table 2 of this disclosure; wherein the sense strand of the siRNA has the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Preparation Example 4: Synthesis of Conjugate 3 The conjugate 3 provided in this disclosure was prepared by the same method as in Preparation Example 3, except that the polypeptide T7 in step (3-3) was replaced with the polypeptide DRI-T7 as shown in Formula (401): DRI-T7 contains a polypeptide ligand with the sequence shown in SEQ ID NO:135, arranged from the N-terminus to the C-terminus. All amino acids in the sequence shown are in the D configuration. HRPYIAH (SEQ ID NO:135) Conjugate 3 has a positive chain as shown in formula (4-3-1): In the formula, Represents a sequence as shown in SEQ ID NO:35 Following the same method as in Preparation Example 3, the antisense chain of conjugate 3, which is the sequence shown in SEQ ID NO: 36, was prepared. The compound and antisense chain of formula (4-3-1) prepared above were dissolved in DEPC water and annealed to obtain conjugate 3. Conjugate 3 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected and concentrated under reduced pressure to dryness to obtain a mixture of triethylamine, methylamine salt and ammonium salt of conjugate 3 as shown in formula (4-3-2). After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value for the sense strand was 8659.89, and the measured value was 8658.61. The theoretical value for the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 3. in, This refers to siRNAa1 in Table 2 of this disclosure; wherein the sense strand of the siRNA has the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Preparation Example 5: Synthesis of Conjugate 4 The conjugate 4 provided in this disclosure was prepared using the same method as in Preparation Example 3, except that the polypeptide T7 in step (3-3) was replaced with polypeptide D-T7 as shown in Formula (501): D-T7 is a polypeptide ligand containing the sequence shown in SEQ ID NO:134, arranged from the N-terminus to the C-terminus. The difference is that all amino acids in the sequence shown are in the D configuration. Conjugate 4 has a positive chain as shown in formula (5-3-1): in, Represents a sequence as shown in SEQ ID NO:35 Following the same method as in Preparation Example 3, the antisense chain of conjugate 4, which is the sequence shown in SEQ ID NO: 36, was prepared. The compound and antisense chain of formula (5-3-1) prepared above were dissolved in DEPC water and annealed to obtain conjugate 4. Conjugate 4 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected and concentrated under reduced pressure to dryness to obtain a mixture of triethylamine, methylamine salt and ammonium salt of conjugate 4 as shown in formula (5-3-2). After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value of the sense strand was 8659.89, and the measured value was 8658.46. The theoretical value of the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 4. in, This refers to siRNAa1 in Table 2 of this disclosure; wherein the sense strand of the siRNA has the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Preparation Example 6: Synthesis of Conjugate 5 (6-1) Preparation of siRNA conjugate positive strand S1-5 Following the method described in Preparation Example 1 of WO2019105418A1, the sequence of the siRNA positive strand in conjugate 5 was synthesized by solid-phase synthesis. The sequence of the siRNA positive strand has the sequence shown in SEQ ID NO:35, the only difference being that, during solid-phase synthesis, a phosphoramidite monomer containing the HO(CH2)6-SS-(CH2)6- group (purchased from Hongene Biotech) was additionally linked before the first nucleoside monomer at the 3' end. Compound S1-5, containing the siRNA conjugate positive strand as shown in Formula (6-1-1), was cleaved from the solid-phase support. (Molecular weight: 6525.52, measured: 6524.52). In the formula, This represents a sequence as shown in SEQ ID NO:35. (6-2) Synthesis of the positive strand S2-5 of the siRNA conjugate: Compound S2-5 was prepared as shown in formula (6-2-1) using the same method as in Preparation Example 3. (Molecular weight: 6393.29, measured: 6392.21). The conjugate 5 provided in this disclosure was prepared using the same method as in Preparation Example 3, except that the polypeptide T7 in step (3-3) was replaced with polypeptide P-T7 as shown in formula (601): P-T7 is a polypeptide ligand containing the sequence shown in SEQ ID NO:134, arranged from N-terminus to C-terminus, where all amino acids are in the D configuration. The difference lies in the fact that the N-terminus of the polypeptide is linked to the 3' end of the siRNA's positive strand via a linker group. The positive strand of conjugate 5 is a compound as shown in formula (6-3-1): In the formula, Represents a sequence as shown in SEQ ID NO:35 Following the same method as in Preparation Example 3, the antisense chain of conjugate 5, which is the sequence shown in SEQ ID NO: 36, was prepared. The compound and antisense chain of formula (6-3-1) prepared above were dissolved in DEPC water and annealed to obtain conjugate 5. Conjugate 5 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected and concentrated under reduced pressure to dryness to obtain a mixture of triethylamine, methylamine salt and ammonium salt of conjugate 5 as shown in formula (6-3-2). After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value for the sense strand was 7428.49, and the measured value was 7427.40. The theoretical value for the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 5. in, This refers to siRNAa1 in Table 2 of this disclosure; wherein the sense strand of the siRNA has the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Preparation Example 7: Synthesis of Conjugate 6 The conjugate 6 provided in this disclosure was prepared using the same method as in Preparation Example 3, except that polypeptide T7 in step (3-3) was replaced with polypeptide