Nanotechnology is demonstrating revolutionary potential in the treatment of liver diseases. By designing sophisticated nanocarriers such as liposomes, polymer micelles, and inorganic nanoparticles, drugs can be precisely delivered to the lesion sites in the liver, significantly increasing the drug concentration in the affected areas while minimizing damage to healthy tissues. This targeted ability not only greatly enhances the utilization rate and therapeutic effect of drugs but also helps overcome many bottlenecks in traditional drug treatments, such as improving the solubility of poorly soluble drugs (like sorafenib), achieving controlled release to maintain steady-state blood drug concentration, and crossing complex physiological barriers such as the sinusoidal endothelium in the liver. Furthermore, nanotechnology has advanced the development of integrated diagnosis and treatment. Nanoplatforms that integrate contrast agents and therapeutic drugs can achieve real-time imaging and monitoring of the treatment process during drug administration. Additionally, these intelligent carriers can be designed to respond to the microenvironment of lesions (such as specific pH values, enzymes, or oxidative stress levels), enabling precise drug release. This multifunctional characteristic allows a single nanosystem to simultaneously load chemotherapy drugs, gene drugs, or immunomodulators, providing a brand-new solution for the combined treatment of various liver diseases, including liver fibrosis reversal, liver cancer, viral hepatitis, and fatty liver. Currently, several nanomedicines, such as liposomal doxorubicin and polymer nanomicelles, are advancing through various phases of development, signifying a shift from experimental to practical application. Despite ongoing challenges in large-scale production and long-term safety evaluation, the strong integration of nanotechnology with materials science and biology is clearly driving the treatment of liver diseases toward a new era marked by greater precision and effectiveness.
The pathogenesis of liver diseases is highly complex, involving multiple intertwined pathological and physiological pathways. Initially, hepatocytes are directly damaged by factors such as viruses, alcohol, metabolic disorders, or drugs, leading to cell necrosis, infiltration of inflammatory cells, and oxidative stress. This, in turn, triggers the production of cytokines (such as TNF-α, IL-6) and activated stellate cells, resulting in excessive collagen deposition, fibrosis, and ultimately cirrhosis. At the same time, the imbalance of the "gut-liver axis" allows bacterial products and endotoxins to enter the portal vein through a damaged intestinal barrier, further exacerbating liver inflammation and immune dysfunction.
When liver function deteriorates, metabolic by-products like bilirubin, bile acids, and ammonia accumulate, leading to jaundice, cholestasis, and hepatic encephalopathy. Portal hypertension, caused by increased portal vein resistance, leads to the formation of collateral circulation, esophageal and gastric varices, and ascites. In terms of treatment, these pathological features create multiple barriers:
Structural Barrier: Fibrosis and nodular changes alter the liver sinusoidal structure, limiting drug penetration and distribution in liver tissue.
Metabolic Barrier: Hepatocyte damage leads to reduced activity of drug-metabolizing enzymes (CYP450), increasing drug accumulation or toxicity.
Immune Barrier: Immune dysfunction and an inflammatory microenvironment accompanying cirrhosis limit the effectiveness of immunomodulatory therapies.
Systemic Barrier: Portal hypertension and collateral circulation reduce the first-pass effect in the portal venous blood flow, lowering drug concentration at the target site.
Heterogeneity Barrier: Different etiologies (viral, alcoholic, metabolic) and disease stages (acute injury, chronic fibrosis) lead to diverse therapeutic targets, lacking a unified, precise treatment approach.
Enhanced Bioavailability: Nanoparticles significantly increase the solubility and stability of drugs, improving the absorption of poorly soluble or easily degradable drugs, thereby raising their concentration in the body.
Precise Targeting: Through surface functionalization (such as ligands, antibodies, or biomimetic layers), nanoparticles can actively recognize and enter specific tissues or cells, greatly reducing exposure to healthy tissues and minimizing systemic side effects.
Controlled Release: Nanoparticles can be designed to release drugs slowly or triggered by specific environments (e.g., pH, enzymes, temperature), enabling sustained therapeutic effects and reducing the frequency of administration.
Protection from Degradation: Nanocarriers encapsulate drugs, preventing enzymatic breakdown or rapid metabolism in the bloodstream, thus extending the drug's half-life and improving storage stability.
Multiple Routes of Administration: Nanoparticles are suitable for a variety of delivery methods, including oral, injectable, inhalation, nasal, and ocular routes, broadening the range of potential treatments.
Reduced Dose and Toxicity: Due to their targeted delivery and high efficiency, the required drug dose can be significantly reduced, thereby minimizing the drug's toxicity and adverse effects.
