L-Arginine and Drug Delivery Systems: Applications of Nanotechnology

L-Arginine (L-Arg), a semi-essential amino acid in the human body, exhibits significant physiological activities in regulating vasomotor function, exerting anti-inflammatory and antioxidant effects, and promoting tissue repair. It shows broad application prospects in the fields of cardiovascular diseases, respiratory diseases, and wound repair. However, traditional L-arginine formulations suffer from drawbacks such as low bioavailability, poor targeting ability, and short in vivo half-life, which limit their clinical application value. The advancement of nanotechnology provides a core solution for optimizing the drug delivery system (DDS) of L-arginine. By constructing nanocarriers to load L-arginine, it is possible to achieve targeted delivery, sustained/controlled release, enhanced bioavailability, and synergistic effects, thus greatly expanding the clinical application scenarios of L-arginine. This article systematically analyzes the construction strategies, core advantages, and application value of L-arginine nanodrug delivery systems in different disease fields.

I. Construction Strategies and Core Carrier Types of L-Arginine Nanodrug Delivery Systems

The core of a nanodrug delivery system is to realize the encapsulation, protection, and precise delivery of L-arginine through the properties of carrier materials. According to the differences in the nature and structure of carrier materials, nanodelivery systems suitable for L-arginine are mainly divided into four categories: natural polymer nanocarriers, synthetic polymer nanocarriers, lipid-based nanocarriers, and inorganic nanocarriers. Each type of carrier has distinct construction strategies and performance characteristics.

1. Natural Polymer Nanocarriers: Green Delivery Systems with Excellent Biocompatibility

Natural polymer materials possess advantages such as good biocompatibility, biodegradability, and low toxicity, making them ideal carriers for L-arginine nanodelivery systems. The main types include chitosan, gelatin, sodium alginate, and albumin.

Chitosan nanoparticles: Chitosan is a cationic polysaccharide that can encapsulate L-arginine via ion gelation or emulsification-crosslinking methods. Its amino groups can form ionic bonds with the carboxyl groups of L-arginine to achieve stable encapsulation. Meanwhile, the cationic property of chitosan can enhance adhesion to negatively charged cells (e.g., vascular endothelial cells, tumor cells), improving cellular uptake efficiency. In addition, chitosan can be degraded by lysozyme, and its in vivo metabolites are non-toxic, ensuring high safety. By adjusting the molecular weight, degree of deacetylation of chitosan, and crosslinking agent concentration, the release rate of L-arginine can be precisely regulated to achieve long-term sustained release.

Albumin nanoparticles: Human serum albumin or bovine serum albumin can load L-arginine via the desolvation-crosslinking method, utilizing the hydrophobic cavity of albumin to bind to the hydrophobic region of L-arginine and form stable nanoparticles. Albumin nanoparticles have good biocompatibility and biodegradability, and can achieve targeted delivery to lesion tissues by modifying targeting ligands (e.g., RGD peptide, folic acid) on the surface. For example, albumin nanoparticles loaded with L-arginine and modified with RGD peptide can specifically recognize integrin receptors on the surface of vascular endothelial cells, enabling targeted enrichment in the treatment of ischemic cardiovascular diseases.

2. Synthetic Polymer Nanocarriers: Smart Delivery Systems with High Controllability

Synthetic polymer materials feature controllable structure, high drug loading capacity, and adjustable drug release characteristics. Smart nanocarriers with environmental responsiveness can be designed through chemical synthesis to realize intelligent release of L-arginine. The main types include poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and polycaprolactone (PCL).

