Application of SLC39A1 specific regulating agent in preparation of medicine for treating acute respiratory distress syndrome

Abstract

The invention discloses application of an SLC39A1 specific regulating agent in preparation of a medicine for treating acute respiratory distress syndrome, and relates to the technical field of biological medicine. The medicine comprises an SLC39A1 specific regulating agent with a therapeutically effective amount and a pharmaceutically acceptable lung directional delivery carrier, the SLC39A1 specific regulating agent is selected from a group consisting of a nucleic acid molecule capable of specifically up-regulating the expression of an SLC39A1 gene, a small molecule compound capable of enhancing the zinc transport activity of the SLC39A1 protein and a recombinant protein; the lung directional delivery carrier is configured to deliver the SLC39A1 specific regulating agent to alveolar macrophages or lung microvascular endothelial cells in a targeted manner.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of an SLC39A1 specific regulator in the preparation of drugs for treating acute respiratory distress syndrome. Background Technology

[0002] Acute respiratory distress syndrome (ARDS) is a common critical illness characterized by non-cardiac pulmonary edema, refractory hypoxemia, and decreased lung compliance, with a persistently high mortality rate. Its core pathology lies in the disruption of the alveolar-capillary barrier and uncontrolled inflammatory responses (i.e., a "cytokine storm"). Current clinical treatments primarily focus on mechanical ventilation support, fluid management, and the use of corticosteroids, but there is a lack of specific drugs that can directly repair the damaged lung barrier or specifically block the inflammatory cascade.

[0003] Zinc plays a crucial role in maintaining immune homeostasis and cell barrier function. Current research indicates that ARDS patients often have significant hypozincemia, and zinc deficiency exacerbates lung epithelial cell apoptosis and the release of inflammatory factors. Zinc homeostasis in the human body mainly depends on the synergistic regulation of two classes of transport proteins: solute carrier family 30 (SLC30 / ZnT), responsible for transporting zinc out of cells, and solute carrier family 39 (SLC39A / ZIP), responsible for transporting zinc into cells. The SLC39A family contains more than ten members (such as ZIP1, ZIP2, ZIP8, and ZIP14), which have specific distribution patterns and functional divisions in different tissues and cells.

[0004] To correct zinc metabolism disorders associated with ARDS, current techniques attempt to intervene through oral or intravenous administration of zinc salts (such as zinc gluconate and zinc sulfate). However, this non-specific systemic zinc supplementation strategy has significant technical limitations. First, in the pathological environment of acute lung injury, specific zinc transport proteins on lung cell membranes may be downregulated due to inflammatory stimulation, resulting in cells remaining in an "intracellular zinc-deficient" state even when plasma zinc levels are sufficient, making it impossible for exogenous zinc salts to effectively enter the cells and exert their effects. Second, systemic high-dose zinc supplementation may cause toxic side effects such as gastrointestinal discomfort and copper metabolism disorders, and the non-specific distribution of zinc ions in the body may inadvertently activate transport pathways associated with fibrosis or other pathological processes (e.g., some studies suggest that excessive activation of ZIP8 may be related to metal toxicity). Furthermore, there is a lack of precise regulatory mechanisms targeting specific immune cells (such as alveolar macrophages) or structural cells (such as pulmonary microvascular endothelial cells).

[0005] In summary, current technologies lack an ARDS treatment approach that can precisely repair zinc transport mechanisms in specific cell types while avoiding the toxic side effects of systemic drug administration. Therefore, there is an urgent need to develop novel drug formulations that can specifically regulate the function of key zinc transport proteins and achieve targeted lung delivery. Summary of the Invention

[0006] This invention provides the application of an SLC39A1 specific regulator in the preparation of drugs for treating acute respiratory distress syndrome, which solves the problem that conventional zinc supplementation in the prior art is difficult to improve intracellular zinc deficiency and has systemic side effects.

