Nanoparticle preparation as well as preparation method and application thereof

Abstract

The invention discloses a nanoparticle preparation as well as a preparation method and application thereof. The nanoparticle preparation comprises amino-modified dendritic mesoporous silicon nanoparticles, and lonidamine and oxacillin which are loaded on the mesoporous silicon nanoparticles. According to the invention, lonidamine and oxacillin, which have a synergistic effect, are loaded on the amino-modified dendritic mesoporous silicon spheres, and by means of the electrostatic adsorption effect of amino and bacteria and the degradation effect of mesoporous silicon, the antibacterial drug is slowly released at the infection part, so that a good SCVs killing effect is achieved, and a new treatment strategy is provided for treating SCVs-related osteomyelitis.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a nanoparticle preparation and a preparation method and application thereof. Background Art

[0002] Osteomyelitis is a progressive bone inflammation caused by pathogenic bacteria colonizing the bone. It is one of the most difficult clinical complications currently faced by trauma orthopedic surgeons. In osteomyelitis, Staphylococcus aureus has always been the most important and destructive pathogen, of which more than 50% of cases are caused by methicillin-resistant Staphylococcus aureus (MRSA). Studies have shown that S. aureus has a tendency to form small colony variants (SCVs) under long-term antibiotic pressure. Compared with the corresponding wild-type (WT) strain, SCVs grow slower, have less pigmentation, and have lower hemolytic activity, accompanied by changes in energy metabolism patterns. SCVs can evade the attack of the immune system by reducing the expression level of virulence factors and maintain the chronic infection state of osteomyelitis. More and more research results suggest that when bone infection is protracted or responds poorly to antibiotic treatment, SCVs should be actively sought.

[0003] The pathophysiological environment of osteomyelitis is relatively complex, and its treatment is challenging. Intravenous antibiotics usually have difficulty reaching bactericidal concentrations at the site of infection, let alone killing SCVs. Polymethyl methacrylate (PMMA) bone cement is commonly used as a drug delivery system in clinical practice, but it has some limitations, including unstable antibiotic release, unsuitability for heat-sensitive antibiotics, and non-biodegradability. Summary of the invention

[0004] The purpose of the present invention is to provide a nanoparticle preparation and a preparation method and application thereof in view of the deficiencies in the prior art.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect is to provide a nanoparticle preparation, comprising amino-modified dendritic mesoporous silica nanoparticles, and lonidamine and oxacillin loaded on the mesoporous silica nanoparticles.

[0007] The second aspect is to provide a method for preparing the above-mentioned nanoparticle preparation, comprising the following steps:

[0008] Step 1, synthesizing dendritic mesoporous silicon nanoparticles;

[0009] Step 2, adding the dendritic mesoporous silicon nanoparticles into a (3-aminopropyl)triethoxysilane solution, stirring for 12-24 hours to allow the surface of the nanoparticles to be evenly grafted with amino groups, washing, drying, and setting aside;

[0010] Step 3, suspending the aminated dendritic mesoporous silica nanoparticles in methanol, adding lonidamine and oxacillin, stirring for 24-36 hours, centrifuging, washing, and collecting the drug-loaded mesoporous silica nanoparticles.

[0011] Furthermore, the specific steps of step 1 are:

[0012] S11, adding cetyltrimethylammonium bromide and sodium salicylate to the triethanolamine aqueous solution and stirring;

[0013] S12, during stirring, adding tetraethoxysilane to the solution obtained in S11, and stirring for 2-5 hours;

[0014] S13, after the reaction is completed, the product is collected by high-speed centrifugation and washed with ethanol several times to remove residual reactants;

[0015] S14, extracting the collected product with dilute hydrochloric acid and methanol solution at 60-70° C. for 6-12 hours, repeating three times to remove the template;

[0016] S15, the product is vacuum dried at room temperature overnight to obtain dendritic mesoporous silica nanoparticles.

[0017] Furthermore, in the step 2, the solvent of the (3-aminopropyl)triethoxysilane solution is anhydrous ethanol, and its concentration is 4.5-10 v / v%.

[0018] Furthermore, in the step 2, the mass ratio of (3-aminopropyl)triethoxysilane to the dendritic mesoporous silicon nanoparticles is (40-50):1.

