Fluorinated Choline Phosphate-Embedded Liposomes for Spatiotemporally Programmed Transdermal Protein Delivery

Focus more directly on the demands and challenges of noninvasive strategies enabling precise, spatiotemporally programmed transdermal protein delivery. Herein, we integrated fluorinated choline phosphate (FCP) conjugated with lipid chains into liposomes to construct FmCPn-lipo. FmCPn-lipo were fabricated, and fluorination conferred an appropriate particle size, improved membrane stability, and unique dual-phobicity, thereby enhancing protein encapsulation, skin penetration, and sustained delivery. This system achieved precisely controlled transdermal delivery of a high-molecular-weight ovalbumin protein (45 kDa) in both spatial (skin depth) and temporal dimensions. The fluorination degree in FmCPn-lipo directly enhanced liposome penetration into deeper skin, likely attributable to fluorine’s dual-phobicity (both hydrophobic and oleophobic properties). Such unique surface characteristics reduce the interfacial tension between the material and the skin surface, weaken the adhesion between lipid layers, and facilitate the insertion and diffusion of the substance into the stratum corneum, thereby promoting skin penetration. Concurrently, increased incorporation of fluorinated FmCPn enhances membrane rigidity and structural stability, thereby reducing the drug diffusion rate and leading to sustained protein release. Leveraging these principles, we engineered a liposomal system containing F7CP at 10%, which functions within 30–60 min, thereby enabling its immunomodulatory and antiaging functions. This platform offers a potential strategy for spatiotemporally precise transdermal protein therapeutics.