Hepatotropic Nanomedicine and Targeted Nanocarriers for Liver Diseases and Hepatocellular Carcinoma

Abstract

Despite the continuous increase in number of patients with liver diseases, including cirrhosis, fibrosis, viral hepatitis, Metabolic dysfunction-associated steatotic liver disease (MASLD), Metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC), conventional drug delivery systems often fail to meet treatment requirements due to low bioavailability, poor water solubility, rapid metabolism in the liver, and dose limitations due to their systemic toxicity. The use of hepatotropic nanomedicine could provide a viable solution by developing drugs and drug-delivery systems in accordance with specific properties of the liver, including its cellular diversity and molecular characteristics related to the development of the particular disease. The current review describes various liver-targeted nanocarriers that take advantage of receptor-mediated uptake, fenestrated sinusoidal endothelium, and some characteristics of the tumor microenvironment, such as acidity, oxidative stress, and overexpression of certain enzymes. The review covers different polymeric, lipid, inorganic, biomimetic, and nucleic acid-based systems with both passive and active approaches for targeting hepatocytes, Kupffer cells, hepatic stellate cells, and HCC cells.

Graphical Abstract

Introduction

Liver disease is a significant and expanding worldwide health concern that results in a disproportionate global burden of morbidity and mortality.^1,2 Chronic liver diseases encompass a broad spectrum of disorders, ranging from the increasingly prevalent MASLD and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis, to advanced cirrhosis arising from diverse etiologies, including metabolic, viral, and toxic insults. These conditions frequently progress to chronic viral hepatitis and hepatocellular carcinoma (HCC), the primary malignancy of the liver, which remains one of the leading causes of cancer-related mortality worldwide. Recent epidemiological syntheses highlight that the prevalence of Metabolic dysfunction-associated steatotic liver disease (MASLD), Metabolic dysfunction-associated steatohepatitis (MASH) continue to rise in parallel with the global obesity and diabetes epidemics. The viral hepatitis remains endemic in many regions and HCC incidence and mortality remain stubbornly high despite preventive measures. Liver disease contributes substantially to years lived with disability and premature mortality, and projections suggest rising HCC cases in coming decades unless prevention and early detection strategies are designed.^1,3–7

Despite advances in surgical, ablative and systemic therapies for advanced liver disease and HCC, clinical outcomes are often suboptimal. Systemic agents (for example, multi-kinase inhibitors and immune checkpoint inhibitors) and loco-regional procedures can extend survival but are limited by incomplete responses, drug resistance and frequent adverse effects.^8,9 A set of recurring pharmacologic limitations underlies many therapeutic failures, including poor aqueous solubility of potent small molecules, rapid hepatic or systemic metabolism and clearance, low and variable oral bioavailability, and broad off-target distribution that precipitate dose-limiting toxicities. Even established HCC drugs such as sorafenib and other targeted agents are hampered by low solubility, restricted bioavailability and non-selective action that translate into systemic side effects and suboptimal intratumoral exposure, issues that motivate the development of optimized formulations and delivery platforms.^10–12

Hepatotropic medicine, the deliberate design of nanoscale delivery systems to exploit liver-specific biology, offers a compelling route to overcome these barriers. The liver’s unique physiology (dual blood supply, high fenestrated sinusoidal endothelium in normal liver, and abundant resident phagocytic cells) and the expression of hepatocyte-specific receptors provide natural entry points for targeted delivery.¹³ Fabrication of nanocarrier enables control over surface charge, particle size, and hydrophilicity to manage the circulation time, opsonization and hepatic uptake. The surface functionalization of nanocarriers with ligands such as glycyrrhizin derivatives, galactose, peptides and antibodies can drive receptor-mediated uptake by the hepatocytes or tumor cells. The incorporation of coatings (such as PEGylation, zwitterionic polymers) can reduce premature clearance and also improve the pharmacokinetics. In case of HCC, the tumor microenvironment (TME), characterized by a change in pH, hypoxia, elevated protease activity, and an immunosuppressive stromaprovides stimuli that can be harnessed by smart nanocarriers to trigger controlled drug release selectively within diseased tissue.^14,15 Collectively, these design principles permit both passive targeting (size and enhanced permeability in tumor regions) and active, ligand-directed targeting to enhance therapeutic index and minimize systemic toxicity. Recent studies reported rapid progress in applying these concepts to imaging, chemotherapy, gene delivery and immunomodulation in liver disease and HCC.^16–18

Smart nanocarriers encompass diverse methods such as liposomes and lipid-based nanosystems that solubilize hydrophobic drugs and enable hepatic uptake. Polymeric nanoparticles and micelles offer tunable release kinetics, inorganic and hybrid nanoparticles (gold, iron oxide, metal-organic frameworks) with theranostic potential, and biomimetic vesicles (exosomes, cell membrane-coated nanoparticles) can evade immune surveillance and present endogenous targeting motifs. Stimuli-responsive platforms fabricated to react to pH changes, redox gradients, enzymatic activity or external triggers (light, magnetic fields, ultrasound) offer spatiotemporal control over load release. In addition, combined approaches utilizing co-delivery of chemotherapy, siRNAs, immunomodulator, or photothermal therapy are being developed to counteract multifactorial resistant mechanisms in HCC.^19,20 Despite all advancements, however, there are several difficulties. Some of these important issues involve scalable production, long-term toxicity, and biocompatibility. An additional challenge is the necessity of having identical preclinical models that precisely replicate the complexity of human liver and tumor heterogeneity and fibrosis.²¹ Issues related to quality control, reproducibility of batches, and demonstration of the enhanced therapeutic index are among some important regulatory aspects that complicate clinical translation. The complex interaction between liver fibrosis and nanoparticle biodistribution needs special consideration since the altered sinusoid structure and function of Kupffer cells significantly affect the fate of nanocarriers. Therefore, there is an urgent need for interdisciplinary approach involving collaboration among material scientists, pharmacologists, hepatologists, and oncologists.^14,17,22

This review is compiled to emphasize recent advancements in hepatotropic nanomedicine, particularly focusing on targeted nanocarrier strategies for liver disease and HCC. It examines design approaches for both active and passive targeting, as well as stimulus-responsive and multipurpose systems. Additionally, it emphasizes TME responsive mechanisms and ligand receptor strategies that have demonstrated potential in preclinical and early clinical research. Additionally, it identifies knowledge gaps and significant topics for future study while critically discussing translational problems related to safety and production. This work aims to give researchers and physicians a clear, current path for using hepatotropic nanocarriers to enhance treatment results in HCC and liver disease.

Liver Microenvironment and Targets for Nanomedicine

The liver is an unusual and complex biological organ where the physiological actions and responses to diseases are governed by a highly specialized environment. All of the unique structural and cellular properties of the liver, along with the receptors expressed on them, have to be considered in relation to the nanomedicines used for hepatotropic delivery. For the development of nanovectors capable of penetrating the hepatic barriers and bypassing the process of clearance for targeted drug action, this understanding becomes essential. The NPs in Liver sinusoidal endothelial cells (LSECs) capillarization-mediated immunosuppression-associated microenvironment of liver fibrosis is shown in Figure 1.²³

Figure 1.

The NPs in LSECs capillarization-mediated immunosuppression-associated microenvironment of liver fibrosis.²³

Abbreviations: MTC, Mannose-modified trimethyl chitosan-cysteine; CMC, Carboxymethyl chitosan; PS, Phosphatidylserine; PLGA, poly(lactic-co-glycolic acid); HA, Hematoxylic acid; LNPs, Lipid nanoparticles.