[0019] Furthermore, in the step 3, the concentration of the aminated dendritic mesoporous silicon nanoparticles in methanol is 4-10 mg / mL.

[0020] Furthermore, in the step three, the mass ratio of the aminated dendritic mesoporous silica nanoparticles, lonidamine and oxacillin is 10:(5-8):(3-5).

[0021] The third aspect is to provide the use of the above-mentioned nanoparticle preparation in the preparation of a drug for clearing small colony variants of osteomyelitis, wherein the small colony variants refer to small colony variants (SCVs) of Staphylococcus aureus formed under long-term antibiotic pressure.

[0022] Furthermore, lonidamine and oxacillin in the nanoparticle preparation have a synergistic effect.

[0023] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:

[0024] The present invention loads lonidamine and oxacillin with synergistic effects on amino-modified dendritic mesoporous silica spheres, and by virtue of the electrostatic adsorption between amino groups and bacteria and the degradation of mesoporous silica, the antibacterial drugs are slowly released at the infected site, which has a good effect of killing SCVs, and provides a new treatment strategy for the treatment of SCVs-related osteomyelitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The schematic diagram is a process flow diagram for preparing nanoparticle preparations according to the present invention.

[0026] Figure 2 Schematic diagram of the nanoparticle preparation of the present invention killing SCVs.

[0027] Figure 3 The synthesis and characterization results of the DMSN@OL particles of the present invention are shown.

[0028] Figure 4 The in vitro bactericidal effect and mechanism of the DMSN@OL particles of the present invention are shown.

[0029] Figure 5 The results show that the DMSN@OL particles of the present invention are effective in treating SCVs-related osteomyelitis. DETAILED DESCRIPTION

[0030] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments, but is not intended to be limiting of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention may be combined with each other without conflict.

[0031] Example 1

[0032] This embodiment provides a method for preparing a nanoparticle preparation (refer to Figure 1 ), including:

[0033] Step 1: Synthesis of dendritic mesoporous silica nanoparticles (DMSN)

[0034] 1) Solution preparation: 0.068 g of triethanolamine (TEA) was added to 25 mL of water and gently stirred in an oil bath at 80° C. for 0.5 h. Then, 380 mg of hexadecyltrimethylammonium bromide (cationic surfactant, CTAB) and 168 mg of sodium salicylate (NaSal) were added to the above solution and stirring was continued for 1 h.

[0035] 2) Adding silicon source: During the stirring process, add 4 mL of tetraethoxysilane (TEOS) to the above solution and keep stirring gently (200-300 rpm) for 2 hours;

[0036] 3) Product collection and washing: After the reaction is completed, the product is collected by high-speed centrifugation and washed with ethanol several times to remove residual reactants;

[0037] 4) Template removal: The collected products were extracted with dilute hydrochloric acid and methanol solution at 60°C for 6 hours, and the extraction was repeated three times to remove the template;

[0038] 5) Finally, the product was vacuum dried at room temperature overnight to obtain the final dendritic mesoporous silica nanoparticles (DMSN).

[0039] Step 2: Amination of DMSN

[0040] 1) Add 10 mL of anhydrous ethanol and 500 μL of (3-aminopropyl)triethoxysilane (APTES) into a flask and stir to mix the two systems thoroughly;

[0041] 2) adding 10 mg of dry dendritic mesoporous silica nanoparticles to the mixed solution, placing it on a magnetic stirrer and stirring it for 12 hours to allow the surface of the nanoparticles to be evenly grafted with amino groups;

[0042] 3) Wash the nanoparticles three times with anhydrous ethanol and dry them in an oven.

[0043] Step 3: Drug loading

[0044] 1) Suspend the aminated DMSN in 5 mL of methanol solution to a concentration of 4 mg / mL, add 10 mg of lonidamine and 6 mg of oxacillin, and stir thoroughly for 24 hours;

[0045] 2) Collect the drug-loaded mesoporous silica nanoparticles (DMSN@OL) by centrifugation and washing.

