Nanoparticle-based systems for liver therapy: Overcoming fibrosis and enhancing drug efficacy

Table 1 Overview of different inorganic and organic nanoparticles used for liver targeting, including their target cells, internalization mechanisms, main benefits, and common limitations

	NPs type	Target cells	Mechanism of action	Advantages	Limitations
Metal/metal oxide	Gold NPs	Kupffer cells, HSCs	Passive targeting; accumulation in hepatic tissue; modulation of inflammatory pathways in cytoplasm	High stability, ease of synthesis, surface functionalization, enable imaging	Non-biodegradable; liver accumulation risk, potential cytotoxicity
Silica-based	Silica NPs	Kupffer cells	Phagocytosis by Kupffer cells; drug release from NP surface within endolysosomal compartments	High stability, customizable surface enables functionalization	Poor biodegradability, potential long-term retention and chronic toxicity
Carbon- based	Carbon nanotubes	Hepatocytes, HSCs	Membrane penetration or endocytosis; direct cytoplasmic delivery of drug or gene (lysosomal bypass possible)	High drug/gene loading, tunable size and shape, and be surface-functionalized for targeting	Non-biodegradable; accumulation and inflammation risks, potential cytotoxicity and oxidative stress
	Fullerenes (C60)	Hepatocytes, Kupffer cells	Passive uptake, ROS scavenging in cytoplasm	Strong antioxidant activity, high liver cellular uptake and accumulation, potential anti-inflammatory effects	Non-biodegradable, accumulation risk, potential hepatotoxicity and oxidative stress
Lipid-based	Liposomes	HSCs (SPARC/RA-mediated)	Receptor-mediated endocytosis; drug release via lysosomal degradation or cytoplasmic escape (formulation-dependent)	Biodegradable, high biocompatibility, encapsulate both hydrophilic/lipophilic drugs and genetic material, surface modifiable for targeting	Cost, possible drug leakage and instability during storage
	Solid Lipid NPs (solid lipid NPs and NLCs)	HSCs, hepatocytes	Endocytosis; gradual drug release within endolysosomal compartments (no lysosomal escape unless specifically engineered)	Biodegradable, good biocompatibility, solid core improves stability, suitable for controlled drug/gene release	Limited loading for hydrophilic drugs (improved in NLC), possible formulation-dependent instability
Polymeric	Polymeric NPs (e.g., PLGA, chitosan)	HSCs (via HA receptor)	Receptor-mediated endocytosis; pH-sensitive release with lysosomal escape (formulation-dependent)	Biodegradable, controlled release, high specificity via receptor-mediated targeting	Some polymers may trigger immune response, potential accumulation risk for some formulations
	Nanomicelles	HSCs	Endocytosis; cytoplasmic drug release (lysosomal escape possible depending on composition)	Biodegradable, small size (< 50 nm), enhance solubility of poorly water-soluble drugs, good stability in circulation	Possible low loading capacity, potential premature drug release and rapid clearance

HA: Hyaluronic acid; HSCs: Hepatic stellate cells; NLCs: Nanostructured lipid carriers; NP: Nanoparticle; PLGA: Poly(lactic-co-glycolic) acid; RA: Retinoic acid; ROS: Reactive oxygen species; SPARC: Secreted protein acidic and rich in cysteine.

Table 2 Overview of drug delivery nanoparticles, including representative surface ligands, typical drug-payload capacity, and predominant internalization mechanisms

Nanoparticle	Representative surface ligands	Typical drug-payload capacity	Predominant cellular internalization pathway
Gold nanoparticles	PEG, folic-acid, RGD peptide, anti-HER2 Ab	5-10 wt% (approximately 80-150 doxorubicin molecules per 20 nm gold NP)	Receptor-mediated clathrin-dependent endocytosis
Silica nanoparticles	PEG, folic-acid, iRGD peptide	25-30 wt% (paclitaxel approximately 250 mg/g MSNP)4	Clathrin-mediated endocytosis; caveolae contribution reported
Carbon nanotubes	PEG, transferrin, RGD peptide	approximately 20 wt% (doxorubicin 2.5 mg/mg carbon nanotube)	Energy-dependent endocytosis and direct membrane penetration
Fullerenes (C60 derivatives)	PEG-C60, malonic-acid-C60, amino-C60	5-15 wt% for hydrophobic drugs	Caveolae-mediated endocytosis and passive diffusion
Liposomes	DSPE-PEG, antibody fragments, folic-acid	10-15 wt% (Doxil® approximately 14 wt% doxorubicin)	Endocytosis/membrane fusion; phagocytosis by macrophages
Solid lipid nanoparticles	PEG, polysorbate 80, lactoferrin	5-12 wt% (curcumin 85 mg/g solid lipid NP)	Clathrin- & caveolae-mediated endocytosis
Polymeric Nanoparticles (PLGA, PLA)	PEG, folic-acid, aptamers, anti-EGFR Ab	5-20 wt% (paclitaxel 120 mg/g PLGA NP)	Receptor-mediated endocytosis (clathrin & caveolae)
Nanomicelles	PEG-PLA or PEG-PCL cores with folate or RGD	10-30 wt% hydrophobics (docetaxel 250 mg/g)	Clathrin-mediated endocytosis; macropinocytosis

AB: Antibody; DSPE: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; iRGD: Integrin RGD; MSNP: Mesoporous silica nanoparticle; NP: Nanoparticle; PCL: Polycaprolactone; PEG: Polyethylene glycol; PLA: Polylactic acid; RGD; Arginine-glycine-aspartic acid; wt%: Weight percentage.