Liver Architecture Relevant to Nanodelivery

Hepatic lobules, which are hexagon-shaped functional units made up of hepatocyte plates that stretch radially from a central vein, make up the structure of the liver. Blood enters each lobule through the portal triads and travels through particular capillaries called sinusoids. LSECs, which have distinctive fenestrations (transcellular pores of 50–150 nm), border these capillaries.²⁴ These fenestrated endothelium structures have the capacity to interchange molecules in both directions, particularly providing a physical foundation for the formation of passive nanoparticles. Such architectural characteristics have been clearly utilized in nanocarrier design to boost hepatic absorption for medication and gene delivery due to ensuring passage through sinusoidal fenestrations to reach hepatocytes or deeper tissue compartments.²⁵ Up to 80–90% of body macrophages are Kupffer cells, which are resident macrophages in the sinusoidal region and are essential for innate immunity and homeostasis. Kupffer cells are extremely active in the phagocytic clearance process, identifying and consuming foreign particles, including nanoparticles. Nanocarriers meant to reach hepatocytes or tumor cells are hindered by this. In conditions when altering macrophage activity is advantageous, scavenger receptor mediated targeting can be used to deliver medications directly to Kupffer cells.²⁶ Hepatic stellate cells (HSCs) are located in the space of Disse, a loose extracellular matrix compartment between hepatocytes and LSECs. Vitamin A is stored by quiescent HSCs in a healthy liver. Nevertheless, they become myofibroblast like cells that create extracellular matrix proteins that cause fibrosis when they are injured or subjected to an inflammatory stimulus. A major therapeutic target in liver disease is HSC activation, and nanocarriers designed to identify molecular markers expressed on active HSCs have the potential to reduce the advancement of fibrosis.²⁷

The phenomenon of metabolic zonation in the liver is physiologically important as it has significant impacts on the transport, distribution, and internalization processes of hepatotropic nanoparticles within the liver. Due to a unique blood flow pattern from periportal to pericentral areas inside the hepatic lobules, there arise differences in the gradients of oxygen, nutrients, hormones, and chemical signaling molecules. Such gradients result in various types of metabolic zones that differ in the specific activities of parenchymal and non-parenchymal cells. As a result, there is an uneven expression of genes and receptors as well as an active endocytosis capacity in hepatocytes, LSECs, Kupffer cells, and other non-parenchymal cells in the liver. In addition, differential zonal distributions in the expression of receptors such as ASGPR and others that bind nanoparticles could modulate the efficiency of targeted nanoparticle delivery into hepatocytes. The gradients along the porto-central axis that govern metabolic processes in the liver will also have an impact on the transport of nanoparticles within the sinusoids and thus the relative availability of nanoparticles to Kupffer cells, LSECs, and hepatocytes. In summary, particle size, composition, surface properties, and ligands will be critical determinants of cell selectivity when taking into account the zoned environment of the liver. It is therefore crucial that liver zonation is considered when designing nanomedicines to treat liver diseases and hepatocellular carcinoma.^27–30

Molecular Targets in Healthy and Diseased Liver

Nanomedicine strategies rely heavily on identifying and exploiting molecular targets that differentiate healthy from pathological liver cells. These include surface receptors and biomarkers that enable active targeting through ligand receptor interactions, thereby enhancing therapeutic efficacy while minimizing off-target effects. The molecular targets in the liver are described below:

Asialoglycoprotein Receptor (ASGPR) on Hepatocytes

ASGPR is a well-characterized lectin abundantly expressed on the sinusoidal and basolateral membranes of hepatocytes. It recognizes terminal galactose or N-acetylgalactosamine (GalNAc) residues on glycoproteins, facilitating their endocytosis and lysosomal degradation. This receptor has been widely exploited for hepatic targeting. For example, GalNAc-conjugated Small interfering RNA (siRNA) and drug carriers demonstrate selective uptake by hepatocytes and have been validated in clinical contexts due to their high specificity and low off-target distribution.³¹

Scavenger Receptors on Kupffer Cells

Scavenger receptors on Kupffer cells recognize a broad range of ligands, including modified lipoproteins and polyanionic molecules, and are responsible for internalization of pathogens and particulates. Nanocarriers designed with ligands such as mannose, fucose, or immunoglobulin fragments can target these receptors to either evade phagocytic clearance or intentionally deliver immunomodulatory agents to macrophages in conditions such as liver inflammation or cirrhosis.^26,27

Integrins and Platelet-Derived Growth Factor Receptors (PDGFRs) on Activated HSCs

Activated HSCs overexpress several surface receptors that serve as viable targets for antifibrotic nanomedicine. These include integrins (eg, αvβ3 and α5β1), which interact with extracellular matrix proteins, and PDGFRs, which are implicated in HSC proliferation and migration. Nanocarriers functionalized with peptides such as cyclic RGD (recognizing integrin motifs) or PDGFR ligands have demonstrated enhanced binding and internalization into activated HSCs. These improve the delivery of antifibrotic drugs to the fibrotic microenvironment.³²

Glypican-3 (GPC3), Transferrin and Epidermal Growth Factor Receptor (EGFR) on HCC Cells

In HCC, several markers are significantly overexpressed compared to normal liver tissue. One of these, glypican-3 (GPC3), is a heparan sulfate proteoglycan specifically upregulated in many HCC patients but not in healthy or cirrhotic liver, making it an attractive target for active targeting through antibody or ligand-mediated nanocarriers.³¹ The transferrin receptor (TfR), which mediates iron uptake, is often overexpressed in rapidly proliferating tumor cells, including HCC, making transferrin-functionalized nanoparticles effective for enhancing tumor cell uptake.²⁵ The EGFR is another receptor frequently upregulated in HCC and other malignancies, which has been targeted using peptide ligands or antibodies conjugated to nanocarriers to improve specificity and therapeutically loaded drug delivery.³³

TME Features: Reactive Oxygen Species (ROS), Matrix Metalloproteinase (MMPs), and Acidity

In addition to specific receptors, TME in HCC is characterized by overproduction of ROS, high MMP activity, and an acidic milieu due to aberrant metabolism. These features have been leveraged to design stimuli-responsive nanocarriers that release drugs in response to elevated ROS or acidic pH, increasing intratumoral drug concentration and reducing systemic exposure.³⁴

Nanocarriers for Hepatotropic Drug Delivery

The complex physiology of life and the development of HCC present significant barriers to effective systemic therapy. Conventional therapies usually have limitations such as poor biodistribution, rapid clearance, systemic toxicity, and limited tumor accumulation. Nanocarrier systems can improve drug pharmacokinetics and enhance targeted delivery to hepatocytes and tumor cells. In this way, they facilitate controlled release and enhance therapeutic efficiency with minimum side effects.³⁵

Lipid-Based Nanocarriers

Lipid‑based nanocarriers have been widely explored as robust platforms for drug and gene delivery due to their inherent biocompatibility, high drug loading capacity and established clinical track record.³⁶ Liposomes are some of the most studied nanocarriers in relation to liver-targeted therapies. Liposomes contain a phospholipid bilayer capable of entrapping either hydrophilic or hydrophobic molecules, with the outer surface coated with polyethylene glycol (PEG) to increase circulation time and decrease RES uptake. They can be further functionalized with active targeting ligands such as galactoside derivatives for receptor-mediated interaction with hepatocyte ASGPR receptors for efficient delivery to the liver and HCC cells.³⁷ Examples of clinical liposome preparations include liposomal doxorubicin, which has received a lot of attention in HCC owing to increased accumulation in tumors and lower cardiotoxicity compared to the free drug.³⁸ Liposomes have been utilized for the co-administration of synergistic agents such as curcumin and doxorubicin within HCC experimental models, where they exhibit increased apoptosis induction, tumor growth inhibition, and reduction in multidrug resistance pathways.³⁹ In addition, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) can be considered more advanced forms of lipid-based nanocarriers incorporating solid and liquid lipids, which enhance stability and loading capacity. Such formulations offer controlled release behavior and better targeting towards liver tissues; as they consist of lipidic materials, they usually exhibit excellent safety features that make them comparable to FDA-approved platforms.⁴⁰ Nanoformulations for the inhibition of liver cirrhosis are shown in Figure 2.²⁷

Figure 2.

Nanoformulations for the inhibition of liver cirrhosis. LSEC serve to keep HSC in a quiescent state (blocking arrow). Various stress factors result in the loss of LSEC fenestration, termed capillarization, and the loss of LSEC-mediated HSC inactivation (dashed blocking arrow). Activated HSCs transdifferentiate to myofibroblasts and generate ECM proteins, resulting in fibrosis, cirrhosis and, ultimately, HCC. Fibrosis-counteracting nanoformulations target LSECs, eg, via mannose and hyaluronic acid and deliver simvastatin to revert capillarization and to reestablish HSC-inhibition by LSECs. Alternatively, nanodrugs may target HSCs especially via vitamin A, and inhibit ECM production, eg, by the delivery of drugs that inhibit collagen expression at various levels.²⁷

Abbreviations: ECM, extracellular matrix; HA, hyaluronic acid; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; LNP, lipid nanoparticle; LSEC, liver sinusoidal endothelial cell; miR, micro RNA; NP, nanoparticle; PLGA, poly(L-lactic-co-glycolic acid); siRNA, small interfering RNA.