[0046] refer to Figure 2 The nanoparticle preparation prepared by the present invention kills SCVs in the following ways: DMSN@OL targets SCVs through electrostatic interactions and releases Oxa and Lon in a weakly acidic environment; subsequently, Lon reduces c-di-AMP levels through a multi-target mechanism, thereby reducing the osmotic pressure in SCVs; this effect synergizes with the inhibitory effect of Oxa on cell wall synthesis; ultimately, the synergistic effect of the two drugs causes SCVs to swell and eventually rupture.

[0047] Verification Example 1

[0048] After the successful synthesis of DMSN, the surface morphology of DMSN was observed by scanning electron microscopy (Gemini 300, ZEISS, Germany), and the morphology was further observed and elemental analysis was performed by transmission electron microscopy (JEM-2100F, JEOL, Japan). The structure and pore size of DMSN were characterized using nitrogen adsorption-desorption isotherm experiments (APSP 2460, Micromeritics, USA). The chemical bonds and molecular structures in DMSN and DMSN@OL were determined by Fourier transform infrared spectroscopy (Nicolet iS20, Thermo Scientific, USA). The particle size and potential of DMSN and DMSN@OL were measured by a particle size-potential meter (Nano ZS90, Malvern Instrument Ltd.), and the changes before and after drug loading were compared.

[0049] For the degradation and drug release experiments of DMSN@OL, the steps are as follows: DMSN@OL was dispersed in PBS and the concentration was adjusted to 1200 μg / mL. Then, 5 mL of the dispersion was taken, the pH was adjusted to 6.0 and 7.4, respectively, and incubated at 37°C for 24 hours. After the incubation, centrifuged at 8000 rpm for 5 minutes, and the supernatant was collected for subsequent analysis. Next, DMSN@OL was resuspended in fresh PBS to continue drug release. This operation was repeated once a day for 15 days. The absorbance of the supernatant was measured at wavelengths of 300 nm and 240 nm using a UV-visible spectrophotometer. The concentration of Lon was measured by OD 300 and standard curve, while the concentration of Oxa was determined by OD 240 (First deduct the absorbance of Lon at 240 nm) and use the corresponding standard curve to determine. In addition, on days 0, 2, 5, and 10, a small amount of solution was added to the ultrathin copper mesh, and the morphological changes of DMSN@OL were observed using a transmission electron microscope (JEOL, Ltd, Tokyo, Japan).

[0050] Experimental results reference Figure 3 The results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that DMSN had a uniform spherical morphology, was monodispersed, had a diameter of about 290 nm, and exhibited a dendritic nanostructure ( Figure 3 a, b). Energy dispersive spectroscopy (EDS) showed that Si, O, and N elements were evenly distributed, proving the successful synthesis of the nanoparticles and their amino modification ( Figure 3 c). In addition, the N2 adsorption-desorption isotherms further confirmed that these DMSN nanoparticles have mesoporous properties, with an average pore size of 22.4 nm and a specific surface area of ​​351.4 m 2 / g, which provides a good structural basis for drug loading ( Figure 3 d). Subsequently, Oxa and Lon were loaded into DMSN by physical pore adsorption. The characteristic peaks observed in the Fourier transform infrared spectrum confirmed the successful loading of the drugs ( Figure 3 e). The DMSN loaded with Oxa and Lon is named DMSN@OL ( Figure 3 f). Figure 3 As shown in Figures 3g and 3h, the particle size showed a slight upward trend and the zeta potential slightly decreased among DMSN, DMSN@Oxa, and DMSN@OL. These results further demonstrated the successful construction of the nanodelivery system.

[0051] Next, the degradation performance and drug release profile of DMSN@OL were evaluated at pH = 7.4 (simulating physiological conditions) and pH = 6.0 (simulating the mildly acidic microenvironment associated with osteomyelitis). Figure 3 As shown in Figure 1, after two days of degradation, the dendritic nanostructure of DMSN@OL at pH = 7.4 was slightly blurred, but its original shape was maintained. In contrast, at pH = 6.0, the dendritic structure showed moderate disorder and entanglement, and the framework of the nanoparticles began to deform or even collapse. By the fifth day, continued degradation under acidic conditions caused the boundaries between DMSN@OL particles to no longer be clear. In a neutral environment, DMSN degraded more slowly, showing only slight dendritic deformation and disorder. By the tenth day, the DMSN structure in a neutral environment gradually collapsed and fused, while in an acidic environment, part of the DMSN@OL structure had completely disappeared and was replaced by a uniform layer of degradation products. Figure 3 The drug release curves in j show that both drugs exhibited slow release under different pH conditions, but released faster under mildly acidic conditions. This pH-responsive release property enhances the bactericidal effect and reduces adverse reactions.