[0007] This invention proposes the application of an SLC39A1 specific regulator in the preparation of a drug for treating acute respiratory distress syndrome. The drug comprises a therapeutically effective amount of the SLC39A1 specific regulator and a pharmaceutically acceptable lung-directed delivery carrier. The SLC39A1 specific regulator is selected from a group consisting of nucleic acid molecules that specifically upregulate SLC39A1 gene expression, small molecule compounds that enhance the zinc transport activity of SLC39A1 protein, and recombinant proteins. The lung-directed delivery carrier is configured to target and deliver the SLC39A1 specific regulator to alveolar macrophages or pulmonary microvascular endothelial cells.

[0008] Preferably, the SLC39A1-specific regulator is a nucleic acid drug targeting SLC39A1 messenger ribonucleic acid (RNA), wherein the nucleic acid drug is selected from at least one of the following: messenger ribonucleic acid encoding full-length or functionally truncated human SLC39A1 protein, antisense oligonucleotides that specifically inhibit SLC39A1 endogenous negative regulatory factors, small interfering RNAs that specifically inhibit SLC39A1 endogenous negative regulatory factors, and gene editing components that specifically stabilize SLC39A1 transcripts based on the CRISPR / Cas13 system; the messenger ribonucleic acid contains chemically modified nucleotides, has a Cap1 structure at its 5' end and a PolyA tail at its 3' end; the endogenous negative regulatory factors include microRNAs or ubiquitin ligases that target and degrade SLC39A1 messenger ribonucleic acid.

[0009] Preferably, the lung-directed delivery carrier is an inhaled lipid nanoparticle, which is composed of ionized cationic lipids, helper phospholipids, cholesterol, and polyethylene glycol lipid derivatives. The acid dissociation constant of the ionized cationic lipids is 6.0 to 6.5, the average particle size of the inhaled lipid nanoparticles is between 80 and 150 nanometers and the polydispersity index is less than 0.2, and the surface of the inhaled lipid nanoparticles is modified with macrophage-targeting ligands selected from mannose, β-glucan, or anti-CD206 antibody fragments.

[0010] Preferably, the drug further comprises a zinc homeostasis cofactor, which is selected from at least one of a metallothionein inducer, the antioxidant N-acetylcysteine, or zinc gluconate at physiological concentrations. The SLC39A1 specific regulator and the zinc homeostasis cofactor constitute a compound preparation.

[0011] Preferably, the drug formulation is a dry powder inhaler or a nebulized inhalation liquid; when prepared as a dry powder inhaler, the drug contains porous microspheres with an aerodynamic particle size of 1 to 5 micrometers. The porous microspheres are prepared by spray drying process using an SLC39A1 specific regulator carrier and leucine or mannitol excipients. The porous microspheres have a wrinkled surface and the fine particle fraction of the porous microspheres exceeds 50%.

[0012] Preferably, acute respiratory distress syndrome (ARDS) encompasses pathological conditions caused by sepsis, pneumonia, mechanical ventilation-induced lung injury, inhalation injury, or coronavirus infection, and the drug is indicated for the treatment of ARDS patients in the cytokine storm phase with hypozincemia.

[0013] Preferably, the drug is suitable for subjects whose SLC39A1 expression levels in peripheral blood mononuclear cells or bronchoalveolar lavage fluid are below 70 percent of the healthy baseline and who have systemic or local zinc deficiency.

[0014] Preferably, the SLC39A1 specific regulator is a small molecule agonist with a binding affinity of less than 10 nanomolars to the SLC39A1 protein and a selectivity ratio of more than 50-fold to the SLC39A8 or SLC39A14 proteins of the same family.

[0015] Preferably, the inhaled lipid nanoparticles are prepared by a method comprising the following steps: mixing an ethanol phase containing dissolved lipid components with an acidic buffer aqueous phase containing dissolved SLC39A1 specific regulator in a microfluidic chip at a flow rate ratio of 3:1 to 5:1 to form primary nanoparticles; subsequently, replacing the external buffer with a neutral pH phosphate buffer or lyophilization protection solution using a tangential flow filtration system; the resulting inhaled lipid nanoparticles exhibit an encapsulation efficiency of over 90% for the SLC39A1 specific regulator.

[0016] Preferably, the drug is a pre-filled nebulized inhalation formulation comprising a first compartment containing a lyophilized SLC39A1 messenger ribonucleic acid lipid nanoparticle complex and a second compartment containing 0.1 to 1.0 mmol / L zinc gluconate and 0.01% polysorbate 80 reconstitution solvent.

