High-molecular polymer, preparation method thereof and application of high-molecular polymer in delivery of nucleic acid
By preparing high molecular polymers with specific structures as nucleic acid drug delivery carriers, the complexity of LNP delivery system preparation and liver targeting issues have been solved, achieving efficient and safe delivery of nucleic acid drugs, especially with good transfection effects in vivo and in vitro.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-12
- Publication Date
- 2026-04-03
AI Technical Summary
Existing lipid nanoparticle (LNP) nucleic acid delivery systems suffer from problems such as cumbersome preparation processes, demanding storage conditions, and the potential to cause immune clearance and liver damage or immune-mediated hepatitis due to liver targeting issues. Furthermore, they lack effective targeting and stability.
A high molecular polymer with a specific structure was developed as a nucleic acid drug delivery carrier. It was prepared by addition reaction and utilized the rapid degradation of glutathione (GSH) in cells via disulfide bonds to achieve efficient delivery of nucleic acids. The high molecular polymer was then purified by lyophilization via dialysis.
It achieves good in vivo and in vitro delivery performance of nucleic acid drugs, with excellent biodegradability and low toxicity and side effects, and realizes efficient delivery to the spleen and lungs, making it suitable for the treatment of genetic diseases, tumors and viral infections.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, and in particular to a polymer, its preparation method, and its application in nucleic acid delivery. Background Technology
[0002] In recent years, nucleic acid-based drug delivery technologies have shown great therapeutic potential in biomedical applications. The strategy involves introducing exogenous nucleic acids (such as antisense oligonucleotides, siRNA, DNA, and mRNA) into target pathological tissues or cells, thereby altering the expression of endogenous genes to cure or prevent related diseases. To achieve ideal therapeutic effects, exogenous nucleic acid molecules must prevent degradation and reach specific target cells. However, targeting, stability, and endosomal escape remain major challenges for nucleic acid delivery systems, thus necessitating safe and efficient nucleic acid delivery vectors.
[0003] Non-viral carriers such as lipid nanoparticles (LNPs), inorganic nanomaterials, and polymer nanoplatforms have attracted much attention. Among them, LNPs have garnered the most attention, with some even being clinically applied in mRNA vaccines against COVID-19, marking a historic milestone in gene therapy. However, LNPs are still plagued by issues such as cumbersome preparation processes, demanding storage conditions, and the potential for immune clearance. Furthermore, because most current LNP delivery systems target the liver, existing LNP delivery systems may lead to severe liver accumulation, potentially causing liver damage or immune-mediated hepatitis. Summary of the Invention
[0004] In view of this, the technical problem to be solved by the present invention is to provide a polymer and its preparation method and its application in nucleic acid delivery. The polymer has good performance in delivering nucleic acid drugs in vivo and in vitro, and the polymer has excellent biodegradability and low toxicity as a nucleic acid drug delivery carrier.
[0005] To achieve the above objectives, the present invention provides a polymer having the structure shown in Formula I:
[0006] Formula I;
[0007] Among them, L1 and L2 are independently selected from ester groups or amide groups;
[0008] Q is either -CH2-CH2- or -SS-;
[0009] R1 is a residue formed by the addition reaction of an amino group and a double bond to a hydrophilic amine;
[0010] R2 is a residue formed by the addition reaction of an amino group and a double bond in an alkylamine hydrophobic amine.
[0011] R3 is a residue formed by the addition reaction of an amino group and a double bond in a diamine end-capping agent;
[0012] x and y represent the degree of aggregation.
[0013] Preferably, L1 and L2 are both selected from ester groups or amide groups.
[0014] In some specific embodiments, the polymer has the structure shown in Formulas 1-4:
[0015] .
[0016] R1 is a residue formed by the addition reaction of an amino group and a double bond of a hydrophilic amine, that is, the group remaining after the amino group of the hydrophilic amine is removed.
[0017] In some specific embodiments, the hydrophilic amine is selected from any of the following:
[0018] .
[0019] In some preferred embodiments, R1 is 2-aminoethylmorpholine, 2-methyl-1H-imidazol-1-propanamine, 4-amino-1-butanol, or N-tert-butoxycarbonyl-1,3-propanediamine.