[0052] Verification Example 2

[0053] 1) Minimum bactericidal concentration of DMSN@OL: SCV or normal strains from the same source in the logarithmic growth phase were adjusted to 0.5 McFarland standard turbidity, and then a series of concentrations of DMSN@OL (100, 200, 400, 800 and 1200 μg / mL) were added and treated for 24 hours. Subsequently, 10 μL of each sample was inoculated on MH agar plates and incubated for another 24 hours. The minimum bactericidal concentration (MBC) of DMSN@OL was determined by the presence or absence of bacterial colonies.

[0054] 2) Live-dead staining: NC or SCV bacterial suspensions were inoculated in confocal culture dishes and treated with 1200 μg / mL DMSN@OL for 24 h. After removing the old culture medium and washing with PBS, the bacteria were stained using the LIVE / DEAD BacLight live staining kit (Thermo Fisher Scientific, Waltham, MA, USA) and then observed using a confocal laser scanning microscope (CLSM, Leica TCS SP8, Germany).

[0055] 3) TEM: After the above treatment, the NC or SCV was collected by scraping and fixed with 2.5% glutaraldehyde. Subsequently, the cells were dehydrated with gradient ethanol solutions and embedded in resin for ultrathin sectioning. The obtained ultrathin sections were stained with uranyl acetate and finally observed using a transmission electron microscope.

[0056] 4) Transcriptomic and metabolomic analysis: SCV treated with DMSN@OL was collected by centrifugation, and untreated SCV was used as a control. Total RNA extraction, cDNA library construction, and subsequent high-throughput sequencing were performed by Novogene Biotechnology Co., Ltd. (Beijing, China). For non-targeted metabolomic analysis, metabolite extraction was performed at Wuhan Maiteville Biotechnology Co., Ltd. (Wuhan, China), followed by liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis. The obtained transcriptomic and metabolomic data were subjected to principal component analysis (PCA), differential expression analysis, and KEGG analysis using the Metware cloud platform (https: / / magic.novogene.com / ). The screening criteria for differentially expressed genes (DEGs) were q value < 0.05 and |log2FC| ≥ 0.5850, while the screening criteria for differentially expressed metabolites (DEMs) were q value < 0.05, |log2FC| ≥ 0.5850, and VIP ≥ 1. Each group for RNA-seq analysis contained three biological replicates, while each group for metabolomics analysis contained four biological replicates.

[0057] 5) Biosafety Analysis:

[0058] MC3T3 cells were seeded in 24-well plates at a density of 1×105 cells / well and cultured overnight at 37°C and 5% CO2. According to the experimental protocol, 1200 μg / mL of DMSN@OL or the same concentrations of Oxa (217.56 μg / mL) and Lon (338.76 μg / mL) were added to the cells and incubated for 12 hours. Cell viability was then assessed using a CCK-8 detection kit (Dojindo, Kumamoto, Japan) according to the manufacturer's instructions. For live / dead staining, the treated cells were stained with calcein-AM and propidium iodide (PI) (Beyotime, Shanghai, China) and observed under a fluorescence microscope (DMi8, Leica Microsystems, Germany).

[0059] The experimental results are as follows Figure 4 As shown:

[0060] The results of MBC test and live / dead staining showed that 1200 μg / mL of DMSN@OL was sufficient to effectively eliminate NC and SCV ( Figure 4 a, b). Transmission electron microscopy (TEM) revealed that DMSN@OL exhibited selective adsorption to negatively charged bacteria, which facilitated the spatially selective release of antimicrobial drugs, significantly improving drug efficiency and reducing side effects ( Figure 4 c). Transcriptome and metabolome analyses further revealed that DMSN@OL disrupted multiple bacterial metabolic pathways, including purine metabolism, pyrimidine metabolism, and glycolysis / gluconeogenesis, which together accelerated the death of SCVs ( Figure 4 d, e).