P-T7 as shown in formula (601). The positive chain of conjugate 6 has the structure shown in formula (7-3-1): In the formula, This represents a sequence as shown in SEQ ID NO:35. Following the same method as in Preparation Example 3, the antisense chain of conjugate 6, which is the sequence shown in SEQ ID NO: 36, was prepared. The structure and antisense chain of formula (7-3-1) prepared above were dissolved in DEPC water and annealed to obtain conjugate 6. Conjugate 6 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected and concentrated under reduced pressure to dryness to obtain a mixture of triethylamine, methylamine salt and ammonium salt of conjugate 6 as shown in formula (7-3-2). After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value of the sense strand was 8659.89, and the measured value was 8658.48. The theoretical value of the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 6. In the formula, This refers to siRNAa1 in Table 2 of this disclosure; wherein the sense strand of the siRNA has the nucleotide sequence shown in SEQ ID NO:35, and the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Preparation Example 8: Synthesis of Conjugate 7 Using a solid-phase nucleic acid synthesis method (solid-phase phosphoramide method), nucleoside monomers were sequentially linked from the 3'-5' direction according to the siRNA sequence shown in SEQ ID NO:133 to obtain the positive strand of the siRNA conjugate 7: UmsCmsCmUmGm(Uhd)CfCfUfUmCmGmAmGmAmCmCmsAmsUm(SEQ ID NO:133) Uppercase letters C, G, U, and A indicate the base composition of the nucleotide; lowercase letters hd indicate that the nucleotide adjacent to the left of hd is a nucleotide modified with 2'-O-hexadecyl. The difference lies in the direction of 3'-5': after linking the nucleoside monomer at position 13 of the 3' end of the positive strand, the Uhd phosphorous amide monomer is linked to position 14 of the 3' end of the positive strand. The Uhd phosphorous amide monomer is prepared according to the preparation method of compound 150 described in paragraphs 0673-0676 of the specification WO2021092371A2. Uhd phosphorus amide monomers have the structure shown in formula (8-1-1): Following the same method as in Preparation Example 3, the antisense chain of conjugate 7 was prepared, and the antisense chain is the sequence shown in SEQ ID NO: 36. The obtained sense and antisense chains were dissolved in DEPC water and annealed to obtain conjugate 7. Conjugate 7 was dissolved in purified water, filtered through a 0.45 μm filter membrane, and purified by Agilent semi-preparative reversed-phase chromatography. The column was XBridge Prep / C18 / 10 μm, 19*250 mm; the mobile phase was A: 100 mM TEAA (pH = 7.1-7.3), B: acetonitrile, gradient: B% 5-65%, 0-40 min. The eluent was collected, concentrated under reduced pressure to dryness, and a mixture of triethylamine, methylamine salt, and ammonium salt of conjugate 7 was obtained. After preparation, the molecular weights of the sense and antisense strands were determined by LC-MS. The theoretical value for the sense strand was 6439.62, and the measured value was 6438.83. The theoretical value for the antisense strand was 7109.84, and the measured value was 7108.98. The measured values ​​were consistent with the theoretical values, indicating that the obtained conjugate contained the sequence corresponding to conjugate 7. The sense strand of conjugate 7 has the nucleotide sequence shown in SEQ ID NO:133, with the 6th nucleotide from the 5' end of the sense strand being Uhd (2'-O-hexadecyluridine acid); the antisense strand has the nucleotide sequence shown in SEQ ID NO:36. Experimental Example 1: In vitro inhibitory activity of the disclosed siRNA against RPTOR mRNA in HepG2 human liver cancer cells. This experiment investigated the inhibitory activity of the disclosed siRNAa2 on RPTOR mRNA in HepG2 human hepatocellular carcinoma cells in vitro. HepG2 human liver cancer cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were cultured in DMEM medium (HyClone) supplemented with 10% fetal bovine serum (FBS, RMBIO) at 37°C in an incubator containing 5% CO2 / 95% air. HepG2 cells were loaded at 2.0 x 10⁻⁶. 5Cells were seeded into 12-well plates with 1 mL of cell culture per well. After culturing for 24 h, the culture medium in the wells was aspirated, and 500 μL of Opti-MEM medium (GIBCO) was added to each well. The siRNAa2 obtained in Preparation Example 1 and the reference conjugate NC were prepared into a 20 μM siRNA working solution using PBS buffer. Prepare 1A solutions, each containing 48.5 μL of Opti-MEM medium and 1.5 μL of 20 μM siRNA working solution. Prepare 1B solutions, each containing 49 μL of Opti-MEM medium and 1 μL of Lipofectamine. TM 2000 (Invitrogen). Prepare 1C solutions, each containing 48.5 μl of Opti-MEM medium and 1.5 μL of the reference conjugate NC working solution. Mix one part of solution 1B with one part of solution 1A and incubate at room temperature for 20 min to obtain transfection complex 1Xa. Mix one part of 1B solution with 50 μL of Opti-MEM medium and incubate at room temperature for 20 min to obtain the transfection complex 1X. m . Mix one part of solution 1B with one part of solution 1C and incubate at room temperature for 20 minutes to obtain transfection complex 1X. c . In two culture wells (both containing HepG2 cells and 500 μL of Opti-MEM medium, the same below), 1Xa transfection complex was added and mixed evenly at a volume of 100 μL / well to obtain a transfection mixture with a final concentration (based on siRNA) of 50 nM, which was designated as the test group. Add 1X of the transfection complex to each of the two culture wells. m Mix thoroughly and add 100 μL per well to obtain a transfection mixture without siRNA, which is designated as the blank control group. Add 1X of the transfection complex to each of the two culture wells. c Mix thoroughly and add 100 μl / well to obtain a transfection