Polymeric Nanoparticles

Polymeric nanocarriers are versatile systems synthesized from biodegradable materials such as PLGA, polyethylene glycol-modified PLGA (PEG-PLGA), polycaprolactone (PCL), and natural polymers like chitosan.⁴¹ These carriers enable controlled drug release through degradation and have tunable physicochemical properties that can be adjusted by altering polymer composition and molecular weight. For liver targeting, surface modification with ligands such as folate or peptides can be incorporated to enhance receptor-mediated uptake by hepatocytes and tumor cells.⁴² PLGA and PEG-PLGA nanocarriers have been developed to co-deliver chemotherapeutic agents and genetic materials, which enable multimodal anti-tumor effects.⁴³ For example, dual-loaded PLGA nanoparticles encapsulating chemotherapeutics and anti-microRNAs have shown improved proliferation inhibition in HCC cell lines relative to single agent carriers, highlighting the potential for combination strategies to overcome chemoresistance.⁴² Figure 3 shows the mechanism of targeting liver cancer stem cells LCSCs by PLGA–PEG copolymer core-shell nanoparticles. The core of the PLGA–PEG copolymer is loaded with Elacridar (ELC) and Doxorubicin (DOX), which then bind to LCSCs and enter the cells via endocytosis. The microenvironment promotes PLGA degradation, leading to the controlled release of DOX and ELC. Then, ELC suppresses the activity of ATP-binding cassette (ABC) transporter proteins, which are overexpressed on the surface of LCSCs, thereby increasing intracellular DOX accumulation and ultimately inducing tumor cell apoptosis.⁴² Natural polymers such as chitosan are attractive for liver therapy because of their mucoadhesive nature, biodegradability, and ease of functionalization. In preclinical studies, chitosan nanoparticles showed efficient targeted delivery of DOX to HCC cells with improved cellular uptake and reduced systemic toxicity. It highlights the applicability of chitosan nanoparticles for effective hepatotropic chemotherapy.⁴⁴

Figure 3.

Targeting mechanism of LCSCs by PLGA-PEG copolymer core-shell nanoparticles.⁴²

Inorganic Nanomaterials

Certain characteristics of inorganic nanoparticles, such as their magnetic and optical qualities, can be used for both therapeutic and diagnostic applications.⁴⁵ Gold nanoparticles (AuNPs) are suited for photothermal treatment due to their stable surface chemistry. In this procedure, near-infrared (NIR) radiation functions as a drug delivery vehicle and causes localised hyperthermia to ablate tumour tissue. Iron oxide and other magnetic nanoparticles are equally significant because they can be guided by external magnetic field, which improves targeted accumulation in liver tumors and makes magnetic resonance imaging (MRI) possible for theranostic purposes. Because of their large surface area for drug loading and controlled release, mesoporous silica nanoparticles (MSNs) are also significant.⁴⁶

Bimimetic and Cell-Derived Carriers

The biomimetic nanocarriers must adhere to biological structures in order to improve immunological compatibility and drug delivery efficiency. Exosomes are naturally occurring extracellular vesicles that may effectively transport drug and nucleic acids into hepatocytes due to their innate liver tropism. Compared to synthetic systems, they have longer circulation times and better immune evasion due to their endogenous origin. So they can be modified to transport certain medications, such as proteins, siRNA, and small molecules.⁴⁷ Similar to this, cell membrane coated nanoparticles use membranes extracted from hepatocytes, cancer cells, or red blood cells to cover synthetic cores with a biological interface that promotes homotypic targeting and immune evasion. These hybrid systems display prolonged systemic persistence and enhanced accumulation in liver tissues, which makes them promising candidates for targeted therapy against liver diseases and HCC.¹⁴ Figure 4 shows the membrane coated homologous targeting capability and immune evasion characteristics of synthesized nanoparticles, and validated by Western blot analysis and in vivo biodistribution studies. The main adhesion molecules, including galectin-3, EpCAM, and CD-147, were successfully preserved on the nanoparticle surface, which enables the efficient homotypic recognition and binding to the parent cancer cells. The fluorescence assays revealed approximately 55.3% cell death induced by lenvatinib-loaded nanoparticles, which is significantly higher than that observed in control and comparator groups. Furthermore, the enhanced antitumor efficiency of the lenvatinib encapsulated nanoparticles was corroborated in vivo, demonstrating a significant suppression of tumor growth, and tumor weights were almost five times reduced compared with other treatment groups.¹⁴

Figure 4.

Schematic illustration of cancer cell membrane-camouflaged lenvatinib-encapsulated pH-sensitive polymeric NPs for HCC.¹⁴

Nanosystems for Gene and Nucleic Acid Delivery

Targeting genetic pathways is pivotal in the treatment of liver fibrosis, viral hepatitis, and HCC. Nanocarrier systems capable of delivering siRNA, microRNA (miRNA), and gene-editing tools such as CRISPR/Cas9 have rapidly advanced, offering the ability to modulate disease-related gene expression with precision. Lipid-calcium-phosphate nanoparticles decorated with liver-targeting ligands such as galactoside derivatives have demonstrated efficient uptake by ASGPR-expressing HCC cells and potent downregulation of vascular endothelial growth factor (VEGF) expression, leading to anti-angiogenic effects in the tumor model.³⁷ Different nanocarrier systems developed for hepatotropic drug and gene delivery in liver diseases and HCC are provided in Table 1.^{15,16,48–58}

Table 1.

Different Nanocarriers for Hepatotropic Drug and Gene Delivery in Liver Diseases and Hepatocellular Carcinoma

Nanoparticle	Cargo Drug	Disease	Stimuli/Targeting Strategy	Target Cell	Reference
Lipid nanoparticles (DNNA-COP-NA LNPs)	siHIF-1α + Silibinin	MASLD	ApoE-mediated LDLR/VLDLR recognition enabling hepatocyte-selective uptake	Hepatocytes	[48]
Biomimetic nano-platelets	Sorafenib + anti-PD-1 antibody	Hepatocellular carcinoma	Platelet membrane-mediated tumor homing and immune modulation	HCC cells and tumor microenvironment	[49]
Hyaluronic acid/cancer cell membrane-coated lipid nanoparticles	Celastrol	Hepatocellular carcinoma	Hyaluronic acid targeting of CD44 receptors and homologous cancer-cell membrane recognition	HCC cells	[50]
MRI-visible lipid nanoparticles	Camptothecin + miR-145	Hepatocellular carcinoma	Active tumor targeting combined with image-guided delivery	HCC cells	[51]
Exosome-coated luteolin nanoparticles	Luteolin (combined with sorafenib therapy)	Hepatocellular carcinoma	Exosome-mediated targeting and remodeling of activated tumor stroma	Hepatic stellate cells (HSCs) and HCC cells	[52]
Hyaluronic acid-modified extracellular vesicles	Doxorubicin	Hepatocellular carcinoma	CD44 receptor-mediated active targeting via hyaluronic acid modification	HCC cells	[53]
GalNAc-modified FeS nanoparticles	FeS therapeutic nanoplatform (gas/chemodynamic therapy)	Orthotopic hepatocellular carcinoma	GalNAc-mediated ASGPR targeting and tumor microenvironment-responsive therapy	Hepatocytes and HCC cells expressing ASGPR	[54]
mRNA-lipid nanoparticles	Dexamethasone-loaded mRNA-LNP formulation	Liver inflammation and inflammatory liver disorders	Intrinsic liver tropism of LNPs and hepatocyte uptake	Hepatocytes and liver immune cells	[55]
Lipid/exosome hybrid nanocarriers	Caffeine (model drug)	Liver fibrosis	Liver accumulation + nano-bio hybrid targeting	Liver tissue	[56]
Self-assembled nanoparticles	Sorafenib + curcumin	HCC	Hydrophobic assembly + enhanced cytotoxicity	HepG2 cells	[57]
Galactose-modified liposomes	Curcumin	HCC	ASGPR-mediated active targeting	Hepatocytes/HCC cells	[16,58]
Mesoporous silica nanoparticles	Doxorubicin	HCC	pH-responsive drug release	HCC cells	[15]

