Nanoscale delivery systems for hepatocellular carcinoma: Functionalization, delivery strategies, and clinical challenges
- 1Hepatic Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China
- 2Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang, 310003, China
- 3Department of Oncology, Shunde Hospital, The First People's Hospital of Shunde, Southern Medical University, Foshan, 528000, China
Abstract
Hepatocellular carcinoma (HCC) remains a leading driver of cancer-related mortality, characterized by profound heterogeneity and a formidable Tumor microenvironment (TME). Conventional therapeutic interventions, including traditional chemotherapy and targeted small molecules, are frequently hindered by critical limitations such as poor aqueous solubility, rapid metabolic clearance, severe systemic toxicity, and the rapid onset of multidrug resistance. Furthermore, these free therapeutic agents struggle to penetrate the dense hepatic stroma. Nanoscale drug delivery systems (NDDS) have emerged as a transformative paradigm to overcome these intractable bottlenecks. By leveraging size-mediated passive accumulation, active ligand recognition, and intelligent microenvironment-responsive designs, nanocarriers can significantly prolong systemic circulation, facilitate deep tumor penetration, and achieve spatiotemporally controlled payload release. This review provides a comprehensive and critical analysis of the evolving landscape of HCC nanomedicine. We systematically evaluate the delivery mechanisms and pharmacokinetics of phytochemicals, synthetic molecules, and advanced gene therapeutic modules (RNAi and CRISPR/Cas9). Furthermore, we provide a comparative evaluation of sustainable "green" biomaterials against traditional carriers, detail sophisticated surface functionalization strategies that range from ranging from ligand-mediated targeting to cell-membrane biomimetic "stealth" coatings and explore multi-stimuli responsive platforms. Finally, we critically discuss current clinical translational bottlenecks, including protein corona formation, immunogenicity, and scalable manufacturing, thereby offering a strategic roadmap for the clinical realization of next-generation hepatic nanotherapeutics.
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BibTeX
@article{fu2026nanoscale,
title = {{Nanoscale delivery systems for hepatocellular carcinoma: Functionalization, delivery strategies, and clinical challenges}},
author = {Zhuoya Fu and Bingzhu Zheng and Jiawei Zhang and Jian Ruan and Dayong Zheng},
journal = {Materials Today Bio},
year = {2026},
month = may,
doi = {10.1016/j.mtbio.2026.103227},
url = {https://doi.org/10.1016/j.mtbio.2026.103227},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Nanoscale delivery systems for hepatocellular carcinoma: Functionalization, delivery strategies, and clinical challenges
AU - Zhuoya Fu
AU - Bingzhu Zheng
AU - Jiawei Zhang
AU - Jian Ruan
AU - Dayong Zheng
PY - 2026
DA - 2026/05/14
JO - Materials Today Bio
DO - 10.1016/j.mtbio.2026.103227
UR - https://doi.org/10.1016/j.mtbio.2026.103227
AB - Hepatocellular carcinoma (HCC) remains a leading driver of cancer-related mortality, characterized by profound heterogeneity and a formidable Tumor microenvironment (TME). Conventional therapeutic interventions, including traditional chemotherapy and targeted small molecules, are frequently hindered by critical limitations such as poor aqueous solubility, rapid metabolic clearance, severe systemic toxicity, and the rapid onset of multidrug resistance. Furthermore, these free therapeutic agents struggle to penetrate the dense hepatic stroma. Nanoscale drug delivery systems (NDDS) have emerged as a transformative paradigm to overcome these intractable bottlenecks. By leveraging size-mediated passive accumulation, active ligand recognition, and intelligent microenvironment-responsive designs, nanocarriers can significantly prolong systemic circulation, facilitate deep tumor penetration, and achieve spatiotemporally controlled payload release. This review provides a comprehensive and critical analysis of the evolving landscape of HCC nanomedicine. We systematically evaluate the delivery mechanisms and pharmacokinetics of phytochemicals, synthetic molecules, and advanced gene therapeutic modules (RNAi and CRISPR/Cas9). Furthermore, we provide a comparative evaluation of sustainable "green" biomaterials against traditional carriers, detail sophisticated surface functionalization strategies that range from ranging from ligand-mediated targeting to cell-membrane biomimetic "stealth" coatings and explore multi-stimuli responsive platforms. Finally, we critically discuss current clinical translational bottlenecks, including protein corona formation, immunogenicity, and scalable manufacturing, thereby offering a strategic roadmap for the clinical realization of next-generation hepatic nanotherapeutics.
SN - 2590-0064
ER -