Development of a multi-level pH-responsive lipid nanoplatform for efficient co-delivery of siRNA and small-molecule drugs in tumor treatment

The combination of nucleic acid and small-molecule drugs in tumor treatment holds significant promise; however, the precise delivery and controlled release of drugs within the cytoplasm encounter substantial obstacles, impeding the advancement of formulations. To surmount the challenges associated with precise drug delivery and controlled release, we have developed a multi-level pH-responsive co-loaded drug lipid nano platform. This platform first employs cyclic cell-penetrating peptides to exert a multi-level pH response, thereby enhancing the uptake efficiency of tumor cells and emdow the nanosystem with effective endosomal/lysosomal escape. Subsequently, small interferring RNA (siRNA) complexes are formed by compacting siRNA with stearic acid octa histidine, which is capable of responding to the lysosome-to-cytoplasm pH gradient and facilitate siRNA release. The siRNA complexes and docetaxel are simultaneously encapsulated into liposomes, thereby creating a lipid nano platform capable of co-delivering nucleic acid and small-molecule drugs. The efficacy of this platform has been validated through both in vitro and in vivo experiments, affirming its significant potential for practical applications in the co-delivery of nucleic acids and small-molecule drugs.