Overcoming Biological Barriers: The small size and surface modifications of nanoparticles enable them to cross challenging barriers like the blood-brain barrier, mucosal barriers, and other difficult-to-reach sites, enhancing treatment potential for refractory diseases.
The key to enhancing treatment efficacy in liver diseases lies in the controlled and targeted release of drugs to the affected hepatic tissue. Nanoparticles can be engineered to release their payload in response to specific stimuli within the liver environment, such as changes in pH, enzymatic activity, or other biological signals.
For example, in fibrotic liver tissue, the lower pH (around 6.5) created by lactic acid accumulation can trigger pH-sensitive nanoparticles, such as histidine-PLA (poly-lactic acid) block copolymer micelles. These nanoparticles expand and increase their pore size at lower pH levels, allowing for controlled drug release. Such pH-triggered release systems can ensure minimal systemic exposure while significantly enhancing the local drug concentration within the fibrotic liver tissue.
Another promising approach involves enzyme-triggered drug release. Hepatic stellate cells, which play a central role in liver fibrosis, overexpress matrix metalloproteinases (MMPs). Nanoparticles designed with MMP-sensitive peptide sequences can selectively release their therapeutic cargo upon interaction with these enzymes. This strategy has been shown to significantly prolong the retention time of drugs in fibrotic tissues, further improving treatment outcomes.
Additionally, light-responsive nanoparticles offer another level of control. By incorporating near-infrared (NIR) dyes into mesoporous silica nanoparticles, the release of drugs such as doxorubicin can be triggered upon exposure to NIR laser light. This "on-demand" drug release system allows for highly localized and precise drug delivery, minimizing off-target effects while maximizing therapeutic efficacy in liver tumors.
Fig.1 Nanoparticle functionalization for liver damage treatment1,2.
Targeted delivery of therapeutic agents to the liver is a critical focus within nanomedicine. Various nanoparticle systems, due to their unique physicochemical properties and biological behaviors, have been developed for this purpose. These systems can encapsulate a range of therapeutic molecules, including drugs and gene-based treatments, protecting them from degradation and enhancing their accumulation in the liver through either passive or active targeting mechanisms. The selection of the appropriate nanoparticle type is crucial to achieving effective liver-targeted therapy, with each type offering distinct advantages and specific applications.
Lipid Nanoparticles (LNPs): Composed of biocompatible lipids, LNPs are widely utilized for liver drug delivery due to their low immunogenicity and biodegradability. These nanoparticles are highly effective at encapsulating hydrophobic drugs and large hydrophilic molecules such as nucleic acids. In gene delivery, LNPs typically contain ionizable cationic lipids that, in acidic environments, become positively charged and form stable complexes with negatively charged nucleic acids. At physiological pH, these particles become neutral, minimizing non-specific interactions and toxicity. Upon reaching liver cells, LNPs can enter via endocytosis, releasing their genetic cargo into the cytoplasm to enable protein expression or gene silencing.
For small-molecule drug delivery, Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) are common choices. These particles offer high drug-loading capacity, excellent storage stability, and controlled release profiles. SLNs loaded with liver-protective drugs have demonstrated promising effects in reducing liver damage in preclinical studies.
Polymeric Nanocarriers provide an effective solution for sustained drug release, particularly in chronic liver diseases that require long-term treatment. These carriers are made from natural or synthetic polymers and can be engineered to control the release kinetics of drugs through adjustments in degradation rates and molecular structures.
Poly (lactic-co-glycolic acid) (PLGA) is a widely studied biodegradable synthetic polymer. Its degradation products, lactic acid and glycolic acid, are naturally occurring intermediates in the body. By adjusting the ratio of lactic and glycolic acid and the molecular weight of PLGA, nanoparticles can be fabricated with release profiles ranging from days to months. This versatility is particularly valuable for the long-term management of chronic liver diseases.
Natural polymers like Chitosan and Alginate are also frequently used for liver-targeted delivery. Chitosan, with its inherent positive charge, interacts with negatively charged proteoglycans on liver cell surfaces, providing some degree of liver targeting. Alginate nanoparticles are known for their excellent water solubility and biocompatibility, making them ideal for the delivery of protein-based drugs.
Polymeric nanocarriers can be synthesized through methods such as emulsion-evaporation or nanoprecipitation, and surface modifications can be made to enhance targeting and pharmacokinetic properties.