[0020] R2 is a residue formed by the addition reaction of an amino group to a double bond in alkylamine hydrophobic amines, that is, the group remaining after the amino group is removed from the alkylamine.
[0021] In some specific embodiments, the alkylamine is a straight-chain or branched alkylamine of C8 to C18, for example, it may be a straight-chain or branched alkylamine of C8, C10, C12, C14, C16 or C18.
[0022] In some specific embodiments, the alkylamine is selected from any of the following:
[0023] .
[0024] In some preferred embodiments, R2 is dodecylamine.
[0025] R3 is a residue formed by the addition reaction of an amino group to a double bond in a diamine end-capping agent; that is, the group remaining after removing the amino group at one end of the diamine end-capping agent.
[0026] In some specific embodiments, the diamine capping agent is selected from any of the following:
[0027] .
[0028] In some preferred embodiments, R3 is propylenediamine or N'N-bis(3-aminopropyl)methylamine.
[0029] x represents the degree of aggregation, preferably any integer from 1 to 100.
[0030] y represents the degree of aggregation, preferably any integer from 1 to 200.
[0031] The present invention also provides a method for preparing the above-mentioned polymer, comprising the following steps:
[0032] Diacrylate or diacrylamide monomers and hydrophilic amine monomers or hydrophobic amine monomers are dissolved in a solvent and polymerized by heating. After the reaction is completed, the polymer is end-capped with diamine at room temperature to obtain a high molecular weight polymer.
[0033] The hydrophilic amine monomer, hydrophobic amine monomer, and diamine are as described above.
[0034] Preferably, the molar ratio of the diacrylate or diacrylamide monomer, the hydrophilic amine monomer, the hydrophobic amine monomer, and the diamine is (1.2~5.2):(0.5~1.0):(0.5~4.0):(0.5~2.0), more preferably (1.2~3.0):(0.5~1.0):(0.5~3.0):(0.5~1.5), and even more preferably 2.8:1.0:1.5:1.5.
[0035] The heating temperature is preferably 40~100℃, more preferably 40~60℃, and for example, it can be 40, 50 or 60℃, with 50℃ being the most preferred.
[0036] The reaction time is preferably 12 to 96 hours, more preferably 24 to 72 hours, and for example, it can be 24, 48, 60, or 72 hours, with 48 hours being the most preferred.
[0037] The solvent is preferably one or more of methanol, ethanol, water, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide, more preferably methanol.
[0038] Preferably, after the heating is completed, the process further includes: dialysis and freeze-drying the obtained heated product to obtain a high molecular weight polymer; the molecular weight cutoff during the dialysis process is 1000~10000 Da.
[0039] The polymer prepared by this invention can be used as a nucleic acid drug delivery carrier for in vivo or in vitro delivery of nucleic acid drugs.
[0040] Based on this, the present invention provides the application of the above-mentioned polymer or the polymer prepared by the above-mentioned preparation method in the preparation of nucleic acid drug delivery carriers.
[0041] The present invention does not impose any special limitation on the nucleic acid, and it can be any type of nucleic acid known to those skilled in the art, including but not limited to one or more of DNA, mRNA, siRNA, microRNA, antisense nucleic acid, and circular RNA.
[0042] Preferably, the mRNA is selected from one or more of the following: mRNA expressing green fluorescent protein (GFP-mRNA), mRNA expressing firefly luciferase (FLuc-mRNA), mRNA expressing red fluorescent protein (mCherry-mRNA), mRNA expressing PD-1 antibody (PD-1-mRNA), mRNA expressing OVA protein (OVA-mRNA), and mRNA expressing interleukin-2 protein (IL-2 mRNA).
[0043] The present invention also provides a complex comprising the above-described polymer or the polymer prepared by the above-described preparation method, and a nucleic acid drug loaded on the surface of the polymer.
[0044] The polymer described in this invention is used as a nucleic acid drug delivery carrier and a nucleic acid drug compound for the preparation of drugs to treat genetic diseases, tumors, viral infections, and other diseases.
