Phosphorothioated DNA engineered fusion liposomes for ultrasound-responsive targeted intracellular protein delivery

Ultrasound-mediated drug delivery, despite its benefits of deep-tissue penetration and minimal side effects, faces significant challenges in terms of targeting specificity and cargo preservation, especially for protein therapeutics. In this study, we introduce a novel liposomal delivery platform that synergizes targeted delivery with spatially controlled ultrasound activation. This system employs aptamer-mediated tumor targeting and ultrasound-induced membrane fusion capabilities, allowing for the precise spatial control of protein cargo release directly into the cytoplasm of target cells. We use Cytochrome <i>C</i> as a model therapeutic protein to demonstrate the efficiency of this fusion liposome system in maintaining protein integrity while achieving efficient intracellular delivery. <i>In vivo</i> studies show significant therapeutic efficacy in tumor models <i>via</i> spatially-resolved ultrasound stimulation. This platform overcomes key limitations of traditional ultrasound-responsive delivery systems by enabling specific targeting and broadening the range of viable therapeutic cargo types. This versatile approach signifies a substantial advancement in controlled deep-tissue protein delivery, presenting wide-ranging potential for various therapeutic applications. The fusion liposome system offers a promising strategy for targeted protein therapeutics, particularly in scenarios requiring spatial precision and deep tissue penetration.