{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:54:46Z","timestamp":1791230086788,"version":"4.1.0"},"reference-count":205,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1854700","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T12:34:26Z","timestamp":1782909266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Toward oral nanomaterial-based drug delivery systems for hepatocellular carcinoma therapy: evidence mapping, route-specific validation, and translational challenges"],"prefix":"10.3389","volume":"17","author":[{"given":"Yang","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixiong","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifeng","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"EVIDoa2100070","DOI":"10.1056\/evidoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Abou-Alfa","year":"2022","journal-title":"NEJM Evid."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1007\/s11095-024-03798-9","article-title":"The role of artificial intelligence and machine learning in accelerating the discovery and development of nanomedicine","volume":"41","author":"Agrahari","year":"2024","journal-title":"Pharm. 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