[0045] The polymer prepared in this invention can be used as a nucleic acid drug delivery carrier to carry nucleic acid drugs for in vitro (cell level) or in vivo (animal level) delivery.
[0046] For example, the in vitro delivery includes, but is not limited to, delivery of nucleic acid drugs in cells such as 293t, CHO, HeLa, MCF-7, DC2.4, HepG2, B16F10, A549, CT26, and BMDCs.
[0047] Experimental results show that the polymer prepared in this invention has good in vitro transfection effect as a nucleic acid drug delivery carrier in the above-mentioned cells.
[0048] The in vivo delivery includes, but is not limited to, the delivery of nucleic acid drugs in animals such as mice, rabbits, and pigs.
[0049] The in vivo delivery can be performed by methods such as intramuscular injection, intravenous injection, pulmonary injection, or intraperitoneal injection.
[0050] The polymer provided by this invention, when used as a nucleic acid drug delivery carrier, exhibits good in vivo transfection effect in the aforementioned animals.
[0051] Furthermore, the polymer serves as a nucleic acid drug delivery carrier, carrying nucleic acid drug OVA-mRNA, resulting in a nucleic acid drug carrier / nucleic acid drug OVA-mRNA complex that strongly promotes cellular immunity.
[0052] Furthermore, the nucleic acid drug carrier in the aforementioned nucleic acid drug carrier / nucleic acid drug OVA-mRNA complex is easily degraded in vitro.
[0053] In this invention, high concentrations of polymers are used as nucleic acid drug delivery carriers, and they show no significant toxicity in DC2.4 cells.
[0054] Therefore, the polymers provided by this invention have the potential to be used as nucleic acid drug delivery carriers.
[0055] The reasons why the polymer provided by this invention can be used as a nucleic acid drug delivery carrier are as follows:
[0056] On the one hand, proteins, as important components of all cells and tissues in the human body, are rich in sulfur;
[0057] On the other hand, the polymer provided by this invention uses disulfide bonds as the main chain to rapidly degrade and release nucleic acids in response to glutathione (GSH), which is widely present in cells.
[0058] Compared with existing technologies, this invention provides a polymer that exhibits excellent in vivo and in vitro delivery performance for nucleic acid drugs due to its good GSH responsiveness. Furthermore, the polymer demonstrates excellent biodegradability and low toxicity, making it suitable as a nucleic acid drug delivery carrier. Using disulfide bonds as the backbone, it rapidly degrades and releases nucleic acids in response to glutathione (GSH), which is widely present in cells. Simultaneously, the degraded small molecules are quickly excreted from the body, showing no significant toxicity to cells or mice. Following tail vein injection, the polymer enables highly efficient spleen- and lung-targeted delivery of nucleic acid drugs. Therefore, its use as a nucleic acid drug delivery carrier and in combination with nucleic acid drugs is of great significance for the preparation of drugs to treat genetic diseases, tumors, viral infections, and other diseases. Attached Figure Description
[0059] Figure 1 The 1H NMR spectrum of the nucleic acid drug carrier prepared in Example 1;
[0060] Figure 2 The 1H NMR spectrum of the nucleic acid drug carrier prepared in Example 2;
[0061] Figure 3 The 1H NMR spectrum of the nucleic acid drug carrier prepared in Example 3;
[0062] Figure 4The 1H NMR spectrum of the nucleic acid drug carrier prepared in Example 4;
[0063] Figure 5 This is a diagram showing the in vitro transfection effect of the nucleic acid drug carrier prepared in Example 1;
[0064] Figure 6 This is a diagram showing the in vitro transfection effect of the nucleic acid drug carrier prepared in Example 2;
[0065] Figure 7 This is a diagram showing the in vitro transfection effect of the nucleic acid drug carrier prepared in Example 3;
[0066] Figure 8 This is a diagram showing the in vitro transfection effect of the nucleic acid drug carrier prepared in Example 4;
[0067] Figure 9 This is a diagram showing the in vivo transfection effect of the nucleic acid drug carrier prepared in Example 1.