PLGA nanoparticles: PLGA is an FDA-approved biodegradable synthetic polymer that can efficiently encapsulate L-arginine via the emulsification-solvent evaporation method. The degradation rate of PLGA can be regulated by adjusting the ratio of lactic acid to glycolic acid, enabling immediate or sustained release of L-arginine. More importantly, PLGA nanoparticles can be engineered into pH-responsive delivery systems—in acidic environments (e.g., tumor microenvironment, inflammatory sites), the degradation rate of PLGA accelerates, leading to rapid release of L-arginine; whereas in neutral physiological environments, the degradation rate is slow, prolonging the drug half-life. This pH-responsive release property can significantly increase the concentration of L-arginine at lesion sites and reduce systemic side effects.

PEGylated nanocarriers: Modifying the surface of nanocarriers such as PLGA and chitosan with PEG can form "stealth nanoparticles", which avoid phagocytosis by the mononuclear phagocyte system (MPS) and extend the in vivo circulation time. PEGylated L-arginine nanoparticles are more stable in the blood circulation and can be targeted to tumor or inflammatory tissues through the enhanced permeability and retention (EPR) effect, making them particularly suitable for scenarios such as tumor angiogenesis inhibition and chronic inflammation treatment.

3. Lipid-Based Nanocarriers: Lipophilic Delivery Systems with High Bioavailability

As a water-soluble amino acid, L-arginine can have its cellular uptake efficiency improved by lipid-based nanocarriers through membrane fusion or endocytosis. The main types include liposomes, nanoemulsions, and solid lipid nanoparticles (SLN).

Liposomes: Vesicular structures composed of phospholipid bilayers that can encapsulate L-arginine in the aqueous core via the thin-film hydration method. Liposomes have good biocompatibility and can fuse with cell membranes to directly release L-arginine into cells, avoiding lysosomal degradation and improving bioavailability. Targeted delivery of L-arginine to ischemic myocardium or tumor blood vessels can be achieved by modifying the liposome surface with targeting ligands (e.g., antibodies against vascular endothelial growth factor receptors). In addition, cationic liposomes can bind to negatively charged cell membranes through electrostatic interactions, further enhancing cellular uptake efficiency, and are suitable for combined gene therapy—for instance, cationic liposomes loaded with L-arginine and vascular endothelial growth factor (VEGF) siRNA can synergistically inhibit tumor angiogenesis.

Solid lipid nanoparticles (SLN): Nanoparticles prepared from solid lipid materials that can load L-arginine via the melt-emulsification method. SLN have advantages such as high drug loading capacity, good physical stability, and scalability for large-scale production. Moreover, the controlled release of L-arginine can be achieved by adjusting the melting point of lipid materials. For example, when SLN loaded with L-arginine are applied topically to the skin, they can slowly penetrate the skin barrier and continuously release the drug in the dermis, which is suitable for wound repair and skin anti-aging treatment.

4. Inorganic Nanocarriers: Multifunctional Composite Delivery Systems

Inorganic nanomaterials have unique physicochemical properties that can be used to construct multifunctional composite delivery systems, realizing targeted delivery and theranostics integration of L-arginine. The main types include mesoporous silica nanoparticles (MSNs), magnetic nanoparticles (e.g., Fe₃O₄), and gold nanoparticles.

Mesoporous silica nanoparticles (MSNs): Possessing regular mesoporous structures and ultra-large specific surface areas, MSNs can efficiently adsorb L-arginine molecules. The pore size of MSNs can be precisely regulated to achieve accurate control over the loading capacity and release rate of L-arginine. Meanwhile, their surface can be modified with targeting ligands and fluorescent probes to enable targeted delivery and real-time tracking. For example, MSNs loaded with L-arginine and modified with tumor-targeting peptides can accumulate at tumor sites and release the drug to inhibit tumor angiogenesis, while monitoring drug distribution via fluorescent signals to achieve theranostics integration.

Magnetic nanoparticles: Nanoparticles with Fe₃O₄ cores that can load L-arginine via the co-precipitation method and achieve targeted enrichment under the guidance of an external magnetic field. Magnetic L-arginine nanoparticles can be accurately delivered to sites such as ischemic myocardium and infarcted brain tissue under magnetic guidance, increasing local drug concentration. Additionally, magnetic nanoparticles can generate local hyperthermia through magnetothermal effects while releasing L-arginine, achieving synergistic treatment of tumors or inflammatory tissues.