[0017] Beneficial Effects: This invention utilizes a specific SLC39A1 regulator combined with a lung-directed delivery carrier, significantly improving the therapeutic efficacy and safety of ARDS. First, unlike conventional non-specific zinc supplementation, this invention directly repairs zinc transport defects in alveolar macrophages and lung microvascular endothelial cells by specifically upregulating SLC39A1 expression or enhancing its activity, overcoming the therapeutic bottleneck of "sufficient extracellular zinc but deficient intracellular zinc" in inflammatory states, effectively inhibiting the NF-κB inflammatory cascade and improving endothelial barrier function. Second, the lung-directed delivery carrier achieves precise drug enrichment at lung injury lesions, significantly reducing the total dose required for systemic administration, avoiding gastrointestinal irritation and systemic metal metabolism disorders that may be caused by high-dose zinc, and greatly extending the safety window of treatment. Finally, this strategy avoids unintended activation of other ZIP family members (such as ZIP8 / 14) that may be involved in toxic pathology, possessing extremely high clinical translational value. Attached Figure Description

[0018] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. Furthermore, the same reference numerals denote the same parts throughout the drawings. In the drawings: Figure 1 This is a typical operation flowchart of treating ARDS patients in a clinical setting based on the technical solution of the present invention, as described in an embodiment of the present invention. Detailed Implementation

[0019] To more clearly illustrate the technical solutions in the embodiments of the invention or the prior art, the invention will be briefly introduced below in conjunction with the accompanying drawings and descriptions of the embodiments or the prior art. Obviously, the following description of the structure of the drawings is only some embodiments of the invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. It should be noted that the description of these embodiments is for the purpose of helping to understand the invention, but does not constitute a limitation on the invention.

[0020] Example 1 This embodiment describes a method for preparing a pharmaceutical formulation for treating acute respiratory distress syndrome (ARDS) and its in vitro and in vivo performance validation. The core component of this formulation is chemically modified human SLC39A1 messenger ribonucleic acid (mRNA), which is encapsulated in inhaled lipid nanoparticles (LNPs) with mannose ligands modified on their surface. Experimental materials include: Core reagents include: custom-synthesized ionized cationic lipids (chemical names omitted, measured acid dissociation constant (pKa) of 6.30); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); cholesterol; 1,2-dimyristoyl-rac-glycero-3-methoxypolyethyleneglycol-2000 (PEG-DMG); and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[mannose(polyethyleneglycol)-2000] (DSPE-PEG-Mannose).

[0021] mRNA synthesis raw materials, N1-methylpseudouridine-5'-triphosphate (N1-me-pseudo-UTP, used to 100% replace natural uridine triphosphate (UTP)); Cap1 cap analog (CleanCap® AG); T7 ribonucleic acid polymerase; linearized deoxyribonucleic acid (DNA) template (containing T7 promoter, human β-globin 5'-untranslated region (UTR), codon-optimized human SLC39A1 coding sequence (CDS), human α-globin 3'-UTR and a 110 nucleotide (nt) poly(A) tail template).

[0022] Cells and Animals: Mouse Alveolar Macrophage Cell Line (MH-S); Human Pulmonary Microvascular Endothelial Cells (HPMEC); C57BL / 6 mice (male, 6-8 weeks old).

[0023] Other reagents included zinc gluconate; lipopolysaccharide (LPS, E. coli O111:B4); FluoZin-3 AM zinc ion fluorescent probe; and human SLC39A1 detection kit.

[0024] Preparation methods include: (1). In vitro synthesis of chemically modified SLC39A1 mRNA: In vitro transcription was performed using the T7 ribonuclease system. In the reaction system, N1-me-pseudo-UTP was used to completely replace the natural UTP to reduce the immunogenicity of the mRNA, and CleanCap® AG reagent was added to achieve co-transcriptional capping, generating the 5' end of the mRNA with the Cap1 structure. After the reaction, the DNA template was removed by digestion with deoxyribonuclease I (DNase I), and the mRNA product was purified by lithium chloride precipitation and cellulose column chromatography to remove double-stranded ribonucleic acid (RNA) impurities. The purified mRNA was dissolved in 25 mM sodium citrate buffer (pH 4.0) and the concentration was adjusted to 0.3 mg / mL.