Passive Targeting Strategies for the Liver and HCC

Passive targeting of nanoparticles is a foundational concept in hepatotropic nanomedicine that leverages unique physiological and pathophysiological features of the liver and HCC to promote nanoparticle accumulation at the disease site without specific ligand receptor interactions.³⁷ These mechanisms form the basis for designing nanocarriers that preferentially localize to liver tissues and tumors, thereby enhancing therapeutic efficacy while reducing systemic toxicity. Several strategies, most notably the enhanced permeability and retention (EPR) effect, size-dependent accumulation, and modulation of surface charge and hydrophobicity, have been extensively studied and optimized to improve passive targeting to the liver and HCC.⁵⁹

Exploiting the Enhanced Permeability and Retention (EPR) Effect

EPR is considered major effect in passive targeting in cancer nanomedicine and HCC, due to the distinct abnormalities in tumor vasculature. The tumors blood vessels in HCC are usually dilated, disorganized, and possess larger and irregular endothelial fenestrations compared to normal liver vasculature. These, with impaired lymphatic drainage, create a permissive environment for nanoparticle extravasation and retention at tumor sites. Basically, this phenomenon was described in solid tumors and has since been confirmed as a critical passive targeting mechanism for nanoparticles. It allows increased local drug concentrations in tumor tissues relative to healthy counterparts without the need for an active targeting ligand.³⁷ In case of liver cancer, the inherent architecture of hepatic sinusoids and the pathological angiogenesis associated with HCC enhance nanoparticle penetration.³⁷

Size Dependent Liver Accumulation

Size of nanoparticles is an important physicochemical parameter affecting biodistribution, accumulation in the liver, cellular uptake, and effectiveness after systemic application. The liver is distinguished with a special microvascular structure, including liver sinusoidal endothelial cells (LSECs) with fenestrations providing the molecular and nanoparticle traffic between blood and hepatic parenchyma. In normal liver, fenestrations in the sinusoids vary between 50 and 150 nm and lack of the continuous basement membrane provides appropriate conditions for nanoparticles penetration into the space of Disse and interaction with hepatocytes. Therefore, nanoparticles less than about 100–150 nm show higher efficiency in trans-sinusoidal trafficking and hepatocyte uptake as compared with large nanoparticles limited only by vascular compartment.^54,60,61

Moreover, the size requirements for nanoparticle transport vary dramatically between healthy and pathologically changed liver tissues. In conditions of liver fibrosis, cirrhosis, and HCC, there occur dramatic changes in the architecture of blood vessels which lead to their increased permeability and to the formation of bigger gaps in endothelium of tumor vessels. In contrast to normal LSECs, tumor vessels in HCC are highly heterogeneous and porous having fenestration and inter-endothelial gaps up to hundreds of nanometers in size. The described pathologies provide higher efficiency of nanoparticle extravasation and accumulation inside the tumor due to mechanisms similar to EPR effect. Therefore, nanoparticles of size approximately 50–200 nm are able to accumulate effectively inside HCC lesions while the small part of nanoparticles of this size is capable of passing normal hepatocyte fenestration.^62–64

Nanoparticle size also influences cell-specific uptake within the liver. Smaller nanoparticles (<100–150 nm) are more likely to penetrate sinusoidal fenestrations and interact with hepatocytes, which are the principal parenchymal cells responsible for metabolic and synthetic liver functions. In contrast, larger nanoparticles are preferentially recognized and internalized by Kupffer cells and other cells of the mononuclear phagocyte system, leading to increased hepatic sequestration and clearance. While Kupffer cell uptake may be advantageous for treating inflammatory liver disorders, excessive phagocytic capture can reduce drug availability at hepatocyte or tumor targets. Therefore, careful optimization of nanoparticle size is essential to balance hepatocyte access, tumor accumulation, and avoidance of premature clearance, thereby maximizing the therapeutic performance of hepatotropic nanomedicines.^48,55,62,65

Surface Charge and Hydrophobicity

The way that nanoparticles interact with blood components, the mononuclear phagocyte system, and liver cells is also greatly influenced by their surface charge, hydrophobicity, and hydrophilicity.⁶⁶ A protein coating formed by the adsorption of serum proteins rapidly envelops the nanoparticles following their injection in the bloodstream, and this may greatly influence their distribution and uptake by cells. Specifically, due to the interaction with scavenger receptors present in these cells, Kupffer cells and LSECs are more prone to recognizing and uptaking negatively charged nanoparticles. Although this receptor-mediated clearance enhances hepatic sequestration, if not well regulated, it may redirect nanoparticles away from their intended tumor sites.⁶¹ In contrast, positively charged nanoparticles tend to bind and be taken up by the hepatocytes, which is helpful when trying to deliver a payload directly to hepatocellular carcinoma cells or other parenchymal cells.⁶¹ Hydrophobic nanoparticles tend to clear out of the circulation system faster because of the ability to adsorb proteins on their surface and undergo opsonization. In order to minimize fast clearance, nanoparticles are often modified with hydrophilic properties, primarily with PEGylation (polyethylene glycol coating). As a result, a steric layer is created and the adsorption of proteins and opsonization are minimized, thus increasing the circulation in blood and probability of passive transport into the tumor tissue because of EPR effect. The efficacy of passive targeting using PEGylated nanoparticles has been shown in HCC models.³⁷ Some passive and active targeting strategies in hepatotropic nanomedicine for liver diseases and HCC are given in Table 2.^{48–55,58,64,67–70}

Table 2.

Passive and Active Targeting Strategies in Hepatotropic Nanomedicine for Liver Diseases and Hepatocellular Carcinoma

Nanoparticle	Targeting Strategy/Cargo Drug	Disease	Stimuli/Targeting Mechanism	Target Cells	References
Lipid nanoparticles (DNNA-COP-NA LNPs)	Active targeting	MASLD	ApoE adsorption followed by LDLR/VLDLR-mediated hepatocyte uptake	Hepatocytes	[48]
GalNAc-modified FeS nanoparticles	Active targeting	Orthotopic hepatocellular carcinoma	GalNAc recognition of asialoglycoprotein receptor (ASGPR); tumor microenvironment-responsive chemodynamic/gas therapy	Hepatocytes and HCC cells expressing ASGPR	[54]
Hyaluronic acid-zein nanoparticles (Cel/Zein@HA)	Active targeting	Hepatocellular carcinoma	CD44 receptor-mediated endocytosis through hyaluronic acid surface modification	HCC cells	[67]
Hyaluronic acid-modified liposomes	Active targeting	Hepatocellular carcinoma	HA-CD44 interaction enhancing tumor accumulation and cellular uptake	CD44-overexpressing HCC cells	[68]
Hyaluronic acid-modified extracellular vesicles	Active targeting	Hepatocellular carcinoma	HA-mediated recognition of CD44 receptors combined with extracellular vesicle-mediated delivery	HCC cells	[53]
MRI-visible lipid nanoparticles co-loaded with camptothecin and miR-145	Active targeting	Hepatocellular carcinoma	Ligand-assisted tumor targeting with image-guided delivery and intracellular gene/drug release	HCC cells	[51]
Biomimetic nano-platelets carrying sorafenib and anti-PD-1	Active targeting	Hepatocellular carcinoma	Platelet membrane-mediated homing to tumor-associated vasculature and immune microenvironment	HCC cells and tumor-associated endothelial cells	[49]
Lipid nanoparticles for mRNA delivery	Passive targeting (natural liver tropism)	Liver inflammation and inflammatory liver disorders	Preferential hepatic accumulation due to nanoparticle physicochemical properties and liver fenestrated vasculature	Hepatocytes and liver immune cells	[55]
Photothermal-immunotherapeutic nanoparticles	Passive + active targeting	Hepatocellular carcinoma	NIR-responsive activation	HCC cells	[64]
Triple-linkage cascade nanosystem	Passive + stimuli-responsive targeting	Hepatocellular carcinoma	Photothermal activation	HCC cells	[69]
Galactose-modified liposomes	Curcumin	HCC	ASGPR-mediated hepatic targeting and lysosomal targeting	Hepatocytes/HCC cells	[58]
Hyaluronic acid/cancer cell membrane-coated lipid nanoparticles	Celastrol	HCC	CD44 targeting and homologous cancer-cell membrane recognition	HCC cells	[50]
Exosome-coated luteolin nanoparticles	Luteolin	HCC	Exosome-mediated stromal remodeling and targeted delivery	Hepatic stellate cells and HCC cells	[52]
Iron-based nanocomplexes	miR-122 + Doxorubicin	HCC	Coordinated nanoparticle-mediated gene/drug co-delivery	HCC cells	[70]

