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 C as a model therapeutic protein to demonstrate the efficiency of this fusion liposome system in maintaining protein integrity while achieving efficient intracellular delivery. In vivo studies show significant therapeutic efficacy in tumor models via 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.