[0068] Figure 10 This is a diagram showing the in vivo transfection effect of the nucleic acid drug carrier prepared in Example 3. Detailed Implementation
[0069] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other instances that are improved or modified by those skilled in the art are within the scope of protection of the present invention. It should be understood that the embodiments of the present invention are only used to illustrate the technical effects of the present invention, and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the methods used in the embodiments are conventional methods.
[0070] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.
[0071] Example 1
[0072] A novel method for preparing a nucleic acid drug delivery vector, the specific steps of which are as follows:
[0073] N,N'-bis(acryloyl)cysteamine, N-tert-butoxycarbonyl-1,3-propanediamine, and dodecylamine were dissolved sequentially in methanol at a feed ratio of 2.8:1.0:1.5. The mixture was heated and stirred at 50°C for 48 h. Subsequently, propanediamine (feed ratio 1.5) was added, and end-capping was performed at room temperature for 6 h. After the reaction was completed, the reaction solution was placed in a dialysis bag and dialyzed against deionized water for 3 days. The dialysate was then lyophilized to obtain the nucleic acid drug delivery carrier.
[0074] The proton NMR spectrum of the prepared nucleic acid drug delivery vector is shown below. Figure 1 As shown.
[0075] Example 2
[0076] A novel method for preparing a nucleic acid drug delivery vector, the specific steps of which are as follows:
[0077] 1,6-hexanediol diacrylate, N-tert-butoxycarbonyl-1,3-propanediamine, and decaamine were successively dissolved in dimethyl sulfoxide at a feed ratio of 2.8:1.0:1.5. The mixture was heated and stirred at 90 °C for 48 h. Subsequently, N'N-bis(3-aminopropyl)methylamine (feed ratio 1.5) was added, and the mixture was capped at room temperature for 6 h. After the reaction was completed, the reaction solution was placed in a dialysis bag and dialyzed against deionized water for 3 days. The dialysate was then lyophilized to obtain the nucleic acid drug delivery carrier.
[0078] The proton NMR spectrum of the prepared nucleic acid drug delivery vector is shown below. Figure 2 As shown.
[0079] Example 3
[0080] A novel method for preparing a nucleic acid drug delivery vector, the specific steps of which are as follows:
[0081] Hexamethylenebisacrylamide, 2-aminoethylmorpholine, and tetradecylamine were sequentially dissolved in dimethyl sulfoxide at a ratio of 2.8:1.0:1.5. The mixture was heated and stirred at 90°C for 48 h. Subsequently, propylenediamine (at a ratio of 1.5) was added, and end-capping was performed at room temperature for 6 h. After the reaction was complete, the reaction solution was placed in a dialysis bag and dialyzed against deionized water for 3 days. The dialysate was then lyophilized to obtain the nucleic acid drug delivery carrier.
[0082] The proton NMR spectrum of the prepared nucleic acid drug delivery vector is shown below. Figure 3 As shown.
[0083] Example 4
[0084] A novel method for preparing a nucleic acid drug delivery vector, the specific steps of which are as follows:
[0085] 2,2-Dithiodiethanol diacrylate, 2-aminoethylmorpholine, and dodecylamine were dissolved sequentially in methanol at a ratio of 2.8:1.0:1.5. The mixture was heated and stirred at 50°C for 48 h. Then, N'N-bis(3-aminopropyl)methylamine (at a ratio of 1.5) was added, and the mixture was capped at room temperature for 6 h. After the reaction was complete, the reaction solution was placed in a dialysis bag and dialyzed against deionized water for 3 days. The dialysate was then lyophilized to obtain the nucleic acid drug delivery carrier.
[0086] The proton NMR spectrum of the prepared nucleic acid drug delivery vector is shown below. Figure 4 As shown.
[0087] Application of the nucleic acid drug delivery vector described in this invention
[0088] Specifically, the prepared degradable cationic polymer is used to support nucleic acid drugs for in vitro (cellular level) and in vivo (animal level) delivery, as detailed below:
[0089] (a) In vitro nucleic acid delivery
[0090] 293t, CHO, HeLa, MCF-7, DC2.4, HepG2, B16F10, A549, CT26, and BMDCs were selected to evaluate the nucleic acid delivery capability of the materials.
