Membrane‐destabilizing ionizable lipid empowered imaging‐guided siRNA delivery and cancer treatment

Abstract

One 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.

Biosafety materials: Ushering in a new era of infectious disease diagnosis and treatment with the CRISPR/Cas system

“…Lipid nanoparticles (LNPs) are one of the most effective nucleic acid delivery systems [32] , [33] . LNPs have been widely used in the delivery of nucleic acids, including DNA, siRNA, and mRNA, due to their excellent transfection ability and low toxicity [3] . The key lipids of LNPs are usually ionizable lipids that possess hydrophilic heads and hydrophobic tails, allowing LNPs to spontaneously assemble into nanoparticles in an aqueous environment and disassemble and release drugs in acidic environments.…”

“…Biosafety materials can be used not only as a core element in the diagnosis and treatment of diseases but also as an “umbrella” for other methods of diagnosis and treatment. For example, they can be used as a safe delivery vehicle for drugs/reagents [3] , [4] , including chemical drugs, genetic drugs, and others. Therefore, biosafety materials have broad application prospects in the detection and treatment of diseases.…”

Nucleic Acids and Their Analogues for Biomedical Applications

“…Alternatively, an effective delivery strategy involved the use of nanocarriers against cancers is urgently needed in the clinical sector such as cancer centers and hospitals. Natural or synthetic compounds including liposomes, polymers, cationic lipids, and lipid-polymer hybrids have been proposed as nanocarriers for systemic delivery of siRNA/miRNAs into the cells [ 208 , 212 , 213 , 214 , 215 , 216 ]. Unfortunately, drug loading efficiency of polymeric nanoparticles is not sufficiently high while the loaded therapeutic drugs had either very low or very fast release kinetics after administration in the blood stream [ 217 , 218 ].…”

Polyester materials for mRNA delivery

“…To address these obstacles and improve the druggability of mRNA, tremendous efforts have been invested in engineering mRNA molecules and developing mRNA delivery systems [10][11][12][13]. Lipids and polymers are the most advanced delivery systems for nucleic acid therapeutics [14][15][16]. Within the group of polymer vectors, polyester and their analogs hold great potential for mRNA delivery by virtue of their good biocompatibility and biodegradable property.…”