Active Targeting Strategies for Hepatotropic Nanomedicine

The concept of active targeting is considered a major breakthrough compared to the passive methods used in hepatotropic nanotherapy in that it facilitates molecular targeting between the carrier nanoparticles and the target cell through selective ligand-receptor interaction. Active targeting involves the attachment of ligands to the nanocarriers which target receptors that are highly expressed on hepatocytes, hepatic macrophages, stellate cells, and/or HCC cells.⁷¹ Through the use of disease-specific receptor expression pattern, active targeting increases cellular uptake and accumulates drugs inside the target cells while avoiding unwanted toxicity. Peptide-based targeting and ligand-receptor binding, as well as carbohydrate/glycan-mediated recognition, have been found to be the best for liver diseases and HCC.⁷²

Peptide Based Targeting

Peptide based targeting ligands have several advantages, including small molecular size, low immunogenicity, high binding affinity, and ease of chemical modification.⁷³ Among these, the SP94 peptide is important for its ability to preferentially bind HCC cells without affecting normal hepatocytes. The SP94 modified nanoparticles have demonstrated enhanced tumor penetration, improved therapeutic outcomes, and increased cellular uptake in multiple HCC models, making them a highly promising ligand for liver cancer targeting.⁷⁴ Beyond cancer therapy, peptide based targeting has also applied in fibrotic liver diseases. Activated HSCs and fibroblasts, such as LX2 cells, play a major role in liver fibrosis. Peptides that selectively bind to LX2 cells have been employed to deliver antifibrotic agents directly to fibrotic lesions and reduce the collagen deposition and disease progression while sparing healthy tissue.⁷⁵

Ligand Receptor Targeting

ASGPR is one of the most extensively studied receptors for hepatocyte-specific drug delivery. It is abundantly and almost exclusively expressed on hepatocytes. ASGPR exhibits high affinity for ligands containing terminal galactose or galactosamine residues, which make them ideal moieties for hepatocyte targeted nanocarrier design.³¹ Nanoparticles functionalized with galactose derivatives demonstrate enhanced uptake through receptor mediated endocytosis, leading to selective accumulation within hepatocytes while reducing systemic exposure.^76,77 Galactosamine modified liposomes, lipid polymer hybrid systems, and polymeric nanoparticles have been reported to improve drug delivery efficiency in liver diseases. Figure 5 shows the galactose modified lipid nanoparticles resveratrol (Gal-LNP-RSV) preparation process and its liver targeted delivery mechanism for alleviating fatty liver disease. In this approach, galactosamine is chemically combined to lipid molecules to create a hepatocyte specific targeting ligand. These functional lipids are then combined with cholesterol, cationic lipids, and other ingredients to form LNPs by employing processes such as microfluidics and ethanol injection. Resveratrol (RSV) is incorporated within the LNP by virtue of hydrophobic interactions, and upon purification, Gal-LNP-RSV complex is formed. Specificity towards liver cells is provided by the specific binding of galactose to ASGPRs, which are abundantly present in the cell membrane of hepatocytes, and leads to receptor-mediated endocytosis. The LNPs release resveratrol in the lysosomes of cells, where it acts against MASLD.⁷⁷ HCC has its own unique molecular profile, and this is due to the presence of tumor-associated antigens and receptors that allow targeted therapies. One such antigen is glypican-3 (GPC3), which is one of the major HCC-specific biomarkers. It is present in over 70% of HCC patients, and it is not present in the adult liver. Nanocarriers conjugated with anti-GPC3 antibodies and antibody fragments have been shown to increase tumor specificity, decrease off-target effects, and improve treatment efficacy in HCC.⁷⁸ Other receptors that bind ligands that are frequently utilized in the development of nanoparticles for treating HCC are the Folate receptors, the transferrin receptors and RGD peptides. This is because there is an increase in the metabolism of HCC cells that leads to the up-regulation of these receptors. Nanoparticles decorated with these ligands have been observed to increase the receptor-mediated delivery of drugs into the cells, particularly in the case of resistant tumors.³³ In addition, aptamers have recently been discovered to be very useful targeting ligands because of their specificity, synthetic feasibility and immunological properties. For instance, AS1411 and epcam-specific aptamers have been used successfully in increasing the binding to HCC cells.^79–81

Figure 5.

Galactose modified lipid nanoparticles resveratrol (Gal-LNP-RSV) preparation process and its liver targeted delivery mechanism for alleviating fatty liver disease.⁷⁷

Abbreviations: DSPC, distearoylphosphatidylcholine; MC3, is DLin-MC3-DMA; SOD, hepatic superoxide dismutase; AST, aspartate aminotransferase; MDA, malondialdehyde; LDL, low-density lipoprotein; TG, triglyceride; TC, total cholesterol.

Carbohydrate and Glycan Targeting

The carbohydrate and glycan targeting approaches utilize the physiological processes of recognition by immune and liver cells.⁷⁶ The mannosylated nanostructures prove to be especially effective in delivering the cargo to the macrophages like Kupffer cells or infiltrating macrophages in conditions like MASH due to their high expression of mannose receptors (CD206).²⁷ Another wisely used glycan ligand is lactobionic acid, which contains a galactose moiety capable of binding ASGPR with high affinity. Lactobionic acid-modified nanocarriers exhibit enhanced hepatocyte specific uptake and have been extensively explored for delivering chemotherapeutics, nucleic acids, and imaging agents to liver tissue and HCC tumors.⁷⁶

Stimuli Responsive Nanocarriers for Liver Diseases

Stimuli responsive nanocarriers represent a transformative advancement in hepatotropic nanomedicine by enabling site-specific, on-demand drug release in response to pathological cues present in liver diseases and HCC.⁸² Unlike conventional nanocarriers that release payloads passively, stimuli-responsive systems are engineered to sense and react to biochemical and physical abnormalities such as acidic pH, enzyme overexpression, oxidative stress, and external energy sources.⁸² The liver disease microenvironment, such as fibrosis, steatosis, chronic inflammation, and tumor progression, provides a rich array of endogenous and exogenous triggers that can be exploited to enhance therapeutic precision, overcome drug resistance, and reduce systemic toxicity.²³

pH Responsive Nanosystems

The acidic microenvironment of tumors and inflamed liver tissues is the important most endogenous stimuli used for controlled drug release.⁸³ In HCC, anaerobic glycolysis, rapid cellular proliferation, and poor perfusion lead to extracellular pH values ranging from 6.5 to 6.8, compared to physiological pH (7.4). This pH gradient enables selective activation of pH sensitive nanocarriers within tumor tissues and remains stable during systemic circulations.^84,85 The pH responsive nanosystems typically incorporate acid labile bonds (such as hydrazone, imine, or acetal linkages) or protonatable moieties that destabilize the structure of nanocarrier under acidic conditions.⁸⁶ The pH sensitive liposomes are among the most extensively studied platforms. In this case, acidic pH triggers lipid bilayer destabilization and rapid drug release within tumor tissues or endo/lysosomal compartments following cellular uptake. Recent studies have shown that pH responsive liposomal systems significantly enhance intratumoral drug accumulation and cytotoxicity in HCC models while minimizing off target exposure.⁸⁷ The MSNs have also gained importance due to their high surface area, tunable pore size, and ease of functionalization. The pH sensitive regulator, including peptides, polymers, or inorganic caps, is commonly used to block drug loaded pores and dissociate under acidic conditions. The pH responsive MSNs have shown greater tumor penetration and efficient drug release in acidic HCC microenvironments. So it offers a versatile platform for combination therapy and theranostic applications.^15,88,89

