Ultrasound‐Sensitive Targeted Liposomes as a Gene Delivery System for the Synergistic Treatment of Hepatocellular Carcinoma

Gene therapy and sonodynamic therapy, as emerging treatment methods, have great potential in cancer treatment. However, there are significant challenges in the in vivo delivery of genes and sonosensitizers during the treatment process, which ultimately affects the therapeutic outcome. In this study, an ultrasound‐sensitive targeted liposome nanoparticle system (MLipsiBcl‐2) is developed to deliver the sonosensitizers and siRNA for the synergistic treatment of hepatocellular carcinoma. Generation of reactive oxygen species (ROS) by MLipsiBcl‐2 can be initiated through ultrasound stimulation, leading to liposome rupture and release of the sonosensitizer and small interfering RNA (siRNA). Furthermore, ROS can disrupt lysosomal membranes, facilitating gene release for downregulating overexpressed antiapoptotic protein levels in cancer cells. Experimental results from in vitro and in vivo studies demonstrated the efficacy of synergistic treatment on hepatocellular carcinoma cells and the high biocompatibility of MLipsiBcl‐2 under ultrasound stimulation. The advancement of this ultrasound‐sensitive targeted gene delivery system shows potential as a versatile therapeutic platform that is easily operable, presenting a prospect for a synergistic treatment approach across various cancer types. This study constructs an ultrasound‐sensitive targeted liposome for the delivery of sonosensitizers and small interfering RNA, which enhances the accumulation of small molecule drugs at tumor sites. It combines sonodynamic therapy with gene therapy for the synergistic treatment of hepatocellular carcinoma. The development of this multifunctional nano‐delivery vehicle provides broader application prospects for the integration of various emerging therapeutic modalities.