Table 2.

Plant bioactive-based nanoparticles against HCC in preclinical studies.

Plant Bioactives	Observations and Outcomes	Cellular/Intracellular Target	References
Liposomes [169]
Aprepitant and curcumin	Reduced ECM deposition and tumor angiogenesis	Drug accumulation in tumor tissues by EPR effect and GA and/or CD44 receptor-medicated endocytosis	[168]
Betulinic acid	Enhanced cell apoptosis and mitochondrial membrane disruption in HepG2 cells	Mitochondrial membrane of HepG2 cells	[170]
Bistorta amplexicaulis extract	Plant extract containing nanoliposomes demonstrated higher cytotoxicity toward HepG2 cells	HepG2 cells in vitro	[171]
Brucea javanica extract	Increased apoptosis of HepG2 cells	DNA synthesis inhibition and blockage of G0/G1 development to S phase	[167]
Celastrol	Suppressed AKT activation, induced apoptosis, and retarded cell proliferation	Uptake in HepG2 cells in vitro through receptor-mediated endocytosis	[172]
Curcumin	Galactose-morpholine modification resulted in better lysosomal targeting efficacy	ASGPR receptors on liver cells in mice	[173]
Curcumin and cisplatin	Exhibited synergistic effects in mouse hepatoma H22 and human HCC HepG2 xenograft models	Nanoliposomes delivered both curcumin and cisplatin to tumor tissues	[174]
Garcinia	Drug loaded nanolipoprotein complex showed higher cell death rate compared to free drug	Scavenger receptor class B type 1 receptors	[175]
Honokiol	Inhibited tumor metastasis by destabilizing EGFR and reducing the downstream pathways	Cellular uptake study was not performed	[176]
Nitidine chloride	Exhibited sustained release and higher cytotoxicity toward Huh-7 cells	Huh-7 cells in vitro	[177]
Oleanolic acid	Suppressed growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice	Cellular uptake study was not performed	[178]
Resveratrol	Improved localization of drug in cancer tissue by 3.2 and 2.2 fold increases, respectively, in AUC and Cmax	HepG2 cells in vitro; cancer tissues in rat liver	[166]
Silibinin and glycyrrhizic acid	Synergistic effect of silibinin with glycyrrhizic acid on HepG2 cell line	Cellular uptake study was not performed	[179]
Tanshinone IIA	Promoted apoptosis in HepG2 and Huh-7 cells	Galactose modified niosomes targeted ASGPR receptors on hepatocytes	[180]
Timosaponin AIII and doxorubicin	TAIII improved uptake of doxorubicin HCC cells and exhibited synergistic effect	HepG2 cells in vitro, and tumor bearing mice model	[181]
Triptolide	Induced cell proliferation arrest and apoptosis via the mitochondrial pathway	Huh-7 cells in vitro, and tumor sites in mice model	[182]
Triptolide and Ce6	Under NIR laser irradiation, liposome released triptolide and, along with Ce6, caused apoptosis of HCC cells	HepG2 cells in vitro, and patient-derived tumor xenograft	[183]
Triptolide and sorafenib	Long circulating liposomes promoted cancer cell apoptosis and inhibited tumor growth through synergistic effects	Huh-7 cells in-vitro, and tumor sites in mice model	[184]
Ursolic acid and ginsenoside	Intervened cell proliferation, apoptosis, and cell cycle of HepG2 cells	Cellular uptake study was not performed	[185]
β-sitosterol	Improved cellular uptake and cytotoxicity in HepG2 cells; increased drug-plasma concentrations by 8 fold	HepG2 cells in vitro	[186]
Solid lipid nanoparticles [187]
Cantharidin	Inhibited tumor growth and prolonged survival in tumor-bearing mice	Hyaluronic acid surface functionalization improved nanoparticle uptake in tumor tissues of rats	[188]
Capsaicin	Stable in circulation for a period of three days	Biodistribution studies revealed nanoparticles accumulated in the liver	[189]
Doxorubicin and curcumin	Synergistic activity was observed, including reversal of multidrug resistance	Cellular uptake and biodistribution study was not performed	[190]
Ganoderic acid	Exhibited significant antitumor effect in vivo by balancing hepatic injury markers, biochemicals, and antioxidants markers	Rapid internalization of nanoparticles in HepG2 cells	[191]
Naringin and coix seed oil	Exhibited synergistic effect by enhancing antitumor activity in xenograft model	Cellular uptake study was not performed	[192]
Quercetin	Creating better penetration into HepG2 cells	-	[193]
Resveratrol	Caused reduction in tumor volume and accumulation of drug in tumor tissues	Accumulation of drug in livers of rats	[194]
Polymer-based nanoparticles [195]
Apigenin	Sustained release of drug at target site with improved AUC and delayed liver clearance	Increased accumulation of nanoparticles in HepG2, Huh-7, and liver tissue in rats	[196]
Camptothecin	Provided higher uptake rate and accumulation in HepG2 cells	CD147 monoclonal antibody	[197]
Curcumin	Stability and aqueous solubility of curcumin were increased by several fold	Targeting HepG2 cells was achieved due to presence of galactose groups	[198]
Farnesol and cisplatin	Exhibited faster drug mobility, sustained particle release, site-specific action, and higher percentage of apoptotic death compared with single drug treatment	ROS generated DNA damage in HepG2 cells	[199]
Quercetin, ellagic acid, and gallic acid	Nanoformulation offered controlled release of bioactives with improved bioavailability	Induced apoptosis-mediated cell death in HepG2 cells	[200]
Umbelliferone β-D-galactopyranoside	Effectively mitigated diethyl nitrosamine-induced HCC as confirmed through both histopathological and biochemical assays.	High hepatic accumulation of drug in rat model	[201]
Ursolic acid	Inhibited the growth of H22 xenograft and prolonged the survival time of tumor-bearing mice	Specific targeting or cellular uptake study was not performed	[202]
Metallic-based nanoparticles [203]
Hesperetin	Suppression of tumor necrosis factor alpha, transcription factor NF-κB, glycoconjugates, and proliferating cell nuclear antigen	Though specific targeting was not performed, the nanoparticles arrested DNA replication at late G1- and early S-phase	[204]
Resveratrol	Suppressed of tumor growth, promoted apoptosis, and decreased the expression of vascular endothelial growth factor.	Accumulation of nanoparticles in liver tissue was reported, along with apoptosis of cancer cells through PI3/Akt pathway	[205]
Epigallo- catechin gallate (EGCG)	Nanocages irradiated by NIR significantly upregulated caspase-3 by nearly two-fold and downregulated B-cell lymphoma 2 and caused cell apoptosis	Induced cancer cell apoptosis through changes in mitochondrial activities	[206]