ROS Responsive Nanoparticles

Oxidative stress is a symptom of many liver diseases, including MASH, viral hepatitis, liver fibrosis, and HCC. The elevated levels of ROS contribute to hepatocyte injury, inflammation, and malignant transformation, which make ROS an attractive endogenous trigger for responsive nanomedicine.⁹⁰ ROS responsive nanoparticles are synthesized using oxidation sensitive moieties such as boronic ester, thioketal, or thioether linkages. These remain stable under normal physiological conditions but rapidly degrade in high ROS environments. Particular thioketal based nanocarriers have been widely employed for liver targeted therapy and enable the selective drug release in inflamed or tumor tissues while sparing healthy hepatocytes.^91–94 In addition to controlled drug release, ROS responsive systems can be designed to exert ROS scavenging activity, thereby providing dual therapeutic benefits. Nanoparticles composed of selenium, cerium oxide, or antioxidant polymers have demonstrated the ability to neutralize excessive ROS, reduce inflammation, and alleviate liver injury in hepatitis and MASH models. These multifunctional platforms are especially promising for chronic liver diseases where oxidative stress plays a central pathogenic role.⁶⁶

Enzyme Responsive Nanocarriers

Enzyme-responsive nanocarriers rely on the overexpression of disease-specific enzymes in cases of liver diseases and HCC to provide selective drug release.⁹⁵ Here, matrix metalloproteinases (MMPs), specifically MMP-2 and MMP-9, are uniquely overexpressed in HCC and are important factors in tumor invasion, degradation of the extracellular matrix, and metastasis. The use of nanocarriers that include MMP-based peptide linkers are stable during circulation but get cleaved when exposed to MMPs in tumor sites, providing localized release of drugs.^96–98 The use of MMP responsive nanocarriers has proven to be effective in terms of tumor specificity and reduced toxicity in experimental models of HCC. The most effective approach here is the use of MMP responsive nanocarriers along with additional targeting methods like ligand-targeted uptake or pH-sensitive drug release.⁹⁹ Cathepsin B is another enzyme that triggers the development of HCC. It is a lysosomal protease which is over-expressed in the liver cancer cells and tumor associated macrophages. Polymeric micelles which are sensitive to cathepsin B can also be degraded in the cells and deliver chemotherapeutic drugs into lysosomes. Thus, this method enhances the availability of drugs inside the cells and bypasses multi-drug resistance.^82,95

Thermal and Light Responsive Systems

The stimuli from the external sources like heat and light provide exact spatiotemporal control on the delivery of drug and the activation of treatment. The photothermal therapy (PTT) is an advanced technique with the help of nanotechnology for the HCC treatment. The AuNPs are extensively utilized in the photothermal therapy owing to their high surface plasmon resonance and efficient conversion of near-infrared light to localized heat.¹⁰⁰ In the case of exposure of near-infrared light, the AuNPs generate hyperthermia that causes the death of tumor cells without causing any harm to the surrounding normal cells. The use of AuNP-based nanocarriers for the photothermal ablation has shown regression in the growth of HCC tumors.⁶⁴ NIR activated drug release mechanisms are better suited for improving precision medicine since they combine both photothermal activity and controlled drug release. When NIR responsive liposomes, polymers, and hybrid nanoparticles come into contact with light, they experience structural transformations, allowing them to release drugs right at the location of the tumor.¹⁰⁰

Nanomedicine in Specific Liver Diseases

Liver diseases have a wide range of pathological conditions, ranging from viral infections, inflammation, fibrosis, metabolic dysfunction, and cirrhosis to HCC. Nanomedicine, with its ability to provide controlled, precise, and targeted delivery of therapeutic agents, offers substantial potential in improving outcomes for liver diseases. The advancements in nanocarrier design, multifunctional systems, and molecular targeting have produced innovations in treating viral hepatitis, fibrosis, MASLD/MASH, and HCC.¹⁰¹ Nanomedicine for specific liver diseases and hepatocellular carcinoma is given in Table 3.^{48,54,62–64,69,102–107}

Table 3.

Representative Nanomedicine Strategies for Specific Liver Diseases and Hepatocellular Carcinoma

Nanoparticle	Disease	Stimuli-Responsive Feature	Target Cells	References
DNNA-COP-NA lipid nanoparticles co-loaded with siHIF-1α and silibinin	MASLD	Disease-associated ApoE-LDLR/VLDLR-mediated hepatocyte targeting; intracellular siRNA release	Hepatocytes	[48]
GalNAc-modified FeS nanoparticles	Orthotopic hepatocellular carcinoma	Tumor microenvironment-responsive chemodynamic and gas therapy; ASGPR-targeted uptake	Hepatocytes and HCC cells	[54]
PIR nanoparticles (phthalyl-pullulan/IR780/R848)	Hepatocellular carcinoma	NIR-responsive photothermal activation combined with immune stimulation	ASGPR-expressing HCC cells	[64]
PDA/AgNPs/GOx triple-linkage nanosystem	Hepatocellular carcinoma	Glucose-responsive catalytic therapy combined with photothermal activation and metal-ion therapy	HCC cells	[69]
TCCHA self-assembled copper-based nanoparticles	Hepatocellular carcinoma	GSH-responsive chemodynamic therapy, ROS amplification, and hypoxia-sensitive photodynamic therapy	HCC cells	[62]
Polyphyllin II/IR780-loaded PLGA nanoparticles	Hepatocellular carcinoma	NIR-triggered photothermal therapy inducing pyroptosis and antitumor immunity	HCC cells and immune cells	[102]
Self-delivery photothermal-boosted nanobike platform	Hepatocellular carcinoma	Tumor microenvironment-responsive release combined with photothermal, chemical, and immune therapy	HCC cells and tumor-associated immune cells	[63]
Metal–polyphenol-network coated R612F nanoparticles	Drug-resistant hepatocellular carcinoma	Acidic tumor microenvironment-responsive drug release and stress-granule inhibition	Sorafenib-resistant HCC cells	[103]
ASGPR-targeted Galactose-decorated lipid nanoparticles (siRNA systems)	Hepatocellular carcinoma	Ligand–receptor mediated hepatocyte/HCC uptake via ASGPR	Hepatocytes and HCC cells	[104]
pH-responsive ferroptosis–chemotherapy hybrid nanocarriers	Hepatocellular carcinoma	Acidic TME-triggered drug release + iron-dependent ferroptosis	HCC cells	[105]
Arsenic trioxide nanoparticles (local delivery system)	Hepatocellular carcinoma	Controlled release in tumor microenvironment	HCC cells	[106]
Chitosan Gal-modified nanoparticles (ASGPR targeting)	Hepatocellular carcinoma	pH-sensitive drug release + ASGPR-mediated uptake	Hepatocytes and HCC cells	[107]

MASLD and MASH

The MASLD and its progressive subtype MASH represent the most common liver diseases throughout the world, with escalating prevalence linked to obesity and metabolic syndrome. Traditional therapies usually focus on lifestyle modification or metabolic agents, but no FDA-approved pharmacotherapies exist specifically for MASH. Nanomedicine presents opportunities to address multiple pathogenic axes, including oxidative stress, inflammation, and fibrogenesis.¹⁰⁸ Nanocarriers can enhance the hepatic delivery of antioxidants, anti-inflammatory drugs, and nuclear receptor agonists, including farnesoid X receptor (FXR) agonists. It promotes the lipid metabolism normalization and attenuation of inflammatory signaling. Polymeric and lipid nanocarriers have enhanced stability and bioavailability of otherwise labile drugs. So these achieve better outcomes in preclinical models of MASLD and MASH.⁷¹ Targeting non-parenchymal cells such as Kupffer cells and HSCs is important for controlling inflammation and fibrosis, hallmark features of MASH progression. Nanocarriers functionalized with macrophage-targeting ligands (eg, mannose) preferentially deliver payloads to Kupffer cells, reducing inflammation, cytokine release, and subsequent hepatocyte injury.¹³ Likewise, HSC targeted nanoparticles conjugated with peptides or ligands recognizing PDGFβR interrupt signaling pathways that drive fibrogenesis, reducing collagen deposition and fibrosis progression.¹⁰⁹ Moreover, nanomedicine facilitates gene silencing strategies against pro-fibrotic cytokines and matrix modulators such as TIMP-1, TGF-β, and CTGF. siRNA or antisense oligonucleotide loading in targeted nanocarriers has shown promise in suppressing fibrogenic pathways. In this way, they mitigate fibrosis progression in animal models of MASH.¹³ These multifaceted approaches, enhancing hepatocyte delivery, modulating inflammatory and fibrotic pathways, and improving pharmacokinetics, position nanomedicine as a versatile platform for treating complex metabolic liver diseases.⁴⁸

