Lipid‐based nanoplatforms: Revolutionary tools for hepatology from design to clinical challenges

This review is led by Jie Wang (Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery) and Xinxin Zhang (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, et al.), with contributions from researchers across Shandong, Tianjin, Shanghai, and Beijing. Liver diseases—encompassing hepatitis, liver fibrosis, fatty liver, and HCC—pose a global health crisis, accounting for approximately 2 million annual deaths worldwide. Conventional treatments are limited by low drug accumulation in the liver, poor target cell selectivity, and severe side effects. LBNCs, leveraging their biocompatibility, versatile drug‐loading capacity, and tunable targeting, have emerged as a promising platform to overcome these barriers.

The team systematically analyzed seven major LBNC types, each with unique structural and functional advantages. Liposomes, for example, form bilayer structures mimicking biological membranes, enabling encapsulation of both hydrophilic and hydrophobic drugs. A study highlighted in the review showed that silibinin‐loaded liposomes (Sil‐Lip) improved the bioavailability of silibinin (a natural product for nonalcoholic fatty liver disease, NAFLD) by avoiding gastrointestinal degradation, significantly enhancing its therapeutic effect on fatty liver. Micelles, with diameters often below 50 nm, can penetrate liver sinusoidal endothelial cell (LSEC) fenestrations to reach target cells like hepatic stellate cells (HSCs). Phosphatidylcholine‐bile salt mixed micelles loaded with SKLB023 (a novel NASH treatment candidate) reduced lipid accumulation, inflammation, and fibrosis in NASH mouse models.

Nanoemulsions, composed of oil, water, and stabilizers, excel at solubilizing poorly soluble drugs. For instance, eicosapentaenoic acid (EPA)‐loaded nanoemulsions improved membrane structure and antioxidant capacity in animal models of liver injury. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) offer high drug‐loading and sustained release; berberine‐loaded SLNs, for example, alleviated hepatic steatosis in db/db mice by regulating lipid metabolism. Lipid nanoparticles (LNPs), the gold standard for nucleic acid delivery, have shown promise in treating viral hepatitis and HCC: SM‐102‐based LNPs (used in Moderna’s mRNA vaccines) effectively delivered CRISPR/Cas9 components to target hepatitis B virus (HBV) DNA, while ionizable lipid‐formulated LNPs carrying universal STING mimic (uniSTING) mRNA inhibited HCC growth in mice.

Biomimetic lipid nanocarriers (BLNs), coated with natural components like cell membranes or exosomes, enhance immune evasion and targeted delivery. Mesenchymal stem cell (MSC) membrane‐coated liposomes loaded with cyclosporin A (CsA) accumulated at liver injury sites in a hepatic ischemia‐reperfusion model, mitigating damage with just one‐tenth the conventional CsA dose. Smart responsive lipid nanocarriers (SRLNCs) release drugs in response to pathological cues (e.g., pH, reactive oxygen species, ROS). Thermosensitive liposomes like ThermoDox, which release doxorubicin at 42°C–45°C, have been tested in HCC clinical trials to achieve tumor‐specific drug delivery.

In clinical applications, several LBNC formulations have advanced to trials or received approval. Epaxal, a hepatitis A vaccine based on liposomes, provides up to 20 years of immune protection. Nanoemulsions combining idarubicin and iodized oil are in Phase II/III trials for HCC via transarterial chemoembolization (TACE), reducing cardiotoxicity compared to free idarubicin. LNPs like OTX‐2002 (targeting MYC oncogene in HCC) and MTS105 (encoding bispecific T‐cell engagers) are in early‐phase trials, with OTX‐2002 showing 55% average MYC downregulation in patients.

Despite these successes, the team identified critical challenges. Rational design hurdles include limited understanding of lipid structure–activity relationships (SAR), off‐target uptake by Kupffer cells or LSECs, and disparities between animal models and human liver diseases. Clinical translation barriers involve scalable production of LBNCs (e.g., batch‐to‐batch variability in BLNs), long‐term safety concerns (e.g., immunogenicity of cationic lipids), and poor patient compliance with injectable formulations.

To address these, the researchers propose innovative strategies: AI‐driven platforms like the Lipid Optimization Network (LiON) to predict high‐performance lipids (e.g., RJ‐A30‐T01, which outperforms FDA‐approved MC3 in liver targeting); organ‐on‐a‐chip (OoC) models to simulate human liver physiology for real‐time LBNC testing; and theranostic LBNCs that combine imaging and therapy for personalized monitoring. “These advances signal a shift toward data‐driven, patient‐specific LBNC engineering,” says Xinxin Zhang. “By bridging fundamental research and clinical practice, we aim to unlock the full potential of LBNCs in hepatology.”

See the article

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

https://doi.org/10.1002/mba2.70025