mixture with a final concentration (based on siRNA) of 50 nM, which is designated as the negative control group. After culturing the test group, blank control group, and negative control group in culture wells for 4 hours, the supernatant in each culture well was aspirated, and 1 mL of Opti-MEM medium was added to each well. The 12-well plate was then placed in a CO2 incubator and cultured at 37°C for another 24 hours. Total RNA was extracted from cells in each well using the Sangon UNIQ-10 column-based total RNA extraction kit (purchased from Sangon Biotech, catalog number: TC13KA4109) according to the method described in the instruction manual. For each well of cells, 1 μg of total RNA was collected and used to reverse transcribe the RNA using the Goldenstar reverse transcription kit. TM The reagents used in the RT6cDNA Synthesis Kit (Beijing Qingke Xinyue Biotechnology Co., Ltd.) were Goldenstar. TM Oligo(dT) 17 As primers, a 20 μL reverse transcription reaction system was prepared according to the reverse transcription procedure in the kit instructions to reverse transcribe the total RNA from the cells in each well. The reverse transcription conditions were as follows: for each reverse transcription reaction system, the system was incubated at 50°C for 50 min, then at 85°C for 5 min, and finally at 4°C for 30 s. 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, take 5 μL of the above solution containing cDNA as a template, and use... The SYBR qPCR SuperMix Plus kit (purchased from Nearshore Protein Technology Co., Ltd., catalog number E096-01B) was used to prepare a 20 μL qPCR reaction system. The PCR primer sequences for amplifying the target gene RPTOR and the internal reference gene GAPDH are shown in Table 3, with a final concentration of 0.25 μM for each primer. Each qPCR reaction system was placed on an ABI StepOnePlus Real-Time PCR instrument, and a three-step amplification method was used. The amplification program was: 95℃ pre-denaturation for 10 min, followed by 95℃ denaturation for 30 s, 60℃ annealing for 30 s, and 72℃ extension for 30 s. This denaturation, annealing, and extension process was repeated 40 times to obtain product W1 containing amplified target gene RPTOR and internal reference gene GAPDH. Product W1 was then incubated sequentially at 95℃ for 15s, 60℃ for 1min, and 95℃ for 15s. The melting curves of the target gene and the internal reference gene GAPDH in product W1 were collected by real-time quantitative PCR instrument to obtain the Ct values ​​of the target gene RPTOR and the internal reference gene GAPDH. Table 3 Primer Information The relative quantification of the target gene RPTOR in each test group was performed using the comparison Ct(ΔΔCt) method, as follows: ΔCt(test group) = Ct(target gene in test group) - Ct(internal reference gene in test group) ΔCt(control group) = Ct(target gene in control group) - Ct(internal reference gene in control group) ΔCt(test group) = ΔCt(test group) - ΔCt(control group average) ΔCt(control group) = ΔCt(control group) - ΔCt(control group average) Here, ΔCt (control group average) is the arithmetic mean of ΔCt (control group) for each of the two culture wells in the control group. Thus, each culture well in both the test group and the control group corresponds to a ΔCt value. The expression level of RPTOR mRNA in the test group was normalized based on the mean of the control group, and the mean of RPTOR mRNA expression level in the blank control group was defined as 100%. The relative expression level of RPTOR mRNA in the test group = 2 - ΔΔCt(test group) × 100% The inhibition rate of RPTOR mRNA in the test group = (1 - relative expression level of RPTOR mRNA in the test group) × 100%. The results showed that in HepG2 human liver cancer cells in vitro, the reference conjugate NC showed almost no inhibitory effect on RPTOR mRNA; siRNAa2 at a concentration of 50 nM showed an RPTOR mRNA inhibition rate of 67.92%, demonstrating excellent RPTOR mRNA inhibitory activity. Experimental Example 2: Inhibitory activity of the disclosed siRNA against RPTOR mRNA in mouse hepatocellular carcinoma cells in vitro. This experiment investigated the inhibitory activity of different concentrations of the disclosed siRNAa2 on RPTOR mRNA in Hepa1-6 mouse hepatocellular carcinoma cells in vitro. Hepa1-6 mouse liver cancer cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were cultured in DMEM medium (HyClone) supplemented with 10% fetal bovine serum (FBS, RMBIO) at 37°C in an incubator containing 5% CO2 / 95% air. The siRNAa2 obtained in Preparation Example 1 was prepared into a 20 μM (as siRNA) working solution using PBS buffer. Press 3×10 5Cells were collected in two replicates per well. 60 μL of EL transfection buffer (Suzhou Yida Biotechnology Co., Ltd.) was added to each well to mix the cells. 3 μL of siRNA was then added to each well to obtain a cell suspension containing siRNA. This siRNA-containing cell suspension was added to a 96-well plate and incubated for 5 min. Electroporation was then performed according to the set parameters: 180V, 100 μs, 6 pulses, 50 ms pulse interval, followed by 24 h of incubation after the pulses. The resulting transfection mixture had a final siRNA concentration of 1 μM. After electroporation, the plate was incubated for 5 min, and 240 μL of culture medium was added to each well. 145 μL of the reaction solution was transferred from each well to a 12-well plate, and 855 μL of DMEM culture medium was added to each well. The plate was then incubated at 37°C for 24 h in a CO2 incubator. Total RNA and reverse transcription were extracted from cells in each well using the same method as in Experiment 1, and relative quantification of RPTOR mRNA in each test group was performed. The results showed that at a low siRNA concentration of 1 μM, siRNAa2 exhibited a 53.1% inhibition rate of RPTOR mRNA, demonstrating excellent efficacy in inhibiting RPTOR mRNA expression. Experimental