[0091] 1) Cell Culture
[0092] Continuous cell culture was performed using a 10% fetal bovine serum incubator with 5% CO2 at a temperature of 37°C. Cells stored in liquid nitrogen were removed and placed in a 37°C water bath. After the solution was completely dissolved, the cells were quickly transferred to a centrifuge tube containing 5 mL of the above culture medium. After mixing, the cells were centrifuged at 1000 rpm for 5 min. The cell pellet in the centrifuge tube was retained, and 10 mL of culture medium was added. The pellet was then transferred to a culture dish and placed in the above-mentioned incubator for further culture. The culture medium was changed every other day.
[0093] 2) Model nucleic acid transfection
[0094] The transfection capacity of the materials was evaluated using 293t, CHO, HeLa, MCF-7, DC2.4, HepG2, B16F10, A549, and CT26 cell lines, as well as luciferase DNA and luciferase mRNA. The cells were cultured at a ratio of 1 × 10⁶ cells per well. 4 Cells were seeded at a density in 96-well plates and cultured overnight in 200 µL of medium. The prepared nucleic acid drug delivery vector was mixed with luciferase DNA and luciferase mRNA in different ratios (the ratio of vector to nucleic acid (luciferase DNA or luciferase mRNA) was 1.25 / 1, 2.5 / 1, 5 / 1, and 10 / 1, respectively), and cultured with cells for 24 h. Then, the medium was aspirated, and cell lysis buffer (for lysing cells and releasing luciferase) and luciferase substrate (for detecting the expression level of luciferase, which catalyzes the production of fluorescence from luciferase) were added. The fluorescence intensity was measured using a fluorometer.
[0095] 3) Intracellular (in vitro model) transfection of drug nucleic acids
[0096] The transfection capacity of the materials for drug mRNA was evaluated using 293t, CHO, HeLa, MCF-7, DC2.4, HepG2, B16F10, A549, and CT26 cell lines and PD-1 mRNA, OVA-mRNA, and IL-2 mRNA. The cells were cultured at a ratio of 1 × 10⁶ cells per well. 4 Cells were seeded at a density in 96-well plates and cultured overnight in 200 µL of medium. The prepared nucleic acid drug delivery vector was mixed with the aforementioned mRNA at different ratios (vector to mRNA ratios of 1.25 / 1, 2.5 / 1, 5 / 1, and 10 / 1), and cultured with cells for 24 h. The culture medium was then aspirated, and the cells were washed three times with PBS. After thorough washing, trypsin was added to digest the cells for 2 min, and the cells were then collected and washed twice with culture medium and PBS, respectively. Cells were stained with fluorescent antibodies, and mRNA expression was analyzed by flow cytometry.
[0097] 4) In vivo model nucleic acid delivery
[0098] Intramuscular injection delivery of nucleic acid drugs: The prepared nucleic acid drug carrier was mixed with luciferase mRNA at different ratios (carrier to nucleic acid ratios of 1.25 / 1, 2.5 / 1, 5 / 1, and 10 / 1, respectively), and the carrier / nucleic acid complex nanoparticles were injected intramuscularly into animals. The nucleic acid dosage was 5 μg for mice, 10 μg for rabbits, and 20 μg for pigs. The in vivo delivery efficiency of the nucleic acid drug was evaluated using a fluorescence imaging device 6 h, 12 h, and 24 h after intramuscular injection.
[0099] Intravenous delivery of nucleic acid drugs: The prepared nucleic acid drug carrier was mixed with luciferase mRNA at different ratios (carrier to nucleic acid ratios of 1.25 / 1, 2.5 / 1, 5 / 1, and 10 / 1, respectively), and the carrier / nucleic acid complex nanoparticles were injected intravenously into animals. The nucleic acid dosage was 5 μg for mice, 10 μg for rabbits, and 20 μg for pigs. The in vivo delivery efficiency of the nucleic acid drug was evaluated using a fluorescence imaging device 6 h, 12 h, and 24 h after intravenous injection.
[0100] Figure 5 The image shows the in vitro transfection effect of the nucleic acid drug vector prepared in Example 1. The results show that the vector prepared in Example 1 carrying mRNA expressing green fluorescent protein (GFP-mRNA) showed significant expression of green fluorescent protein in DC2.4, B16F10, and MCF-7 cells.
