AbstractOne of the imperative medical requirements for cancer treatment is how to establish an imaging‐guided nanocarrier that combines therapeutic and imaging agents into one system. siRNA therapeutics have shown promising prospects in controlling life‐threatening diseases. However, it is still challenging to develop siRNA formulations with excellent cellular entry capability, efficient endosomal escape, and simultaneous visualization. Herein, we fabricated multifunctional ionizable lipid nanoparticles (iLNPs) for targeted delivery of siRNA and MRI contrast agent. The iLNPs comprises DSPC, cholesterol, PEGylated lipid, contrast agent DTPA‐BSA (Gd), and ionizable lipid termed iBL0104. siRNA‐loaded iLNPs (iLNPs/siRNA) could be decorated with a tumor targeting cyclic peptide (c(GRGDSPKC)) (termed GARP), or without targeting modification (termed GAP). Data revealed that GARP/siRNA iLNPs exhibited significantly higher cellular entry efficiency than GAP/siRNA iLNPs. GARP/siRNA iLNPs rapidly and effectively escaped from endosome and lysosome after internalization. Compared with GAP/siPLK1, GARP/siPLK1 exhibited better tumor inhibition efficacy in both cell‐line derived xenograft and liver cancer patient derived xenograft murine models. In addition, GARP formulation displayed ideal MRI effect in tumor‐bearing mice, and was well tolerated by testing animals. Therefore, this study provides an excellent example for achieving imaging‐guided and tumor‐targeted siRNA delivery and cancer treatment, highlighting its promising potential for translational medicine application.