Lipid‐Based Nanoplatforms in Hepatology: From Rational Design to Clinical Translation Challenges

Abstract

Liver diseases—encompassing hepatitis, liver fibrosis, fatty liver, and hepatocellular carcinoma—constitute a formidable global health challenge. Existing treatments are often limited by several key issues, such as low drug accumulation, poor selectivity for target cells, and the toxic side effects of drugs. Lipid-based nanocarriers (LBNCs) have emerged as an up-and-coming platform, leveraging their biocompatibility, versatile drug-loading capacity, and tunable targeting capabilities to overcome these limitations. This comprehensive review critically examines recent advances in the rational design of LBNCs, including liposomes, micelles, nanoemulsions, solid lipid nanoparticles, lipid nanoparticles, biomimetic lipid nanocarriers, and smart responsive lipid nanocarriers, as well as their applications in lipid materials. Subsequently, we delve into their translational application, meticulously reviewing preclinical successes and current clinical progress (encompassing active clinical trials and FDA-approved LBNC formulations). Finally, by analyzing the challenges from rational design to clinical translation, we propose forward-looking perspectives and strategic recommendations to overcome these hurdles and accelerate the realization of LBNC-based therapies in clinical hepatology. This review aims to serve as a valuable reference for researchers, providing in-depth insights into the evolving field of LBNCs and their significant therapeutic potential in hepatology.

Introduction

The liver, a multifunctional organ central to metabolism, detoxification, and immune homeostasis, is besieged by a rising tide of chronic disorders, including nonalcoholic fatty liver disease (NAFLD) [1], viral hepatitis [2], hepatocellular carcinoma (HCC) [3], and liver fibrosis [4, 5]. Globally, liver diseases account for approximately two million deaths annually, with NAFLD alone affecting 25% of the global population and HCC ranking as the third leading cause of cancer-related mortality [6]. Despite decades of research, clinical management remains suboptimal, hindered by late diagnosis, the complex pathogenesis, and the limited efficacy of conventional therapies. Small-molecule drugs, such as sorafenib for HCC or obeticholic acid for primary biliary cholangitis, often suffer from rapid systemic clearance, off-target toxicity, and poor penetration into fibrotic or tumor tissues [7]. Furthermore, the liver’s dual blood supply and dense stromal architecture create biological barriers that impede drug delivery [8], perpetuating the urgent need for innovative therapeutic strategies.

Nanotechnology has emerged as a transformative paradigm in precision medicine, offering solutions to overcome pharmacokinetic limitations and enhance therapeutic specificity. Notably, lipid-based nanocarriers (LBNCs) have garnered significant attention due to their unique advantages in terms of biocompatibility, biodegradability, minimal toxicity, and ease of scalability in production, compared to polymeric or inorganic counterparts [9, 10]. LBNCs—including liposomes, micelles, nanoemulsions, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), lipid nanoparticles (LNPs), biomimetic lipid nanocarriers (BLNs), and smart responsive lipid nanocarriers (SRLNCs)—are composed of biocompatible lipids that mimic biological membranes, minimizing immune recognition and toxicity [11]. Their amphiphilic nature enables efficient encapsulation of diverse cargoes, from hydrophobic chemotherapeutics (e.g., paclitaxel [12]) to hydrophilic nucleic acids (e.g., small interfering RNA (siRNA) [13], mRNA [14, 15]). For instance, poly- (ethylene glycol) (PEG) modified liposomes loaded with seladelpar (Livdelzi) [16] have demonstrated prolonged circulation and reduced cardiotoxicity, underscoring the clinical potential of LBNCs. Livdelzi is approved for the treatment of primary biliary cholangitis in combination with or as monotherapy for patients who are unable to tolerate or have an inadequate response to ursodeoxycholic acid.

Liver diseases each have distinct target cells and pathological characteristics. Hepatitis mainly targets hepatocytes, featuring hepatocyte necrosis, inflammatory cell infiltration, and hepatocyte regeneration [17]. Liver fibrosis focuses on hepatic stellate cells (HSCs), with activated stellate cells, excessive deposition of extracellular matrix (ECM), and pseudo-lobule formation as its pathological signs [18]. Fatty liver disease primarily affects hepatocytes, presenting with hepatocyte steatosis, mild inflammatory cell infiltration, and potential hepatic fibrosis [19]. HCC mainly involves hepatocytes and intrahepatic biliary epithelial cells, characterized by tumor cell proliferation, tissue destruction, necrosis, and bleeding, and a high likelihood of metastasis [20]. These pathological factors pose challenges to LBNC-based drug delivery. In addition, nonspecific uptake by nontarget cells, such as Kupffer cells [21] and liver sinusoidal endothelial cells (LSECs) [22], reduces the proportion of LBNCs reaching target hepatocytes, thereby impacting therapeutic efficacy. To address these limitations, the rational design of LBNCs integrates tissue- or cell-specific targeting, pathology-responsive drug release, programmable metabolic regulation, and adaptive biomimetic strategies to overcome biological barriers and optimize clinical outcomes. For instance, by functionalizing LBNCs with targeting ligands (e.g., galactose [23], hyaluronic acid [HA] [24]), targeted delivery is achieved for precise therapy. Stimuli-responsive lipids (e.g., reactive oxygen species [ROS]-sensitive phosphatidylcholine [PC] [25, 26]) allow spatiotemporal control over drug release.

Currently, there is a limited number of LBNCs that are clinically or commercially approved for the treatment of liver disease. Thus, the objective of this review is to discuss the rational design of LBNCs and the clinical translation challenges in hepatology (Figure 1). We first delineate the structural and functional diversity of LBNCs, including liposomes, micelles, nanoemulsions, SLNs and NLCs, LNPs, BLNs, and SRLNCs, emphasizing their rational design and mechanistic advantages. Next, we explore their therapeutic applications across various liver pathologies, ranging from hepatitis to HCC, highlighting preclinical breakthroughs and clinical advancements, including FDA-approved formulations and ongoing trials. A critical analysis of challenges from rational design to clinical translation is provided to contextualize the gap between laboratory success and clinical application. Finally, we propose forward-looking strategies, including AI-driven lipid optimization and patient-specific nanotherapy, to refine the efficacy and safety of LBNCs. By bridging fundamental research, clinical insights, and industrial perspectives, this review aims to illuminate the transformative potential of LBNCs and provide direction and a basis for the clinical treatment of hepatology.

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Excipients mentioned in the study: Lipoid S100, Kolliphor HS15, and Labrafac WL 1349/Peceol

Lipid‐Based Nanoplatforms in Hepatology: From Rational Design to Clinical Translation Challenges, Jie Wang, Qian Zhang, Lin Yang, Zijian Cheng, Chunhong Wang, Runlin Song, Honglan Dai, Xinxin Zhang, Received: 20 March 2025, Revised: 29 July 2025, Accepted: 6 August 2025, Funding: This study was funded by the National Key Research and Development Program of China (Grant 2022YFC2304104), National Natural Science, Foundation of China (Grants 82222066, U24A20783), and Postdoctoral Innovation Program of Shandong Province (Grant SDCX‐ZG‐202501045). MedComm – Biomaterials and Applications, 2025; https://doi.org/10.1002/mba2.70025

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