Example 3: Activity of siRNA conjugates in mice The conjugate 1 obtained in Preparation Example 2 was dissolved in PBS to prepare solutions of 0.2 mg / ml, 0.6 mg / ml, and 1.8 mg / ml (based on siRNA). C57BL / 6 mice (female, 16-18 g weight, 6-8 weeks old, purchased from Spiering Biotechnology) were randomly divided into a low-dose group (1 mg / kg), a medium-dose group (3 mg / kg), and a high-dose group (9 mg / kg), with 5 mice in each group, and were numbered accordingly. The siRNA conjugate solution was administered to each group of mice via subcutaneous injection in the neck and back. Mice were weighed and their body weight was recorded before administration. The dosage was based on body weight, with an administration volume of 5 mL / kg, serving as the test group. In another group, each mouse was given PBS at an administration volume of 5 mL / kg, serving as the blank control group. Day 1 was calculated from the time of drug administration. Mice were weighed and their body weight recorded on day 8 post-administration. Liver tissue was collected from each mouse in both the test and control groups and preserved using RNAlater. Total RNA and reverse transcription were extracted from cells in each well using the same method as in Experiment 1, and the relative quantification of the target gene RPTOR in each test group was performed. The primer information used is shown in Table 4. Table 4 Primer Information The inhibition rate results are shown in Table 5: Table 5. Inhibition rate of siRNA conjugate 1 on RPTOR mRNA in mice. As shown in Table 5, compared with the blank control group, the inhibition rate of RPTOR mRNA in mouse hepatocytes after administration of conjugate 1 reached 47.01% at a low dose of 1 mg / kg, and reached a maximum of 77.21% with increasing dose, demonstrating high inhibitory activity, and the inhibition rate showed a dose-dependent effect. On the other hand, compared with the blank control group, the body weight of mice in each group did not change significantly after 8 days of administration of different doses of conjugate 1. Therefore, it can be seen that the conjugate 1 disclosed herein did not show obvious toxic reactions in in vivo experiments. Experimental Example 4: Activity of the disclosed conjugate in mice after intracerebroventricular injection. This experiment investigated the inhibitory activity of the prepared conjugate 2 on RPTOR mRNA in mice, especially in the central nervous system. The mice used in this experiment were purchased from Spefair Company. They were of ICR strain, SPF grade, and all were male, with a purchase weight of 25±1g. The detailed steps are as follows: [1] Administration via intraventricular injection in mice: Dissolve and dilute conjugate 2 with PBS to prepare an injection solution with a concentration of 20 μg / μL (based on the amount of siRNA) for later use. Ten mice were randomly divided into two groups of five each: a control group and a test group. Mice in the control group received no medication, while mice in the test group received conjugate 2 at a dose of 10 μL per mouse. The specific procedure was as follows: Each mouse was anesthetized by intraperitoneal injection of 5% chloral hydrate (purchased from Shanghai Yuanye Biotechnology Co., Ltd.) at a dose of 400 mg / kg body weight. After anesthesia took effect, the drug was injected into the right ventricle using a 25 μL microinjection needle (purchased from Hamilton) via a microinjection pump (model: 78-8130, purchased from KDSCIENTIFIC). The injection took 10 minutes, and the needle was left in place for 5 minutes before being slowly withdrawn. The needle hole was then sealed with bio-adhesive (purchased from Minnesota Mining Manufacturing Co., Ltd.), and the head skin was sealed. After the mice regained consciousness, they were returned to the animal enclosure for continued rearing. The day of injection was recorded as day one. [2] Sample collection On day 8 post-injection, each mouse was anesthetized by intraperitoneal injection of 5% chloral hydrate at a dose of 400 mg / kg body weight. Parietal cortex, hippocampus, cerebellum, medulla oblongata, thalamus, and striatum were extracted and stored in RNA later (catalog number: MFCD03453003, purchased from SIGMA). Subsequently, RNA was extracted using RNAVzol (purchased from Wieglas Biotech (Beijing) Co., Ltd., catalog number N002) according to the method described in the instructions, and q-PCR was performed to detect RPTOR mRNA expression. [3] Detection Four samples were extracted from each region of the brain of each mouse. 1 μg of total RNA was taken from each sample. The relative quantification of the target gene RPTOR mRNA in the test group was performed using the same method as in Experiment 3. The inhibition rate of RPTOR mRNA by the siRNA conjugate in different brain regions is summarized in Table 6. Table 6 shows the inhibition rate of conjugate 2 on RPTOR mRNA in the mouse central nervous system. As shown in Table 6, the conjugate 2 of this disclosure, conjugated with polypeptide ligands, exhibited good inhibition rates against RPTOR mRNA in different regions of the mouse brain, with an inhibition rate as high as 73.0% in the cortex. The inhibition rates in the hippocampus and medulla oblongata both exceeded 50%, reaching 50.4% and 52.2%, respectively. Example 5: The activity of the disclosed conjugates and siRNA in mice was investigated using the same method as in Example 4. The inhibitory activity of the prepared conjugates 2-7 and siRNAa1 on RPTOR mRNA in mice, especially in the central nervous system, was examined. The only difference was that, for the test group, the conjugates used were conjugates 2, 3, 4, 5, 6, 7, and siRNAa1. The results are summarized in Table 7. Table 7. Inhibition rate of conjugates on RPTOR mRNA in the mouse central nervous system As shown in Table 7, at a dosage of 200 μg per mouse, the conjugates 2-7 and siRNAa1 disclosed herein exhibited good inhibitory