Cancer cell membrane-camouflaged pH-responsive nanoparticles for enhancing siRNA effect and synergistic anti-tumor therapy

RNA-based therapies, especially small interfering RNA (siRNA), have attracted extensive attention for tumor treatment. However, most siRNA can't exert a therapeutic effect due to a lack of targeting to tumor cells and entrapment in lysosomes upon administration. To address the challenges associated with siRNA delivery, a delivery system was developed using zinc oxide nanoparticles (ZnO NPs) coated with cancer cell membranes. ZnO nanoparticles (ZnO NPs) have been recognized as effective pH-responsive nanoparticles and are widely used in the development of pH-responsive drug delivery systems. The ZnO NPs were combined with chitosan to encapsulate siRNA, allowing for dissolution in acidic lysosomes and the subsequent release of siRNA and chitosan complexes. The dissolution of ZnO NPs would also disrupt lysosomes, facilitating the escape of siRNA and enhancing its gene silencing effect. However, the chitosan and ZnO NPs nano-complexes (CS/ZnO@siRNA) were unstable in solution and lacked a specific targeting effect for tumor cells. Thus, a homologous cancer cell membrane was coated onto the nanoparticles, which has been shown to be an effective strategy for enhancing their stability and targeting capabilities. Moreover, ZnO NPs not only dissolve in acidic lysosomes to enhance the efficacy of siRNA but also elevate oxidative stress levels in cells, leading to the induction of cellular apoptosis. It was demonstrated both in vitro and in vivo that the ZnO NPs could synergistically combine with the anti-tumor siRNA (siSurvivin) to inhibit the growth of the 4T1 tumor. Altogether, the developed drug delivery system (CCM-CS/ZnO@siSurvivin) offers a new strategy for enhancing the therapeutic effect of siRNA, while synergistically inhibiting tumor growth.