II. Core Advantages of L-Arginine Nanodrug Delivery Systems

Compared with traditional L-arginine formulations, nanodrug delivery systems exhibit significant advantages in bioavailability, targeting ability, drug release characteristics, and synergistic effects through the optimization of carrier properties, which are specifically reflected in the following four aspects.

1. Enhanced Bioavailability and Extended In Vivo Half-Life

Traditional oral L-arginine is easily degraded by arginase in the gastrointestinal tract and undergoes significant first-pass metabolism in the liver, resulting in extremely low bioavailability (less than 20%). In contrast, nanocarriers can protect L-arginine from enzymatic degradation and first-pass metabolism, significantly enhancing bioavailability. For example, L-arginine encapsulated in chitosan nanoparticles has improved stability in the gastrointestinal tract, is less susceptible to arginase degradation, and chitosan can promote uptake by intestinal epithelial cells, increasing bioavailability by 3–5 times. Meanwhile, PEGylated nanocarriers can avoid phagocytosis by the MPS, extending the half-life of L-arginine in the blood circulation from 1–2 hours (traditional formulations) to 12–24 hours, thus reducing the frequency of administration.

2. Targeted Delivery and Reduced Systemic Side Effects

Traditional L-arginine formulations are widely distributed in the body, difficult to accumulate at lesion sites, and prone to cause systemic side effects such as gastrointestinal discomfort and headache. In contrast, nanodelivery systems can achieve precise enrichment of L-arginine at lesion tissues through active or passive targeting mechanisms. Passive targeting relies on the EPR effect to accumulate nanoparticles at sites with high vascular permeability (e.g., tumors, inflammation); active targeting achieves recognition and binding to specific cells by modifying targeting ligands on the surface. For example, L-arginine liposomes modified with vascular endothelial cell-targeting peptides can be specifically enriched in ischemic myocardium, increasing local drug concentration by 10–20 times and significantly reducing systemic side effects.

3. Regulated Drug Release Rate to Match Disease Treatment Needs

Different diseases have different requirements for the administration rate of L-arginine—acute diseases (e.g., acute lung injury, myocardial infarction) require rapid drug release to exert efficacy quickly, while chronic diseases (e.g., hypertension, chronic obstructive pulmonary disease) require long-term sustained release to maintain stable blood drug concentration. Nanodelivery systems can achieve immediate, sustained, or pulsatile release of L-arginine through the selection of carrier materials and structural design. For example, PLGA nanoparticles can realize sustained release of L-arginine by adjusting the lactic acid/glycolic acid ratio, which is suitable for the long-term treatment of chronic cardiovascular diseases; pH-responsive nanoparticles can release drugs rapidly in the acidic environment of inflammatory sites, making them suitable for the treatment of acute inflammation.

4. Synergistic Therapy and Expanded Clinical Application Scenarios

Nanocarriers can load multiple drugs or therapeutic factors simultaneously, realizing synergistic therapy of L-arginine with other drugs to improve treatment efficacy. For example, liposomes loaded with L-arginine and paclitaxel can inhibit tumor angiogenesis via L-arginine while killing tumor cells via paclitaxel, synergistically enhancing anti-tumor effects; chitosan nanoparticles loaded with L-arginine and siRNA can improve vascular endothelial function via L-arginine while silencing pro-inflammatory genes via siRNA, achieving synergistic treatment of atherosclerosis. This synergistic therapy strategy greatly expands the clinical application scenarios of L-arginine.

III. Clinical Application Scenarios of L-Arginine Nanodrug Delivery Systems

Based on the above advantages, L-arginine nanodrug delivery systems have demonstrated clear application value in the fields of cardiovascular diseases, tumor therapy, respiratory diseases, and wound repair, providing new schemes for the precise treatment of diseases.