[0025] (2). Microfluidic assembly of mannose-modified lipid nanoparticles (Man-LNP): Organic phase preparation: Ionized cationic lipids, DSPC, cholesterol, PEG-DMG, and DSPE-PEG-Mannose were dissolved in anhydrous ethanol at a molar ratio of 50:10:37.5:1.5:1.0, resulting in a total lipid concentration of 15 mM. Aqueous phase preparation: An acidic buffer containing SLC39A1 mRNA prepared in the above steps. Using a microfluidic nanomedicine preparation system (e.g., NanoAssemblr®), the flow rate ratio of the aqueous phase to the organic phase was set to 4:1, with a total flow rate of 10 mL / min, allowing the two phases to rapidly mix within the microfluidic chip to form primary nanoparticles.

[0026] (3) Purification and Characterization: The primary nanoparticle solution was collected and immediately replaced with buffer using a tangential flow filtration (TFF) system (molecular weight cutoff 100 kDa). The dialysis medium was phosphate-buffered saline (PBS, pH 7.4), with a replacement volume 30 times the sample volume to remove ethanol and adjust the external pH to neutral. Dynamic light scattering (DLS) analysis revealed that the average particle size of the obtained Man-LNPs was 105 ± 3 nm, the polydispersity index (PDI) was 0.12, and the zeta potential was -4.1 mV. The mRNA encapsulation efficiency was determined to be 95.5% using RiboGreen reagent. TNS probe titration confirmed an apparent pKa of 6.35 for the LNPs.

[0027] In vitro performance evaluation includes: (1) Cellular uptake and targeting: Cy5-labeled Man-LNP mRNA and unmodified mannose-containing LNP mRNA were co-incubated with MH-S cells and HPMEC cells for 4 hours, respectively. Flow cytometry analysis showed that in MH-S cells, the average fluorescence intensity of the Man-LNP group was 3.5 times that of the unmodified group, indicating that the mannose ligand significantly enhanced the uptake efficiency of macrophages. HPMEC cells also showed effective uptake of Man-LNP.

[0028] (2). SLC39A1 Expression and Function Verification: HPMEC cells were transfected with Man-LNP-SLC39A1 mRNA for 24 hours. Western blotting showed that the SLC39A1 protein expression level in the transfected group was approximately 5-fold higher than that in the control group. In the zinc ion influx experiment using the FluoZin-3 AM probe, under the condition of extracellular administration of 10 μM zinc source, the fluorescence intensity in the transfected group was significantly higher than that in the untransfected group, demonstrating that the exogenously expressed SLC39A1 protein has transport activity and can increase the intracellular free zinc level.

[0029] In vivo pharmacodynamic evaluation (LPS-induced ARDS model) includes: (1). Model establishment and drug administration: A mouse ARDS model was established by intratracheal instillation of LPS (5 mg / kg). One hour after model establishment, Man-LNP-SLC39A1 mRNA nebulizer solution (mRNA dose 0.5 mg / kg) was administered via a small animal nebulizer, and the administration was repeated once after 24 hours.

[0030] (2) Efficacy assessment was performed 48 hours after modeling. Results showed that compared to the LPS model group, the wet / dry weight ratio (W / D) of the lungs in the treatment group was significantly reduced (from 6.7 to 5.0), indicating improved pulmonary edema. The total protein content and levels of inflammatory factors (IL-1β, TNF-α) in the bronchoalveolar lavage fluid (BALF) were significantly decreased. Histopathological examination of lung tissue sections (hematoxylin and eosin, H&E) showed that alveolar structural damage, inflammatory cell infiltration, and hemorrhage were significantly reduced in the treatment group compared to the model group.

[0031] (3) Synergistic effect verification: An experimental group was set up in which a low concentration of zinc gluconate (0.2 mg / kg) was added to the Man-LNP-SLC39A1 mRNA nebulizer while administering the nebulizer. The results showed that the combined administration group was more effective than the group that used the mRNA preparation alone in reducing the lung W / D ratio and inhibiting inflammatory factors, indicating that supplementing the SLC39A1 transporter while providing the zinc substrate can produce a synergistic therapeutic effect.