Viral Hepatitis (HBV, HCV)

Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the main global causes of liver-related morbidity and progression to cirrhosis and HCC. Although nucleostide/nucleoside analogues such as tenofovir and entecavir effectively suppress viral replication, they do not eradicate virus and often require long term dosages, with risks of resistance and toxicity. Nanocarrier systems reduce dosage, enhance delivery efficiency, and improve pharmacokinetic profile.^26,110,111 Increased stability, decreased systemic circulation, and higher liver targeting were observed in the case of LNPs and polymeric nanocarriers used for the delivery of antiviral drugs. For instance, there is evidence that the formulations of nanocarriers increase hepatic delivery of tenofovir and entecavir derivatives with antiviral efficiency and reduced side effects in preclinical models of viral hepatitis.¹³ Apart from antiviral drugs, RNA interference (RNAi) and genome editing techniques, including siRNA and CRISPR/Cas9 system, can be utilized to directly silence virus parts, particularly covalently closed circular DNA of HBV. Nanocarriers provide protection from the degradation and effective delivery of RNAi and CRISPR components into hepatocytes. Recent scientific findings demonstrate the use of nanocarriers of polymeric and lipid types for the delivery of siRNA targeting HBV transcriptome. These significantly reduce viral antigen expression in vivo and in vitro systems.¹¹² Additionally, although CRISPR therapeutics face delivery challenges but nanotechnology offers solutions to target hepatocytes specifically and improve editing efficiency while minimizing off target effects.²⁶ Active targeting strategies further enhance delivery system. The ligands, such as ASGPR ligands (eg, GalNAc), enable hepatocyte specific uptake of therapeutic nanocarriers, which increase delivery to the primary site of viral replication.¹³

Liver Fibrosis and Cirrhosis

Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins following chronic injury, can progress to cirrhosis, organ failure, and HCC. The absence of approved antifibrotic therapies underscores the need for innovative strategies to target the cellular drivers of fibrosis (principally activated HSCs). Nanomedicine enhances targeted delivery of antifibrotic compounds such as silymarin and pirfenidone, whose clinical efficacy is limited by poor bioavailability and off-target toxicity. Encapsulation in nanocarriers increases hepatic uptake and sustained release, thereby improving therapeutic outcomes in preclinical models of fibrosis.¹¹³ Targeting HSCs has been advanced using HSC specific ligands such as collagen binding peptides or PDGFβR ligands, which direct nanocarriers to fibrogenic cells, increasing drug concentration at sites of active fibrosis while sparing healthy liver cells. Nanomedicine also enables spatiotemporally controlled release of antifibrotic drugs in response to pathological cues (eg, ROS, pH), reducing systemic exposure and toxicity.¹¹³

Hepatocellular Carcinoma

As the most common primary liver cancer, HCC arises from chronic liver injury, including viral hepatitis, MASLD/MASH, and cirrhosis. Conventional therapies, surgical resection, ablation, and systemic chemotherapy, often exhibit limited survival benefits due to poor tumor selectivity and chemoresistance. Nanomedicine offers significant advancements in delivering chemotherapeutics, modulating immune responses, and enabling theranostics. Nanoparticles mediated chemotherapy enhances delivery of conventional drugs such as doxorubicin, sorafenib, and lenvatinib, reducing systemic toxicity and improving tumor accumulation via both passive and active targeting mechanisms, including EPR and ligand-mediated hepatocellular targeting.¹¹⁴ Immuno nanomedicine represents a major breakthrough in HCC therapy. Nanocarrier systems can deliver checkpoint inhibitors (eg, PD-1/PD-L1 blockers) and immunostimulatory agents directly to tumor sites while modulating the immunosuppressive TME. Recent studies demonstrate that combining nanoparticle based delivery of immune modulators with targeted therapies enhances anti-tumor immune responses and suppresses tumor growth more effectively than nanotherapies.¹¹⁵ In addition to checkpoint blockade, nanovaccines and dendritic cell (DC) nanovaccines are emerging to stimulate robust, antigen specific anti-tumor immunity. Nanovaccines formulated with tumor antigens and immune adjuvants improve antigen presentation to DCs and enhance T-cell memory responses, offering potential for both therapeutic and prophylactic applications in HCC.¹¹⁶ Theranostic platforms integrate diagnostics and therapeutics into single nanocarriers, enabling MRI imaging concomitant with drug delivery or combining photothermal therapy (PTT) with chemotherapy. AuNPs and other inorganic carriers have been engineered for dual functions: tumor ablation via photothermal effects and controlled release of chemotherapeutics, providing real-time monitoring of treatment and enhanced therapeutic efficacy.^35,37,64 Through these multidimensional platforms, nanomedicine not only enhances drug delivery but also enables personalized and adaptive therapeutic strategies tailored to specific molecular and immunological profiles of HCC.

Nanomedicine Based Combination Therapies for HCC

Combine therapies couple interactions of two or more modalities to overcome the limitations of monotherapy, such as resistance pathways, immunosuppression, and tumor heterogeneity, and result in amplified therapeutic effects with reduced therapy.

Immunotherapy and Photothermal Therapy

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment but due to the immunosuppressive TME, it exhibits limited response rates in case of HCC. Nanomedicine enables the combination of immunotherapy with photothermal therapy (PTT) to elicit immuneogenic cell death (ICD), enhancing antitumor immune responses.⁶⁴ Photothermal agents such as AuNPs convert NIR light into localized heat, which induces tumor cell apoptosis and release of tumor antigens. When combined with ICIs (eg, PD-1/PD-L1 blockers), PTT not only physically ablates tumor tissue but also provokes the release of damage associated molecular patterns (DAMPs) that stimulate dendritic cells and cytotoxic T-cell activation. Recent studies demonstrate that AuNPs combined with anti-PD-L1 therapy generate robust immune responses and extended survival in HCC models compared to either modality alone. It indicated the synergistic effects through enhanced antigen presentation and checkpoint blockade reinforcement.³⁵

Chemotherapy and Gene Therapy

Combining chemotherapy with gene therapy addresses inherent and acquired chemoresistance mechanisms in HCC. For example, co-delivery of sorafenib with siRNA targeting resistance pathways (eg, STAT3) through multifunctional nanocarriers has demonstrated enhanced tumor inhibition as compared to either modality alone. STAT3 plays a crucial role in HCC proliferation, survival, and resistance, and simultaneous suppression with cytotoxic agents, which leads to synergistic effects. It sensitizes the tumor cells to chemotherapy while minimizing required drug dosages. Nanocarrier platforms such as lipid or polymeric nanoparticles enable co-encapsulation and controlled release of chemotherapeutics and siRNAs. It ensures synchronized delivery at the tumor site and enhances gene silencing efficacy in vivo system.^13,114

Dual Drug Loading Nanocarriers

The dual drug loading in single nanocarriers provides a streamlined approach to combination therapy by delivering two complementary agents simultaneously. For example, liposomal carriers co-encapsulating doxorubicin and curcumin leverage curcumin’s anti-inflammatory and chemosensitizing properties to enhance the antitumor efficacy of doxorubicin and mitigate its cardiotoxicity. The curcumin component can inhibit pro-survival signaling pathways and modulate the TME, increasing HCC susceptibility to doxorubicin-induced apoptosis.¹¹⁷ Nanocarriers formulated with specific ratios of synergistic drugs ensure optimal pharmacodynamics and reduce systemic exposure. Preclinical evaluations demonstrate that dual drug nanocarriers achieve superior tumor inhibition with less side effects compared to monotherapy, highlighting their potential for clinical translation in HCC management.^117,118 Summary of outcomes and limitations: nanomedicine-based combination therapies for HCC are given in Table 4.^64,117,118

Table 4.

