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.