1. Cardiovascular Disease Treatment

In cardiovascular diseases such as coronary heart disease, myocardial infarction, and pulmonary arterial hypertension, L-arginine nanodelivery systems can achieve targeted vascular repair and functional regulation. For example, RGD-modified nanoparticles loaded with L-arginine can dilate blood vessels, improve myocardial microcirculation, promote myocardial angiogenesis, and repair damaged myocardial tissue by targeting vascular endothelial cells. In the treatment of pulmonary arterial hypertension, magnetic L-arginine nanoparticles can be targeted to pulmonary blood vessels under external magnetic guidance, releasing L-arginine to dilate pulmonary arterioles and reduce pulmonary arterial pressure, while avoiding the systemic hypotension side effects caused by traditional oral formulations.

2. Tumor Therapy

L-arginine can exert anti-tumor effects by inhibiting tumor angiogenesis and enhancing immune cell activity, and nanodelivery systems can further improve its targeting ability and efficacy. For example, PEGylated PLGA nanoparticles loaded with L-arginine can accumulate in tumor tissues through the EPR effect, releasing L-arginine to inhibit the proliferation of tumor vascular endothelial cells, while reducing the vascular permeability of tumor tissues and decreasing the risk of tumor metastasis. In addition, nanoparticles loaded with L-arginine and immune checkpoint inhibitors can synergistically activate the anti-tumor immune response of the body, improving the efficacy of immunotherapy.

3. Respiratory Disease Treatment

In respiratory diseases such as acute lung injury, asthma, and chronic obstructive pulmonary disease, nebulized inhalable L-arginine nanoformulations can directly act on the airways and lung tissue, enhancing local therapeutic efficacy. For example, solid lipid nanoparticles loaded with L-arginine, after nebulized inhalation, can penetrate the airway mucus barrier and accumulate in alveolar epithelial cells, releasing L-arginine to generate NO, dilate airway smooth muscle, reduce pulmonary inflammation, and promote the repair of the alveolar epithelial barrier, which is suitable for the adjuvant treatment of acute respiratory distress syndrome.

4. Wound Repair and Skin Health

L-arginine nanodrug delivery systems have unique advantages in skin wound repair and anti-aging. When chitosan nanoparticles loaded with L-arginine are applied topically, they can promote the proliferation of skin fibroblasts and collagen synthesis, accelerating wound healing; meanwhile, their anti-inflammatory and antioxidant effects can reduce the inflammatory response of wounds and lower the risk of scar formation. In terms of skin anti-aging, liposomes loaded with L-arginine can penetrate the stratum corneum of the skin and continuously release the drug in the dermis, improving skin microcirculation, promoting collagen synthesis, and reducing wrinkle formation. Moreover, the moisturizing properties of nanocarriers can further enhance the skin care effect.

Despite the significant progress made in L-arginine nanodrug delivery systems, several challenges remain: first, the biocompatibility and degradation product toxicity of some synthetic polymer carriers need further verification, especially the safety of long-term administration; second, the large-scale production process of nanoformulations is complex and the production cost is high, which limits their clinical translation; third, the in vivo pharmacokinetic and pharmacodynamic studies of nanocarriers are insufficient, lacking support from large-sample clinical data.

In the future, efforts should be made to promote the development of L-arginine nanodrug delivery systems from the following three aspects: first, develop composite carriers of natural and synthetic polymers to balance biocompatibility and controllability; second, optimize the preparation process of nanoformulations to achieve large-scale, low-cost production; third, conduct multi-center, large-sample clinical studies to clarify the optimal administration scheme, efficacy, and safety of different nanoformulations in different diseases. With the integrated development of precision medicine and nanotechnology, L-arginine nanodrug delivery systems are expected to become a new generation of targeted therapeutic drugs, providing new strategies for the treatment of various diseases.