[0101] Figure 6The image shows the in vitro transfection effect of the nucleic acid drug vector prepared in Example 2. The results show that the vector prepared in Example 2 carrying mRNA expressing green fluorescent protein (GFP-mRNA) showed significant expression of green fluorescent protein in DC2.4, B16F10, and MCF-7 cells.
[0102] Figure 7 The image shows the in vitro transfection effect of the nucleic acid drug vector prepared in Example 3. The results show that the vector prepared in Example 3 carrying mRNA expressing green fluorescent protein (GFP-mRNA) showed significant expression of green fluorescent protein in DC2.4, B16F10, and MCF-7 cells.
[0103] Figure 8 The image shows the in vitro transfection effect of the nucleic acid drug vector prepared in Example 4. The results show that the vector prepared in Example 4 carrying mRNA expressing green fluorescent protein (GFP-mRNA) showed significant expression of green fluorescent protein in DC2.4, B16F10, and MCF-7 cells.
[0104] Figure 9 The image shows the intramuscular transfection effect of the nucleic acid drug vector prepared in Example 1. The results indicate that the vector prepared in Example 1 carrying luciferase-expressing mRNA (Luc-mRNA) exhibits a high fluorescence signal upon intramuscular delivery in mice.
[0105] Figure 10 The image shows the intramuscular transfection effect of the nucleic acid drug vector prepared in Example 3. The results indicate that the vector prepared in Example 3 carrying luciferase-expressing mRNA (Luc-mRNA) exhibits a high fluorescence signal upon intramuscular delivery in mice.
[0106] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.
Claims
1. A polymer having the structure shown in Formula I: Formula I; in, L1 and L2 are independently selected from ester or amide groups; Q is either -CH2-CH2- or -SS-; R1 is a residue formed by the addition reaction of an amino group and a double bond to a hydrophilic amine; R2 is a residue formed by the addition reaction of an amino group and a double bond in an alkylamine hydrophobic amine. R3 is a residue formed by the addition reaction of an amino group and a double bond in a diamine end-capping agent; x and y represent the degree of aggregation.
2. The polymer according to claim 1, characterized in that, It has the structure shown in Equations 1-4 as follows: 。 3. The polymer according to any one of claims 1 to 2, characterized in that, The hydrophilic amine is selected from any of the following: 。 4. The polymer according to any one of claims 1 to 2, characterized in that, The alkylamine is a C8-C18 straight-chain or branched alkylamine.
5. The polymer according to claim 4, characterized in that, The alkylamine is selected from any of the following: 。 6. The polymer according to any one of claims 1 to 2, characterized in that, The diamine-based capping agent is selected from any of the following: 。 7. A method for preparing the polymer according to any one of claims 1 to 6, comprising the following steps: Diacrylate or diacrylamide monomers and hydrophilic amine monomers or hydrophobic amine monomers are dissolved in a solvent and polymerized by heating. After the reaction is completed, the polymer is end-capped with diamine at room temperature to obtain a high molecular weight polymer.
8. The preparation method according to claim 7, characterized in that, The molar ratio of the diacrylate or diacrylamide monomer, the hydrophilic amine monomer, the hydrophobic amine monomer, and the diamine is (1.2~5.2):(0.5~1.0):(0.5~4.0):(0.5~2.0). The heating temperature is 40~100℃; The reaction time is 12 to 96 hours; The solvent is one or more selected from methanol, ethanol, water, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide; After the heating is completed, the process further includes: dialysis and freeze-drying the obtained heated product to obtain a high molecular weight polymer; the molecular weight cutoff during the dialysis process is 1000~10000 Da.
9. The use of the polymer according to any one of claims 1 to 6 or the polymer prepared by the preparation method according to any one of claims 7 to 8 in the preparation of nucleic acid drug delivery carriers.
10. A complex, characterized in that, The polymer includes the polymer as described in any one of claims 1 to 6 or the polymer prepared by the preparation method described in any one of claims 7 to 8, and a nucleic acid drug loaded on the surface of the polymer.