Inorganic Nanoparticles: These materials, such as mesoporous silica and metal-organic frameworks (MOFs), have gained attention for liver-targeted delivery due to their unique magnetic, optical, and electronic properties. Inorganic nanoparticles are characterized by uniform size and shape, and their surfaces can be easily functionalized for enhanced targeting.
Mesoporous Silica Nanoparticles (MSNs): MSNs have well-ordered pore structures and high surface areas, allowing for the loading of large amounts of drugs. The silica hydroxyl groups on their surfaces facilitate the attachment of various targeting ligands. MSNs are chemically stable in physiological environments, protecting drug cargo from premature degradation.
Gold Nanoparticles (AuNPs): The size and shape of AuNPs can be adjusted to optimize their biodistribution and cellular uptake. Spherical AuNPs in the 10-100 nm range show favorable accumulation in the liver, while gold nanorods, due to their anisotropic structure, offer potential applications in photothermal therapy and imaging.
Magnetic Iron Oxide Nanoparticles (MIONs): These nanoparticles can be directed to liver lesions under an external magnetic field, enhancing their accumulation at the target site. MIONs also serve as contrast agents for magnetic resonance imaging (MRI), combining diagnostic and therapeutic capabilities.
Hybrid Systems: Hybrid nanoparticles combine the advantages of organic and inorganic materials. For example, lipid-polymer hybrid nanoparticles leverage the flexibility and biocompatibility of lipids along with the mechanical stability and high drug-loading capacity of polymers. These systems can be designed to release drugs in a controlled manner and improve targeting efficiency.
Ligand-Functionalized Nanoparticles enable targeted delivery to specific liver cell types by modifying the surface of nanoparticles with ligands that recognize and bind to overexpressed receptors on target cells. This active targeting strategy significantly enhances the uptake of nanoparticles into liver cells.
Galactosylation is a well-established strategy for targeting hepatocytes. The galactose moiety specifically binds to the asialoglycoprotein receptor (ASGPR) on liver cells, enabling receptor-mediated endocytosis. By anchoring galactose or its derivatives to nanoparticle surfaces, efficient liver cell targeting can be achieved.
For targeting hepatic stellate cells, nanoparticles are often functionalized with retinol or ligands that recognize the platelet-derived growth factor receptor (PDGFR), as these receptors are highly expressed on activated stellate cells during liver fibrosis. This targeted delivery is essential for antifibrotic therapies.
To target Kupffer cells, the abundant macrophages in the liver, ligands such as mannose, fucose, or specific peptides can be used. These ligands bind to pattern recognition receptors or scavenger receptors on Kupffer cells, enabling specific delivery of immunomodulatory drugs.
The density, spatial distribution, and binding affinity of ligands on the surface of nanoparticles are critical parameters influencing the targeting efficiency. Optimizing these factors can help balance nanoparticle stability in circulation and enhance their uptake by target cells. Additionally, the use of multiple ligands in combination can allow for precise targeting of complex cell populations in the liver, further improving therapeutic outcomes.
BOC Sciences offers versatile nanoparticles engineered for targeted drug delivery and therapeutic applications. Our customized solutions enhance treatment efficacy and precision.
The efficient accumulation and action of nanoparticles in the liver rely on a series of biological processes, covering multiple stages from initial targeting to eventual cellular uptake.
Nanoparticles can achieve liver targeting through both passive and active mechanisms.
Passive targeting depends on the physicochemical properties of the nanoparticles, especially their size. Research has shown that particles with a size range of 200-400 nm are naturally captured by the liver's mononuclear phagocyte system when injected intravenously, after which they are rapidly cleared. In contrast, particles smaller than 100 nm tend to accumulate more slowly in the bone marrow. This size-dependent distribution provides a foundational principle for designing liver-targeting nanocarriers.
Active targeting, on the other hand, involves modifying the surface of nanoparticles with specific ligands that can recognize and bind to receptors on particular liver cells. For instance, nanoparticles modified with galactose can target the asialoglycoprotein receptor, highly expressed on hepatocytes, while those modified with hyaluronic acid can target CD44 receptors overexpressed on activated hepatic stellate cells. Unlike passive targeting, active targeting does not rely on the physical properties of the particles but instead utilizes molecular recognition to achieve higher specificity.
Once nanoparticles enter the liver, their fate largely depends on their interactions with liver cells. Hepatocytes, as the primary functional cells of the liver, actively internalize specific nanoparticles through receptor-mediated endocytosis. For example, nanoparticles modified with galactose can be efficiently internalized by hepatocytes via binding to the asialoglycoprotein receptor.