[0032] Example 2 This embodiment illustrates the screening and validation of other types of SLC39A1-specific regulators besides mRNA. Other types of regulators can also achieve the technical effects of this invention.

[0033] A small molecule agonist, Z1-A, was screened using a cell-based high-throughput screening platform for zinc ion influx. Surface plasmon resonance (SPR) analysis showed that Z1-A has a dissociation constant (KD) of 5.2 nM with human SLC39A1 protein. Selectivity experiments demonstrated that Z1-A did not significantly increase zinc influx in cells overexpressing the family proteins SLC39A8 or SLC39A14, with a selectivity ratio greater than 60-fold. In a mouse ARDS model, Z1-A was encapsulated in the Man-LNP described in Example 1 and nebulized, resulting in reduced pulmonary edema and suppressed inflammation.

[0034] A CRISPR / Cas13 gene editing component was designed to specifically target the adenine-uracil-rich element (ARE) in the 3'-UTR of SLC39A1 mRNA (CRISPR RNA, crRNA). Here, CRISPR refers to clustered regularly interspaced short palindromic repeats. An LNP containing Cas13d protein mRNA and the aforementioned crRNA was constructed. Upon entry into cells, the Cas13d-crRNA complex binds to and masks the unstable element on SLC39A1 mRNA, thereby inhibiting its degradation. Testing in HPMEC cells showed that treatment with this system prolonged the half-life of endogenous SLC39A1 mRNA by approximately 2.5-fold and significantly increased the level of stable protein.

[0035] Example 3 This embodiment illustrates the further processing of the LNP suspension prepared in Example 1 into a dry powder inhaler (DPI) form suitable for long-term storage and portable use.

[0036] The Man-LNP-SLC39A1 mRNA suspension purified by TFF in Example 1 was mixed with leucine and mannitol as excipients to achieve a total solids content of 2% (weight / volume, w / v), with a lipid:leucine:mannitol mass ratio of 1:1:2. The mixture was spray-dried with the following parameters: inlet air temperature 95°C, outlet air temperature 55°C, and atomizing gas flow rate 650 L / h. The resulting powder was collected and characterized. Scanning electron microscopy (SEM) revealed a wrinkled surface on the microspheres. Aerodynamic performance was measured using a Next Generation Impactor (NGI). The results showed a mass median aerodynamic diameter (MMAD) of 3.1 μm and a fine particle fraction (FPF, i.e., the proportion of particles with an aerodynamic diameter <5 μm) of 62%, indicating that the microspheres are suitable for deep lung deposition.

[0037] Example 4 Please see Figure 1This embodiment provides a typical operating procedure for treating ARDS patients in a clinical setting based on the technical solution of the present invention. This procedure strictly adheres to the design concepts of "precision medicine" and "closed-loop management throughout the entire process," ensuring that the drug is used only in patients with clear molecular pathological characteristics and guaranteeing the on-site activity of the formulation and the effectiveness of drug administration.

[0038] Step 1: Patient screening and stratified diagnosis. For patients admitted to the intensive care unit and diagnosed with ARDS (Berlin definition), biomarker screening is performed during the inflammatory exudative phase within 24 to 48 hours of onset.

[0039] The specific procedure is as follows: Collect 5 mL of peripheral venous blood and (if conditions permit) BALF sample from the patient. Peripheral blood mononuclear cells (PBMCs) are separated using density gradient centrifugation, and total RNA is extracted. The relative expression level of the SLC39A1 gene is detected using real-time quantitative polymerase chain reaction (RT-qPCR), with the housekeeping gene GAPDH used as an internal control. Simultaneously, plasma zinc ion concentration is measured using inductively coupled plasma mass spectrometry (ICP-MS) or colorimetric methods.

[0040] Inclusion and Dosing Criteria: The treatment program for the drug in this embodiment was initiated only if the test results met both of the following conditions: (1) the expression level of SLC39A1 in PBMCs or BALF cells was less than 70% of the baseline value for healthy individuals of the same age; and (2) there was evidence of systemic hypozincemia (plasma zinc <70 μg / dL) or localized pulmonary zinc deficiency. This step ensured targeted treatment and avoided ineffective intervention in non-SLC39A1-deficient patients.