rates against RPTOR mRNA in different sites of the central nervous system in mice. Compared to conjugates with lipophilic groups, the conjugates with different polypeptide ligands showed comparable inhibitory activity against RPTOR mRNA in the right cortex and right hippocampus, with inhibition rates ranging from 40% to 50%. In the right cortex, the lipophilic group-conjugate showed a 17% higher inhibition rate against RPTOR mRNA compared to siRNAa1; in the right hippocampus, the lipophilic group-conjugate showed at least a 14% higher inhibition rate against RPTOR mRNA compared to siRNAa1. The inhibitory efficiency against RPTOR mRNA in the right brain region was significantly higher than that in the corresponding left region, indicating that the conjugates exhibited a stronger local accumulation effect in the right brain region after injection into the right lateral ventricle. Experimental Example 6: Activity of the disclosed conjugate in mice Following the same method as in Experiment 4, the inhibitory activity of the prepared conjugate 7 on RPTOR mRNA in mice, especially in the central nervous system, was investigated. The results are summarized in Table 8. Table 8. Inhibition rate of conjugate 7 on RPTOR mRNA in the mouse central nervous system As shown in Table 8, at a dosage of 200 μg / animal, the conjugate 7 of this disclosure exhibited regionally selective RPTOR mRNA inhibitory activity against the central nervous system. The hippocampus showed the highest inhibition rate, followed by the medulla oblongata and cortex. The conjugate of this disclosure, with its lipophilic group, showed an inhibition rate of greater than 50% against RPTOR mRNA in the cortex, hippocampus, medulla oblongata, and striatum. Specifically, in the cortex, hippocampus, and medulla oblongata, the inhibition rate of RPTOR mRNA by conjugate 7 was greater than 60%, especially in the hippocampus where the inhibition rate reached as high as 69.64%. These experimental data provide experimental basis for the design of mTOR pathway-targeted drugs and suggest their translational potential in neurodegenerative diseases such as Alzheimer's disease. Experimental Example 7: Activity of the disclosed conjugate in mice under intrathecal administration This experiment investigated the inhibitory activity of conjugates 4-7 and siRNAa1 on RPTOR mRNA in mice, particularly in the central nervous system. The same method as in Experiment 4 was used, except that intrathecal administration was replaced with intracerebral administration of the drug in the lateral ventricle of the mice, with an injection dose of 1 mg per mouse. On day 29 post-injection, RNA was extracted from each mouse according to the method described in the instructions, and q-PCR was performed to detect the expression of RPTOR mRNA. Eight samples were extracted from each region of the brain of each mouse. 1 μg of total RNA was taken from each sample. The relative quantification of the target gene RPTOR mRNA in the test group was performed using the same method as in Experiment 3. The inhibition rate of RPTOR mRNA by siRNA and its conjugates in different brain regions is summarized in Table 9. Table 9 shows the inhibition rate of the conjugates on RPTOR mRNA in the mouse central nervous system. Table 9 shows that the conjugates disclosed herein exhibit region-specific RPTOR mRNA inhibitory activity in the mouse central nervous system via intrathecal administration. Experimental data show that on day 29 of administration, the lumbar spinal cord showed the highest inhibition rate of RPTOR mRNA (≥60%), indicating high local enrichment and sustained effect of the drug in the spinal cord; the cortical inhibition rate was second highest (maximum inhibition rate 56.05%), while the inhibition rate of RPTOR mRNA in deep brain regions (such as the striatum and hippocampus) remained at no less than 20%. Notably, conjugate 7 showed a targeted delivery advantage in the striatum (46.89% inhibition rate of RPTOR mRNA) and thalamus (49.86% inhibition rate of RPTOR mRNA), significantly higher than other conjugates and siRNAa1. The long-term effect results after 29 days validate the long-term inhibitory effect of the drug, providing crucial experimental evidence for the development of drugs regulating the central nervous system mTOR pathway. Based on the above experimental results, the siRNA disclosed herein can effectively inhibit the expression of RPTOR mRNA in cells, and therefore shows good potential in the preparation of drugs for the treatment and / or prevention of diseases or related symptoms associated with abnormal mTORC1 activation and autophagy, such as NASH or neurodegenerative diseases. The preferred 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. To avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately. Furthermore, various different embodiments of this disclosure can also be combined arbitrarily, 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 siRNA comprising a sense strand and an antisense strand, wherein each nucleotide in the siRNA is independently a modified or unmodified nucleotide, wherein, The sense strand contains a nucleotide sequence I, and the antisense strand contains a nucleotide sequence II. Nucleotide sequence I and nucleotide sequence II are at least partially anticomplementary to form a double-stranded region. Nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO:1 and differs by no more than 3 nucleotides. Nucleotide sequence II is equal in length to the nucleotide sequence shown in SEQ ID NO:2 and differs by no more than 3 nucleotides. 5'-UCCUGUCCUUCGAGACCAZ a1 -3'(SEQ ID NO:1); 5'-Z a2 UGGUCUCGAAGGACAGGA-3'(SEQ ID NO:2), Among them, Z a1 For U, Z a2 For A, the nucleotide sequence I contains a position corresponding to Z. a1 nucleotide Z a3 The nucleotide sequence II contains a position corresponding to Z. a2 nucleotide Z a4 The Z a4 It is the first nucleotide at the 5' end of the antisense strand.