[0061] Subsequently, the in vitro biosafety of DMSN@OL was evaluated using live / dead cell staining ( Figure 4 f). At a concentration of 1200 μg / mL, DMSN@OL showed no significant toxicity in MC3T3 cells. In contrast, co-administration of equal concentrations of Oxa and Lon resulted in partial cell death. This result was further confirmed by CCK-8 assay ( Figure 4 g). These results suggest that nanodelivery systems have great potential in alleviating drug side effects.

[0062] Verification Example 3

[0063] Sixty male mice aged 6 to 8 weeks were randomly assigned to two groups for the construction of NC-related and SCV-related osteomyelitis models (day -3). The modeling steps were as follows: Mice were anesthetized by inhalation anesthesia induction (3% isoflurane) and maintenance (1.5% isoflurane). The right leg of each mouse was shaved and disinfected. A longitudinal incision was made on the anterolateral side of the distal femur, and the muscles and fascia were dissected layer by layer until the bone surface was exposed. A single cortical hole was made on the bone surface using a micro drill equipped with a 27G needle. 10 μL of 1×106 CFU / mL NC or SCV suspension was injected into the bone marrow cavity through the hole using a micro syringe. The bone defect was then closed with bone wax, and the muscles and skin were sutured in layers. Finally, the skin surface was disinfected again. In both models, 6 mice were not inoculated with bacteria and were marked as the No bacteria group (NB group).

[0064] After MRI confirmed successful modeling (day -1), the wounds of infected mice were cut again, and equal volumes (10 μL) of DMSN@OL (6000 μg / mL), Oxa (1087.8 μg / mL), Oxa and Lon mixed solutions (1087.8 μg / mL and 1693.8 μg / mL, respectively) and PBS were injected into the bone marrow cavity by microsyringe according to the grouping. After suturing the incision, 40 μL of the corresponding preparation was injected into the soft tissue infection focus. The same treatment was repeated on the 4th and 9th days. Every three days, the body weight and knee circumference of the mice were measured. On the 10th and 30th days, a small amount of blood was collected from the retroorbital venous plexus for hematological analysis.

[0065] On day 30, mice were MRI scanned as described previously, euthanized, and the infected legs were removed for observation and photography. A small amount of infected soft tissue around the knee joint was collected, weighed, ground, and diluted proportionally to assess bacterial load by standard plate count method.

[0066] The samples were fixed, decalcified, dehydrated, and embedded before sections were prepared, and then stained with HE, Gram, Masson, and TRA and observed under a microscope.

[0067] The experimental results are as follows Figure 5 As shown:

[0068] By constructing mouse models of NC and SCV infection, the efficacy and safety of DMSN@OL in the treatment of osteomyelitis were systematically evaluated. Figure 5 During the in vivo experiment, the severity of infection was initially assessed by monitoring the body weight of mice. The trends of body weight changes in the NC and SCV infection models were similar ( Figure 5b). From day -3 to day 0, all groups lost significant weight due to bacterial infection, except for the NB group without bacterial inoculation (which only had a slight weight loss due to surgical trauma). A few days after treatment, the weight of all groups showed an upward trend, with the DMSN@OL group gaining the fastest weight, close to the NB group, while the Oxa+Lon group gained weight more slowly but still exceeded the Oxa group and the control group. At the same time, the knee circumference was measured to assess the severity of local swelling and infection, and the results were consistent with the weight changes ( Figure 5 c).

[0069] In the T2-weighted MRI images on day -1, the proximal femurs of all groups showed high signal intensity, indicating extensive edema and abscess formation, confirming the presence of osteomyelitis. After combined treatment with Lon and Oxa (Oxa+Lon group and DMSN@OL group), the infection signal was significantly reduced compared with the other infection groups. Especially in the SCV infection model, the effect of the DMSN@OL group was better than that of the Oxa+Lon group ( Figure 5 d). After mice were euthanized, specimens were collected and the residual bacterial load at the infection site was quantified by standard plate count method ( Figure 5 In the NC-related model, the amount of residual bacteria in the PBS group, Oxa group, Oxa+Lon group, and DMSN@OL group gradually decreased. In the SCV-related model, there was no significant difference in the bacterial content between the PBS group and the Oxa group, indicating that the efficacy of Oxa alone on SCV is limited.