[0041] Step two, on-site preparation of the drug formulation, is performed using the dedicated dual-chamber pre-filled nebulizer described in the examples. The first compartment of the device is sealed with Man-LNP-SLC39A1 mRNA lyophilized powder (containing 5% sucrose protectant) prepared in Example 3 under sterile and anhydrous conditions, and the second compartment is sealed with a reconstitution solvent (containing 0.5 mM zinc gluconate and 0.01% (w / v) polysorbate 80 in water for injection).

[0042] Operating Procedure: Healthcare professionals open the sterile packaging at the bedside and firmly press the pusher at the end of the device to allow the central rubber stopper to slide out or the bypass channel to open, thus forcing the solvent from the second compartment into the first compartment. Then, gently shake the device horizontally at a frequency of 2 Hz for 60 seconds until the lyophilized powder is completely dissolved. At this point, the drug solution should be visually inspected. A qualified solution should be a translucent, bluish-white, homogeneous colloidal solution without any visible precipitates or particles. The particle size of the mRNA-LNP complex in the reconstituted solution should return to the 100-120 nm range, and it must be used within 2 hours of preparation to prevent mRNA degradation or lipid fusion.

[0043] Step three involves administering the drug via nebulization. The reconstituted drug solution prepared in step two (typically 2 to 4 mL) is injected into the drug cup of a medical vibrating screen nebulizer. This type of nebulizer generates a low-velocity aerosol, minimizing damage to the shear-sensitive mRNA-LNP structure. Examples of medical vibrating screen nebulizers include the Aeron Solo.

[0044] Dosage parameter settings: Connect the nebulizer to the inspiratory end of the ventilator circuit (15-20 cm from the Y-tube) or via a nasal high-flow oxygen therapy cannula. Adjust the nebulization rate to 0.3-0.5 mL / min to ensure the generated aerosol MMAD is stable at 1-5 μm, guaranteeing effective drug deposition in the deep alveoli and bronchioles. Dosage regimen: The initial dose is a loading dose (e.g., 0.5 mg / kg mRNA), administered as soon as possible after diagnosis and stratification; followed by a maintenance dose every 12-24 hours for 3-5 days until the cytokine storm has passed.

[0045] Step four, efficacy monitoring and endpoint assessment: During treatment, implement strict closed-loop monitoring to assess the pharmacodynamic response and safety of the drug.

[0046] Primary efficacy endpoints: Daily monitoring of oxygenation index (PaO2 / FiO2), aiming for recovery to above 300 mmHg; monitoring of lung compliance and absorption of exudates in chest computed tomography (CT) or ultrasound images. Molecular biological endpoints: Peripheral blood samples will be collected again at 48 and 72 hours post-drug administration to detect the recovery of SLC39A1 mRNA expression in PBMCs (aiming for recovery to above 90% of baseline) and the decreasing trend of plasma inflammatory factors (such as IL-6, IL-1β). Safety monitoring: Due to the presence of zinc cofactors in the drug, serum ceruloplasmin and plasma copper concentrations should be monitored daily to prevent secondary copper deficiency due to excessive zinc intake; liver and kidney function indicators should also be monitored to ensure that lipid carrier metabolites do not cause cumulative toxicity. If unexplained bronchospasm or allergic reactions occur, administration should be stopped immediately and symptomatic treatment should be given.

[0047] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0048] Finally, it should be noted that although embodiments of the present invention have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. The application of an SLC39A1-specific modulator in the preparation of drugs for treating acute respiratory distress syndrome, characterized in that, The drug comprises a therapeutically effective amount of an SLC39A1-specific regulator and a pharmaceutically acceptable lung-directed delivery vector. The SLC39A1-specific regulator is selected from the group consisting of nucleic acid molecules that specifically upregulate SLC39A1 gene expression, small molecule compounds that enhance the zinc transport activity of SLC39A1 protein, and recombinant proteins. The lung-directed delivery vector is configured to target the SLC39A1-specific regulator to alveolar macrophages or pulmonary microvascular endothelial cells.

