Oral Liposome Surface Modifications Enhance Drug Bioavailability by Overcoming GI Barriers

Oral administration is the preferred route for drug delivery due to its non-invasiveness and high patient compliance. However, many therapeutic drugs suffer from low oral bioavailability due to formidable gastrointestinal (GI) barriers, including acid degradation, enzymatic hydrolysis, poor epithelial permeability, and first-pass metabolism. Liposomes, as promising nanocarriers, offer excellent biocompatibility and versatile drug-loading capacity, yet their poor physicochemical stability and inadequate cargo protection in the harsh GI environment severely limit their clinical application. Addressing these stability and permeability challenges is crucial for expanding oral drug delivery.

This comprehensive review systematically summarized the latest advances in surface modification strategies designed to enhance the oral delivery of liposomes. The authors categorized and analyzed various engineering approaches, including modifications with synthetic polymers, natural biomacromolecules, and small-molecule ligands. They also explored advanced composite and multi-layer modification strategies. Furthermore, the review critically examined the translational hurdles from laboratory research to clinical application, specifically focusing on industrial scale-up and long-term biosafety evaluations for these advanced nanocarriers.

The review detailed several effective surface modification strategies for oral liposomes. Synthetic polymer modifications, such as PEG, TPGS, pH-responsive Eudragit, and polydopamine, were shown to significantly boost the physicochemical stability of liposomes, prevent premature drug efflux, and improve mucus penetration across the GI tract. Natural biomacromolecule modifications, including natural polysaccharides, proteins, peptides, and aptamers, effectively enhanced liposome mucoadhesion, cellular internalization into intestinal cells, and active targeting capabilities. Meanwhile, small-molecule ligand modifications, such. as folic acid, vitamin B12, and bile acids, actively promoted intestinal transcytosis and targeted absorption by hijacking specific endogenous transporters. Notably, composite or multi-layer modification strategies, like layer-by-layer assembly, achieved synergistic effects, enabling liposomes to effectively overcome successive GI barriers. The review emphasized that these sophisticated surface engineering technologies are pivotal for the future clinical and commercial success of advanced oral nanocarriers. > These sophisticated surface engineering technologies are pivotal for the future clinical and commercial success of advanced oral nanocarriers.