[0070] HE staining analysis showed that in both animal models, the inflammatory infiltration of the infected site in the DMSN@OL group was similar to that in the non-infected group (NB group), and the inflammation was significantly reduced compared with the other groups ( Figure 5 h). In Gram staining, bacteria appear as blue dots, and their density and distribution also support the above findings ( Figure 5 i) These results suggest that Oxa and Lon combination therapy is superior to Oxa monotherapy in the treatment of NC and SCV-related osteomyelitis. In particular, the efficacy was significantly enhanced when co-delivered via DMSN, which is due to its targeted delivery and responsive release.

[0071] In addition, in vivo biosafety is another key consideration for the potential clinical application of nanomedicines. We analyzed the hematological parameters of each group at early stage (day 10) and after treatment (day 30) ( Figure 5j). On day 10, the levels of white blood cells (WBC), granulocytes (Gran), lymphocytes (Lymph), and monocytes (Mon) in the Oxa+Lon and DMSN@OL groups were lower than those in the PBS and Oxa groups. By day 30, these indicators in the DMSN@OL group dropped to normal levels in both models and were lower than those in the Oxa+Lon group. On the other hand, the levels of alanine aminotransferase (ALT) were elevated in the Oxa group, especially the Oxa+Lon group, on day 10, suggesting impaired liver function. These results suggest that although high-dose drug administration may temporarily control bacterial loads, it cannot completely eliminate pathogens in a complex osteomyelitis environment and may cause biological toxicity. In contrast, nanocarrier-mediated targeted delivery and responsive release can effectively reduce these side effects.

[0072] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the specification and illustrations of the present invention should be included in the protection scope of the present invention.

Claims

1. A nanoparticle preparation, characterized in that: The invention comprises amino-modified dendritic mesoporous silicon nanoparticles, and lonidamine and oxacillin loaded on the mesoporous silicon nanoparticles.

2. A method for preparing the nanoparticle preparation according to claim 1, characterized in that: The steps include: Step 1, synthesizing dendritic mesoporous silicon nanoparticles; Step 2, adding the dendritic mesoporous silicon nanoparticles into a (3-aminopropyl)triethoxysilane solution, stirring for 12-24 hours to allow the surface of the nanoparticles to be evenly grafted with amino groups, washing, drying, and setting aside; Step 3, suspending the aminated dendritic mesoporous silica nanoparticles in methanol, adding lonidamine and oxacillin, stirring for 24-36 hours, centrifuging, washing, and collecting the drug-loaded mesoporous silica nanoparticles.

3. The preparation method according to claim 2, characterized in that: The specific steps of step 1 are: S11, adding cetyltrimethylammonium bromide and sodium salicylate to the triethanolamine aqueous solution and stirring; S12, during stirring, adding tetraethoxysilane to the solution obtained in S11, and stirring for 2-5 hours; S13, after the reaction is completed, the product is collected by high-speed centrifugation and washed with ethanol several times to remove residual reactants; S14, extracting the collected product with dilute hydrochloric acid and methanol solution at 60-70° C. for 6-12 hours, repeating three times to remove the template; S15, the product is vacuum dried at room temperature overnight to obtain dendritic mesoporous silica nanoparticles.

4. The preparation method according to claim 2, characterized in that: In the step 2, the solvent of the (3-aminopropyl)triethoxysilane solution is anhydrous ethanol, and the concentration thereof is 4.5-10 v / v%.

5. The preparation method according to claim 2, characterized in that: In the step 2, the mass ratio of (3-aminopropyl)triethoxysilane to dendritic mesoporous silicon nanoparticles is (40-50):

1.

6. The preparation method according to claim 2, characterized in that: In the step 3, the concentration of the aminated dendritic mesoporous silica nanoparticles in methanol is 4-10 mg / mL.

7. The preparation method according to claim 2, characterized in that: In the step 3, the mass ratio of the aminated dendritic mesoporous silica nanoparticles, lonidamine and oxacillin is 10:(5-8):(3-5).

8. Use of the nanoparticle preparation according to claim 1 in the preparation of a drug for eliminating small bacterial colony variants in osteomyelitis.

9. The use according to claim 8, characterized in that: The lonidamine and oxacillin in the nanoparticle formulation have a synergistic effect.

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