2. The siRNA as described in claim 1, wherein, The nucleotide sequence I differs from the nucleotide sequence shown in SEQ ID NO:1 by no more than one nucleotide, and / or the nucleotide sequence II differs from the nucleotide sequence shown in SEQ ID NO:2 by no more than one nucleotide.

3. The siRNA as described in claim 1 or 2, wherein, The nucleotide differences between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO:2 include Z. a4 The difference in position, and Z a4 Selected from U, C, or G.

4. The siRNA according to any one of claims 1-3, wherein, Z a3 Is with Z a4 Complementary nucleotides, or Z a3 It is a reverse debasing deoxynucleotide.

5. The siRNA according to any one of claims 1-4, wherein, The nucleotide sequence I and the nucleotide sequence II are substantially anticomplementary, substantially anticomplementary, or completely anticomplementary; substantially anticomplementary means that there is no more than 3 base mismatches between the two nucleotide sequences; substantially anticomplementary means that there is no more than 1 base mismatch between the two nucleotide sequences; completely anticomplementary means that there are no mismatches between the two nucleotide sequences.

6. The siRNA according to any one of claims 1-5, wherein, The sense and antisense strands may be the same or different in length, with the sense strand being 19-23 nucleotides long and the antisense strand being 19-26 nucleotides long; and nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO:3, and nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO:

4. 5'-UCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:3); 5'-Z a4 UGGUCUCGAAGGACAGGA-3'(SEQ ID NO:4), Among them, Z a3 Choose from ia, A, U, G, or C, and Z a3 When it is not ia, Z a4 Is with Z a3 Complementary nucleotides.

7. The siRNA of claim 6, wherein Z a3 For U or ia, Z a4 The answer is A.

8. The siRNA according to any one of claims 1-7, wherein, The sense strand further contains nucleotide sequence III, and the antisense strand further contains nucleotide sequence IV. Nucleotide sequence III and nucleotide sequence IV are each independently 1-4 nucleotides in length. Nucleotide sequence III is attached to the 5' end of nucleotide sequence I, and nucleotide sequence IV is attached to the 3' end of nucleotide sequence II. Nucleotide sequence III and nucleotide sequence IV are of equal length and are substantially anticomplementary or completely anticomplementary. Substantially anticomplementary means that there is no more than one base mismatch between the two nucleotide sequences; completely anticomplementary means that there is no mismatch between the two nucleotide sequences.

