Imidazolyl Lipids Enhanced LNP Endosomal Escape for Ferroptosis RNAi Treatment of Cancer

Abstract Treatments for cancer that incorporate small interfering RNA (siRNA) to target iron‐dependent ferroptosis are thought to be highly promising. However, creating a reliable and clinically feasible siRNA delivery system continues to be a major obstacle in the field of cancer treatment. Here, three imidazole‐based ionizable lipid nanoparticles (LNPs) with pH‐sensitive effects are rationally designed and synthesized for siRNA delivery. LNPs formulated with the top‐performing lipid (O12‐D3‐I3) encapsulating FVII siRNA (FVII@O‐LNP) elicited greater gene silencing than those with the benchmark Onpattro lipid DLin‐MC3‐DMA (MC3) due to its stronger endosomal escape. Moreover, Fc‐siRNA@O‐LNPs encapsulated with ferrocene (Fc) and SLC7A11/Nrf2‐targeted siRNA is formulated. The outcomes demonstrate optimal safety profiles and a significant anti‐tumor effect by inducing long‐lasting and efficient ferroptosis through a synergistic action in vivo. In summary, this work shows that imidazolyl lipid‐prepared LNPs are efficient delivery vehicles for cancer therapy and ferroptosis‐targeting siRNA administration, both of which have extensive clinical application potential.