Mitochondrial dysfunctions cause numerous human disorders and the development of mitochondria-targeted nanocarriers for drug delivery has aroused great attention. Herein, we report the synthesis of a liposomal nanohybrid cerasome modified with triphosphonium (TPP) for drug delivery to the mitochondrial matrix. The cerasomes were observed to possess an average size of about 38 nm in diameter, and the theoretical simulation of GBEMP mapping demonstrated that the amphiphilic organotrialkoxysilanes were stable as a bilayer equilibrium conformation after self-assembly. The cerasomes showed good stability, excellent biocompatibility and sustainable drug release behavior. Moreover, the TPP-targeted cerasomes resulted in greater drug accumulation in mitochondria, thus leading to a greater antitumor effect as compared to non-targeted cerasomes by using doxorubicin as a modal drug. The specific accumulation of TPP-targeted cerasomes within mitochondria was also confirmed by using JC-1 as the fluorescent probe to analyze the mitochondrial transmembrane potential change.