9. The siRNA as described in claim 8, wherein, The nucleotide sequence I is equal in length to the nucleotide sequence shown in SEQ ID NO:1, and differs by no more than 3 nucleotides. Furthermore, both nucleotide sequences III and IV are 1 nucleotide in length, and the base of nucleotide sequence III is A; or, both nucleotide sequences III and IV are 2 nucleotides in length, and the base composition of nucleotide sequence III is UA in the 5' to 3' direction; or, both nucleotide sequences III and IV are 3 nucleotides in length, and the base composition of nucleotide sequence III is AUA in the 5' to 3' direction; or, both nucleotide sequences III and IV are 4 nucleotides in length, and the base composition of nucleotide sequence III is CAUA in the 5' to 3' direction.

10. The siRNA according to any one of claims 1-9, wherein, The antisense strand further contains a nucleotide sequence V, which is 1 to 3 nucleotides in length, attached to the 3' end of the antisense strand to form a 3' overhang of the antisense strand; and / or the positive strand further contains a nucleotide sequence VI, which is 1 to 3 nucleotides in length, attached to the 3' end of the positive strand to form a 3' overhang of the positive strand.

11. The siRNA of claim 10, wherein, The length of the nucleotide sequence V and / or nucleotide sequence VI is 2 nucleotides.

12. The siRNA as described in claim 10 or 11, wherein, The nucleotide sequence V and / or VI is two consecutive thymine deoxyribonucleotides or two consecutive uracil ribonucleotides; or the nucleotide sequence V is complementary to the nucleotide at the corresponding position of the target mRNA, and / or the nucleotide sequence VI is identical to the nucleotide at the corresponding position of the RPTOR mRNA.

13. The siRNA according to any one of claims 1-12, wherein, The sense strand of the siRNA contains the nucleotide sequence shown in SEQ ID NO:5, and the antisense strand contains the nucleotide sequence shown in SEQ ID NO:

6. 5'-UCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:5); 5'-Z a4 UGGUCUCGAAGGACAGGAUA-3'(SEQ ID NO:6); Wherein, the Z a4 It is the first nucleotide at the 5' end of the antisense strand, Z a3 Choose from ia, A, U, G, or C, and Z a3 When it is not ia, Z a4 Is with Z a3 Complementary nucleotides; Alternatively, the sense strand of the siRNA contains a nucleotide sequence as shown in SEQ ID NO:7, and the antisense strand of the siRNA contains a nucleotide sequence as shown in SEQ ID NO:

8. 5'-UAUCCUGUCCUUCGAGACCAZ a3 -3'(SEQ ID NO:7); 5'-Z a4 UGGUCUCGAAGGACAGGAUAUG-3'(SEQ ID NO:8); Wherein, the Z a4 It is the first nucleotide at the 5' end of the antisense strand, Z a3 Choose from ia, A, U, G, or C, and Z a3 When it is not ia, Z a4 Is with Z a3 Complementary nucleotides.

14. The siRNA according to any one of claims 1-13, wherein, The siRNA is one of siRPTORa1, siRPTORa2, and siRPTORa3.

15. The siRNA according to any one of claims 1-14, wherein, At least one nucleotide in the sense strand and the antisense strand is a modified nucleotide, and / or at least one phosphate group is a phosphate group with a modifying group.

16. The siRNA according to any one of claims 1-15, wherein, Each nucleotide in the sense strand and the antisense strand is independently a fluorinated or non-fluorinated nucleotide.

17. The siRNA of claim 16, wherein, The fluorinated nucleotides are located in nucleotide sequences I and II, and, in the direction from the 5' end to the 3' end, at least the 7th, 8th, and 9th nucleotides of nucleotide sequence I are fluorinated nucleotides; and in the direction from the 5' end to the 3' end, at least the 2nd, 6th, 14th, and 16th nucleotides of nucleotide sequence II are fluorinated nucleotides.

18. The siRNA according to any one of claims 1-17, wherein, The siRNA is one of siRPTORa1-M1, siRPTORa1-M2, siRPTORa1-M3, siRPTORa2-M1, siRPTORa2-M2, siRPTORa2-M3, siRPTORa3-M1, siRPTORa3-M, and siRPTORa3-M3.

19. The siRNA of claim 15, wherein, The phosphate ester group with the modifying group is a thiophosphate ester group formed by replacing at least one oxygen atom in the phosphate diester bond of the phosphate ester group with a sulfur atom.

20. The siRNA according to any one of claims 1-19, wherein, The siRNA is siRPTORa1-M1S, siRPTORa1-M1X, siRPTORa1-M2S, siRPTORa1-M2X, siRPTORa1-M3S, siRPTORa1-M3X, siRPTORa2-M1S, siRPTORa2-M1X, siRPT One of ORa2-M2S, siRPTORa2-M2X, siRPTORa2-M3S, siRPTORa2-M3X, siRPTORa3-M1S, siRPTORa3-M1X, siRPTORa3-M2S, siRPTORa3-M2X and siRPTORa3-M3S.