Summary of Nanomedicine-Based Combination Therapies for HCC: Outcomes and Limitations

Combination Strategy	Nanocarrier/System	Therapeutic Components	Experimental Model	Main Findings	Key Limitations	Reference
Immunotherapy + Photothermal Therapy	ASGPR-targeted phthalyl-pullulan nanoparticles (PIR NPs)	IR780 + R848 + NIR irradiation	Hepa1-6 HCC model	Enhanced ICD, increased CD8+ T-cell infiltration, reduced Treg population, superior tumor suppression compared with monotherapy	Preclinical study only; small animal cohorts; uncertain long-term immune memory; clinical feasibility of NIR penetration in liver tumors remains unclear	[64]
Dual Drug Loading	Liposomal nanocarriers	Doxorubicin + Curcumin	Murine metastatic tumor model	Reversal of multidrug resistance; enhanced antitumor activity; reduced metastasis	Not HCC-specific; pharmacokinetic behavior in humans unknown; scalability not evaluated	[117]
Dual Drug Loading	Lactosylated pH-responsive nanoparticles	Sorafenib + Curcumin	HCC-bearing animal model	Enhanced tumor targeting and growth inhibition compared with free drugs	Older preclinical study; no clinical translation data; long-term toxicity not evaluated	[118]

Clinical Translation of Hepatotropic Nanomedicine

Despite significant preclinical progress, translating hepatotropic nanomedicine into clinical practice has both milestones and challenges.

FDA-Approved and Clinical Stage Nanomedicines for Liver Diseases

A handful of nanomedicines has achieved clinical success in liver disease and oncology. Liposomal doxorubicin has been approved and widely used to treat various cancers and has been investigated in liver cancer settings due to its altered biodistribution and reduced cardiotoxicity compared to free doxorubicin.¹¹⁹ In viral hepatitis, early RNA targeting nanotherapeutics have reached clinical evaluation. ARC-520, a siRNA therapy targeting HBV, progressed into clinical trials, which offers proof of concept for RNAi approaches. However, it was ultimately terminated due to delivery-associated toxicity. ARC-520 established the feasibility of siRNA approaches in chronic HBV management.¹²⁰ Subsequent developments include LNP based siRNA therapeutics targeting HBV mRNA, such as DCR-HBVS, which demonstrated significant viral load reduction in preclinical models and entered early clinical evaluation, underscoring the potential of lipid nanoparticle systems in anti-HBV therapy.¹²⁰ In clinical setting of HCC, it also includes RNA nanomedicine efforts, with siRNA LNP formulations evaluated in advanced HCC patients. These studies demonstrate safety and gene silencing activity, though diverse clinical efficiency and highlight the complexity of therapeutic translation in oncology.¹²¹

Challenges in Clinical Translation

There are several significant challenges in the way of converting hepatotropic nanomedicine into standard treatments. It is still very difficult to synthesize nanocarriers with stable physicochemical characteristics on a therapeutic scale. Pharmacokinetics, biodistribution, and safety profiles can be impacted by changes in size, surface chemistry, and drug loading capacity, which might complicate regulatory approval. The distribution and absorption of nanomedicines are influenced by physiological variations in blood flow, liver shape, sinusoidal fenestration, and receptor expression. To overcome this unpredictability, patient classification techniques and predictive biomarkers are crucial. By reducing delivery to target cells and perhaps triggering immunological reactions, liver resident macrophages quickly sequester nanocarriers. Immunogenicity is decreased and circulation time is enhanced by surface modifications and biomimetic coatings (such as PEGylation or cell membrane coating). However, immunological interactions and long-term implications need to be carefully considered. Furthermore, the unique properties of nanoparticles may cause unanticipated safety problems. A thorough preclinical and clinical toxicological study is necessary for long-term toxicity, off target accumulation, and unanticipated interactions with organs, including impacts on chronic disease settings that are frequently present in liver patients.^{14,27,122,123}

Although the preclinical studies have been successful for hepatotropic nanomedicine, the transition into clinical settings has not been easy, and there have been only few candidates reaching the point of regulatory approval. The most prominent factor behind the problem is that there is great disparity between the animal model used in preclinical studies and human pathology. Most preclinical studies utilize genetically identical models, either by xenograft or chemical induction, which do not reflect the complexity found in human liver cancer (HCC).^{12,14,123,124} Moreover, the enhanced permeability and retention (EPR) effect, which is considered one of the key phenomena contributing to nanoparticle localization in tumors, exhibits considerable variations and usually is weaker in humans compared to mouse studies, leading to poor intratumoral nanoparticle localization during clinical treatment.^12,124,125 Other challenges in the process of clinical translation of the technology are represented by fast clearance of nanoparticles by the mononuclear phagocyte system, manufacturing inconsistency between batches of the drug, limited ability to scale up the complex formulation, challenges with maintaining consistent physical-chemical properties of the nanoparticles, and regulatory aspects related to quality control and toxicological safety studies.^122,123 Besides, considerable variations in individual patients’ liver functionality, receptor expression, and disease status may affect nanoparticle biodistribution and pharmacological efficiency. Thus, standardization of manufacturing procedures, creation of clinically relevant disease models, development of biomarkers for patient selection, and comprehensive pharmacokinetics/pharmacology/toxicology testing are needed for future clinical translation.

Future Prospects

Artificial intelligence may incorporate multi omics data, nanocarrier design, patient physiology, and factors to create prediction models that direct customized nanomedicine strategies, including dosage optimization, moieties targeting, and medication combinations for specific patients. Biomimetic nanocarriers that use extracellular vesicles or cell membrane coatings have the potential to evade immune clearance and achieve homologous targeting, which improves therapeutic efficacy while lowering immunogenicity.¹⁴ Spatial and temporal accuracy are improved by including sense regulated release methods and reactivity to biological stimuli (such as enzymes, pH, and ROS). These lessen off target effects and allow for regulated release patterns that are adapted to the microenvironment and severity of the disease. Combining nanomedicine with minimum invasive diagnostics (eg, liquid biopsies) can enable real-time monitoring of disease progression and therapeutic response. It also facilitates adaptive treatment strategies and early detection of therapeutic resistance.

Conclusion and Future Outlook

Hepatotropic nanomedicine has emerged as a novel technique for identifying and treating liver illnesses, including HCC, by addressing the fundamental limitations of existing therapy. Different nanocarrier platforms have shown increased drug bioavailability, improved therapeutic index, and decreased off-target toxicity by taking advantage of the distinct hepatic microenvironment, which includes fenestrated sinusoidal architecture, disease-specific cellular targets, and pathological stimuli like acidic pH, enzymes, and oxidative stress. The precise delivery of small molecules, biologics, and nucleic acids to hepatocytes, Kupffer cells, hepatic stellate cells, and HCC cells has been made possible by developments in lipid-based, polymeric, inorganic, and biomimetic nanosystems. Moreover, the integration of active targeting ligands, stimuli responsive mechanisms, and combination therapy strategies has shown substantial promise in overcoming drug resistance, modulating the tumor microenvironment, and achieving synergistic therapeutic outcomes.

Despite advancements, limitations with large-scale production, patient biological diversity, immunological clearance, and long-term safety issues continue to limit clinical translation. To allow customised liver-targeted therapeutics, future research should focus on rational nanocarrier design informed by systems biology and artificial intelligence. Precision medicine techniques are anticipated to be significantly improved by the creation of biomimetic and cell derived carriers, multi-stimuli responsive and logic-gated nanosystems, and theranostic platforms that combine imaging and therapy. Furthermore, clinical assessment and treatment monitoring may be made easier by combining hepatotropic nanomedicine with liquid biopsy biomarkers and real-time imaging. To move hepatotropic nanomedicine from the laboratory to the bedside and enhance outcomes for patients with chronic liver disease and HCC, ongoing multidisciplinary initiatives, including nanotechnology, hepatology, and clinical sciences, are crucial.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Sharing Statement

No primary research results, software or code have been included, and no new data were generated or analyzed as part of this review.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.