2. The application according to claim 1, characterized in that, The SLC39A1-specific regulator is a nucleic acid drug targeting SLC39A1 messenger ribonucleic acid (RNA). The nucleic acid drug is selected from at least one of the following: messenger ribonucleic acid encoding full-length or functionally truncated human SLC39A1 protein; antisense oligonucleotides that specifically inhibit endogenous negative regulators of SLC39A1; small interfering RNAs that specifically inhibit endogenous negative regulators of SLC39A1; and gene editing components that specifically stabilize SLC39A1 transcripts based on the CRISPR / Cas13 system. The messenger ribonucleic acid contains chemically modified nucleotides, has a Cap1 structure at its 5' end, and a PolyA tail at its 3' end. The endogenous negative regulator includes microRNAs or ubiquitin ligases that target and degrade SLC39A1 messenger ribonucleic acid.

3. The application according to claim 1, characterized in that, The lung-directed delivery carrier is an inhaled lipid nanoparticle, which is composed of ionized cationic lipids, helper phospholipids, cholesterol, and polyethylene glycol lipid derivatives. The acid dissociation constant of the ionized cationic lipids is 6.0 to 6.

5. The average particle size of the inhaled lipid nanoparticles is between 80 and 150 nanometers and the polydispersity index is less than 0.

2. The surface of the inhaled lipid nanoparticles is modified with macrophage-targeting ligands selected from mannose, β-glucan, or anti-CD206 antibody fragments.

4. The application according to claim 1, characterized in that, The drug also contains a zinc homeostasis cofactor, which is selected from at least one of metallothionein inducers, antioxidant N-acetylcysteine, or physiological concentrations of zinc gluconate. The SLC39A1 specific regulator and the zinc homeostasis cofactor constitute a compound preparation.

5. The application according to claim 1, characterized in that, The drug formulation is in the form of a dry powder inhaler or a nebulized inhalation liquid; when prepared as a dry powder inhaler, the drug comprises porous microspheres with an aerodynamic particle size of 1 to 5 micrometers, the porous microspheres being prepared by spray drying of an SLC39A1 specific regulator carrier and leucine or mannitol excipients, the porous microspheres having a wrinkled surface and the fine particle fraction of the porous microspheres exceeding 50%.

6. The application according to claim 1, characterized in that, The acute respiratory distress syndrome (ARDS) encompasses a pathological condition caused by sepsis, pneumonia, mechanical ventilation-induced lung injury, inhalation injury, or coronavirus infection. The drug is indicated for the treatment of patients with ARDS who are in the cytokine storm phase and have hypozincemia.

7. The application according to any one of claims 1 to 6, characterized in that, The drug is indicated for subjects whose SLC39A1 expression levels in peripheral blood mononuclear cells or bronchoalveolar lavage fluid are below 70 percent of the healthy baseline and who have systemic or local zinc deficiency.

8. The application according to claim 1, characterized in that, The SLC39A1-specific regulator is a small molecule agonist, the small molecule agonist has a binding affinity of less than 10 nanomolars for the SLC39A1 protein, and the small molecule agonist has a selectivity ratio of more than 50-fold for the SLC39A8 or SLC39A14 proteins of the same family.

9. The application according to claim 3, characterized in that, The inhaled lipid nanoparticles are prepared by a method comprising the following steps: mixing an ethanol phase containing dissolved lipid components with an acidic buffer aqueous phase containing dissolved SLC39A1 specific regulator in a microfluidic chip at a flow rate ratio of 3:1 to 5:1 to form primary nanoparticles; subsequently, replacing the external buffer with a neutral pH phosphate buffer or lyophilization protection solution using a tangential flow filtration system; the encapsulation efficiency of the SLC39A1 specific regulator in the resulting inhaled lipid nanoparticles exceeds 90%.

10. The application according to claim 1, characterized in that, The drug is a pre-filled nebulized inhalation formulation comprising a first compartment containing a lyophilized SLC39A1 messenger ribonucleic acid lipid nanoparticle complex and a second compartment containing 0.1 to 1.0 mmol / L zinc gluconate and 0.01% polysorbate 80 reconstitution solvent.

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