Kupffer cells, the resident macrophages in the liver, play a crucial role in clearing nanoparticles from the blood circulation. These cells possess strong phagocytic capabilities and can quickly recognize and internalize most foreign nanoparticles. Studies indicate that up to 99% of systemically administered nanoparticles are eventually cleared by the liver, with Kupffer cells playing a central role. Interestingly, when the dose of nanoparticles exceeds a certain threshold, the phagocytic capacity of Kupffer cells may become saturated, leading to a reduction in liver retention of the particles and increased accumulation in other tissues.
The biodistribution and clearance of nanoparticles in the body are influenced by several factors. Apart from particle size, the surface charge, hydrophobicity, and material composition can all significantly affect their distribution and metabolic clearance. Positively charged particles tend to interact more readily with negatively charged cell membranes, facilitating cell uptake, whereas negatively charged or neutral particles may stay in circulation for longer periods.
In terms of clearance, smaller nanoparticles (typically<10 nm) are more easily filtered and cleared by the kidneys, while larger nanoparticles are primarily eliminated via the liver and biliary system, ultimately being excreted in the feces. Understanding these distribution and clearance characteristics is critical for designing nanoparticles with ideal pharmacokinetic profiles.
Successful liver-targeted delivery requires overcoming several biological barriers. For oral administration, nanoparticles must first traverse the intestinal epithelial barrier. Studies have shown that using bile acid transporters to mediate endocytosis can significantly enhance nanoparticle absorption in the intestine. For instance, corn protein nanocapsules functionalized with deoxycholic acid can leverage bile acid transporters to improve uptake by intestinal epithelial cells, thus enabling efficient oral liver-targeted delivery.
Once in the bloodstream, nanoparticles must pass through the fenestrated endothelial cells of the liver sinusoids to reach hepatocytes or hepatic stellate cells. Finally, nanoparticles need to be effectively internalized by specific cells and release their therapeutic payload inside the cell. To overcome these barriers, researchers have developed several strategies, including optimizing nanoparticle rigidity to enhance epithelial transport and using pH-sensitive materials to enable endosomal/lysosomal escape.
As nanotechnology and biomedicine continue to converge, liver-targeted nanoparticle systems are evolving towards more precise, intelligent, and efficient platforms.
Nanoparticle systems can simultaneously carry small molecule drugs and nucleic acid-based therapeutics such as siRNA, enabling synergistic treatment. For example, combining anti-fibrotic small molecules with siRNA targeting pro-fibrotic genes in the same nanoparticle carrier can address multiple stages of the fibrosis process simultaneously. This co-delivery strategy is especially beneficial for the long-term management of chronic liver diseases, as it can overcome challenges related to pharmacokinetic differences between different drugs while simplifying treatment regimens and improving patient compliance.
Intelligent, responsive nanoparticles that release drugs in response to specific pathological signals are emerging as a promising approach for liver disease treatment. These nanoparticles can be designed to respond to specific biomarkers in the fibrosis or inflammation microenvironment, such as reactive oxygen species, enzymes, or pH changes. For instance, a novel system based on STING (stimulator of interferon genes) alkylation has been developed to programmatically reverse liver fibrosis by degrading extracellular matrix components while specifically blocking the STING pathway in macrophages, ultimately disrupting the ECM-cell-ECM vicious cycle and reversing the fibrotic process.
Integrated diagnostic and therapeutic nanoparticle platforms, known as theranostic nanoparticles, represent the cutting edge of liver nanomedicine. These systems not only deliver therapeutic agents but also provide imaging contrast, enabling real-time monitoring of drug distribution and therapeutic responses. Nanoparticles functionalized for surface-enhanced Raman scattering (SERS) imaging, in combination with functionalized nanomaterials (such as iron oxide-based nanoparticles), can provide highly sensitive molecular imaging capabilities. This integration allows for real-time tracking of nanoparticle distribution and drug release during treatment.
Multifunctional platforms, such as gold nanocube systems, demonstrate the potential of such integration. These platforms can simultaneously achieve tumor imaging, chemotherapy, and photothermal therapy triggered by miRNA-21, while also offering fluorescence imaging capabilities.
In addition to optical imaging, nanoparticles can be integrated with other imaging techniques such as MRI, ultrasound, or positron emission tomography (PET), providing versatile solutions for diverse diagnostic requirements. This theranostic approach offers significant potential for personalized medicine, enabling treatment strategies to be dynamically tailored based on individual responses.
As material science, molecular biology, and nanotechnology continue to advance, liver-targeted nanoparticle systems are becoming increasingly sophisticated, intelligent, and efficient, offering new hope for the treatment of various liver diseases.