21. The siRNA according to any one of claims 1-20, wherein, The 5' terminal nucleotide of the antisense strand is a 5'-phosphate nucleotide or a nucleotide modified with a 5'-phosphate analogue.

22. The siRNA of claim 21, wherein, The siRNA is siRPTORa1-M1P1, siRPTORa1-M2P1, siRPTORa1-M3P1, siRPTORa2-M1P1, siRPTORa2-M2P1, siRPTORa2-M3P1, siRPTORa3- M1P1, siRPTORa3-M2P1, siRPTORa3-M3P1, siRPTORa1-M1SP1, siRPTORa1-M2SP1, siRPTORa1-M3SP1, siRPTORa2-M1SP1, siRPTORa2- One of M2SP1, siRPTORa2-M3SP1, siRPTORa3-M1SP1, siRPTORa3-M2SP1, siRPTORa3-M3SP1, siRPTORa1-M1XP1, siRPTORa1-M2XP1, siRPTORa1-M3XP1, siRPTORa2-M1XP1, siRPTORa2-M2XP1, siRPTORa2-M3XP1, siRPTORa3-M1XP1, siRPTORa3-M2XP1, and siRPTORa3-M3XP1.

23. A pharmaceutical composition comprising the siRNA as described in any one of claims 1-22 and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein, The weight ratio of the siRNA to a pharmaceutically acceptable vector is 1:(1-500).

25. The pharmaceutical composition of claim 24, wherein, The weight ratio of the siRNA to the pharmaceutically acceptable vector is 1:(1-50).

26. An siRNA conjugate comprising the siRNA of any one of claims 1-22 and a conjugate group conjugated to the siRNA, the conjugate group comprising at least one pharmaceutically acceptable targeting group and / or delivery helper group; optionally, the conjugate group further comprising a linker, and the siRNA, the linker, and the targeting group or the delivery helper group are sequentially linked; optionally, each of the targeting groups is selected from ligands capable of binding to cell surface receptors, and / or each delivery helper group is selected from groups capable of increasing the biocompatibility of the siRNA conjugate in the target organ or tissue for delivery.

27. The siRNA conjugate of claim 26, wherein the delivery helper group is a lipophilic group; or, the lipophilic group contains a straight-chain aliphatic hydrocarbon, a branched aliphatic hydrocarbon, or a steroid; or, the lipophilic group contains a saturated or unsaturated C4-C30 hydrocarbon chain; or, it is a straight-chain or branched saturated hydrocarbon group with a length of 15-25 carbon atoms; or, it is a saturated straight-chain hexadecyl group.

28. The siRNA conjugate of claim 26, wherein at least one targeting group is a ligand targeting a receptor on the surface of a target cell in the CNS; or the targeting group is a polypeptide ligand; or the polypeptide ligand, in the direction from N-terminus to C-terminus, each polypeptide ligand contains the sequence shown in SEQ ID NO:134 or SEQ ID NO:

135. HAIYPRH (SEQ ID NO:134); HRPYIAH (SEQ ID NO:135) Alternatively, at least one or each of the target groups is independently selected from ligands capable of binding to desialyl glycoprotein receptors on the surface of hepatocytes; or, at least one or each of the target groups is galactose or N-acetylgalactosamine.

29. Use of one or more of the siRNA according to any one of claims 1-22, the pharmaceutical composition according to any one of claims 23-25, and the siRNA conjugates according to claims 26-28 in the preparation of a medicament for inhibiting RPTOR mRNA expression in cells.

30. Use of one or more of the siRNA of any one of claims 1-22, the pharmaceutical composition of any one of claims 23-25, and the siRNA conjugate of claims 26-28 in the preparation of a medicament for treating and / or preventing diseases or symptoms related to RPTOR function regulation.

31. The use as described in claim 30, wherein, The diseases or symptoms associated with RPTOR function regulation are those related to mTORC1 activation and abnormal autophagy function.

32. The use as described in claim 31, wherein, The diseases or symptoms associated with RPTOR function regulation are neurodegenerative diseases or non-alcoholic steatohepatitis.

33. The use as described in claim 32, wherein, The neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease, preferably Alzheimer's disease.

34. A method for treating and / or preventing diseases or symptoms associated with RPTOR function regulation, the method comprising administering to a subject in need an effective amount of one or more of the following: siRNA as described in any one of claims 1-22, a pharmaceutical composition as described in any one of claims 23-25, and an siRNA conjugate as described in claims 26-28.

35. A method for inhibiting RPTOR mRNA expression in cells, the method comprising contacting the cells with an effective amount of one or more of the siRNA of any one of claims 1-22, the pharmaceutical composition of any one of claims 23-25, and the siRNA conjugate of claims 26-28.

36. A kit comprising one or more of the following: siRNA according to any one of claims 1-22, pharmaceutical composition according to any one of claims 23-25, and siRNA conjugate according to any one of claims 26-28.

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