Toward oral nanomaterial-based drug delivery systems for hepatocellular carcinoma therapy: evidence mapping, route-specific validation, and translational challenges.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and current systemic therapies are limited by advanced-stage diagnosis, dose-limiting toxicity, drug resistance, and incomplete response rates. Oral nano-drug delivery systems (nano-DDS) are being explored as patient-friendly platforms to improve gastrointestinal protection, intestinal absorption, and hepatic exposure of anticancer agents. However, the evidence base remains uneven: only a minority of HCC nano-DDS studies have been validated through oral administration, whereas many mechanistically important studies rely on intravenous, other parenteral, or in vitro models. To avoid overstatement, this review maps the literature according to route of administration, model relevance, comparator choice, pharmacokinetic reporting, and translational readiness. We synthesize design strategies for polymeric, lipid-based, inorganic, biomimetic, stimulus-responsive, ligand-targeted, magnetic, natural product-loaded, and microbiome-modulating systems, while distinguishing direct oral evidence from non-oral mechanistic evidence. We further emphasize practical requirements for clinical translation, including clinically meaningful comparators such as marketed oral formulations, fed/fasted and portal pharmacokinetics, orthotopic and fibrotic/cirrhotic HCC models, long-term hepatotoxicity and immunotoxicity testing, gut microbiome safety assessment, manufacturing reproducibility, and minimum characterization packages under biorelevant gastrointestinal conditions. Rather than presenting oral nano-DDS as a mature therapeutic class, this review frames the field as a promising but incompletely validated area that requires route-specific validation and standardized go/no-go criteria before clinical development for HCC.