Surface modification strategies of oral liposomes are pivotal for overcoming industrial scale-up bottlenecks and ensuring future clinical success

Oral administration is the most prevalent and preferred clinical route due to its non-invasiveness, high patient compliance, and convenience. However, the oral delivery of many therapeutic drugs is hindered by low bioavailability, attributed to multiple gastrointestinal (GI) barriers including acid degradation, enzymatic hydrolysis, poor epithelial permeability, and first-pass metabolism. Liposomes have emerged as promising oral nanocarriers owing to their biocompatibility, versatile drug-loading capacity, and biomimetic membrane structure. Nevertheless, their poor physicochemical stability and inadequate cargo protection in the harsh GI environment limit clinical applications. This review summarizes the latest advances in surface modification strategies for liposomes to address these challenges. Synthetic polymer modifications (e.g., PEG, TPGS, pH-responsive Eudragit, and polydopamine) significantly boost the physicochemical stability of liposomes, prevent drug efflux, and improve mucus penetration. Natural biomacromolecule modifications (e.g., natural polysaccharides, proteins, peptides, and aptamers) effectively enhance mucoadhesion, cellular internalization, and active targeting capabilities. Meanwhile, small-molecule ligand modifications (e.g., folic acid, vitamin B12, and bile acids) actively promote intestinal transcytosis and targeted absorption by hijacking specific endogenous transporters. Notably, composite or multi-layer modification strategies (e.g., layer-by-layer assembly) achieve synergistic effects in effectively overcoming successive GI barriers. Furthermore, this review addresses the critical translational hurdles from bench to bedside, emphasizing that overcoming industrial scale-up bottlenecks (e.g., via microfluidic technologies) and conducting rigorous long-term biosafety evaluations are pivotal for the future clinical and commercial success of these advanced nanocarriers. Ultimately, these sophisticated surface engineering technologies remarkably enhance the physicochemical integrity, mucus penetration ability, and cellular uptake efficiency of liposomes, laying a solid foundation for translating efficient oral nanotherapeutics from bench to market.