BOC Sciences offers remarkable technical strengths in the field of nanotechnology and hepatic medicine, providing high-quality, innovative nanoparticle design and customized solutions, particularly in liver-targeted drug delivery research. With a solid foundation in research and production, BOC Sciences has established itself as a leader in the development of advanced nanomedicines for liver diseases.
BOC Sciences specializes in custom nanoparticle design for liver research, offering tailored solutions based on specific research needs. We design nanoparticles with precise control over parameters such as particle size, surface characteristics, and drug loading capacity, ensuring that the nanoparticles are optimized for liver targeting. By incorporating advanced nanotechnology, we can develop nanoparticles that precisely target the liver, improving drug delivery efficiency while reducing off-target effects.
Table 1. Custom Nanoparticle-Based Drug Delivery Systems for Liver Diseases.
| Product Name | Description | Applicable Areas | Inquiry |
| Lipid Nanoparticles (LNPs) | Composed of biocompatible lipids, effective for encapsulating both hydrophilic and hydrophobic drugs, widely used in liver-targeted drug delivery. | Gene therapy, drug delivery | Inquiry |
| Polymeric Nanoparticles | Biodegradable and capable of sustained drug release, ideal for long-term treatment of chronic liver diseases. | Chronic liver diseases, fibrosis treatment | Inquiry |
| Gold Nanoparticles (AuNPs) | Biocompatible and magnetic, suitable for photothermal therapy and imaging in liver cancer treatment. | Liver cancer treatment, tumor imaging | Inquiry |
| Solid Lipid Nanoparticles (SLNs) | High drug-loading capacity, excellent storage stability, commonly used for small molecule drug delivery. | Small molecule drug delivery | Inquiry |
| Magnetic Iron Oxide Nanoparticles (MIONs) | Can be guided to liver lesions using an external magnetic field, also serve as MRI contrast agents. | Magnetic imaging, liver-targeted therapy | Inquiry |
To enhance the specificity and biocompatibility of nanoparticles, BOC Sciences provides expert surface modification and ligand conjugation services. We modify the surface of nanoparticles with specific molecular ligands (such as galactose, hyaluronic acid, etc.) to target particular liver cells, such as hepatocytes, hepatic stellate cells, or Kupffer cells. These custom ligand conjugation services not only improve nanoparticle-cell interactions but also significantly boost the therapeutic specificity and efficacy of the drug delivery system.
BOC Sciences offers comprehensive characterization and stability analysis to ensure the quality and reliability of nanoparticles in research applications. We use advanced characterization techniques such as dynamic light scattering (DLS), transmission electron microscopy (TEM), and particle size analysis to thoroughly examine the particle size, morphology, distribution, and surface charge of nanoparticles. Additionally, we offer long-term stability testing to evaluate the nanoparticles' resilience under different storage conditions and their capacity to maintain drug payloads. These comprehensive analytical services guarantee that the final products meet the stringent standards necessary for research and potential commercial applications.
Table 2. Tailored Services for Liver-Targeted Nanoparticle Development.
| Service Name | Description | Applicable Areas | Inquiry |
| Custom Nanoparticle Design | Design nanoparticles based on specific research needs, optimizing parameters like size, surface properties, and drug-loading capacity for efficient liver targeting. | Liver-targeted drug delivery, gene therapy | Inquiry |
| Surface Modification and Ligand Conjugation Services | Modify the surface of nanoparticles with specific ligands (e.g., galactose, hyaluronic acid) to enhance targeting to liver cells like hepatocytes, hepatic stellate cells, or Kupffer cells. | Liver-targeted drug delivery, hepatocyte targeting | Inquiry |
| Nanoparticle Characterization and Stability Analysis | Use advanced techniques such as DLS, TEM, and particle size analysis to ensure nanoparticle stability and quality. | Nanoparticle quality control, drug development | Inquiry |
| Research Support for Hepatic Nanomedicine Projects | Provide technical consultation, experimental design, and data analysis support to accelerate the development of liver-targeted nanoparticle systems. | Liver disease treatment, pharmaceutical research | Inquiry |
BOC Sciences also provides full research support for hepatic nanomedicine projects. Whether in basic research or preclinical stages, our team offers technical consultation, experimental design, and data analysis support to meet specific project requirements. We partner with top research institutions and pharmaceutical companies to drive the development of liver-targeted nanoparticle applications, particularly for treating liver diseases such as fibrosis and liver cancer. Through ongoing technological innovation and research support, BOC Sciences helps accelerate the development of liver-targeted nanocarrier systems, facilitating breakthroughs in the treatment of liver-related diseases.
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