Lung‐Endothelium‐Targeted Nanoparticles Based on a pH‐Sensitive Lipid and the GALA Peptide Enable Robust Gene Silencing and the Regression of Metastatic Lung Cancer

Abstract

The development of efficient gene delivery systems targeting the lung endothelium remains a serious challenge. This study reports on the design and optimization of a multifunctional envelope‐type nanodevice (MEND) for an efficient siRNA delivery to the lung endothelium based on GALA‐peptide targeting ability. The incorporation of a pH‐sensitive lipid (YSK05) results in a dramatic improvement in silencing efficiency by enhancing endosomal escape, but this also causes a reduction in the lung selectivity. Contrary to the assumption that active targeting is largely dependent on the presence of a targeting ligand, the findings of the present study indicate that nanocarrier composition is critical for achieving the organ selectivity. Interestingly, helper lipids substantially mask the liver delivery resulting in optimum lung targeting. The optimized YSK05‐MEND is 40‐fold more efficient than a previously developed MEND, with a robust lung endothelium gene knockdown at small doses. The YSK05‐MEND strongly inhibits a metastatic lung cancer model and exerts superior control over lung metastasis compared to chemotherapy or the previously developed MEND. The YSK05‐MEND is well‐tolerated in mice after acute or chronic administration. As far as it is known, YSK05‐MEND achieves the most efficient lung endothelium gene silencing reported thus far with a median effective dose of 0.01 mg siRNA kg−1 while minimally affecting the endothelium of other organs.

Lipid Nanoparticles for Cell-Specific <i>in Vivo</i> Targeted Delivery of Nucleic Acids

“…[46][47][48] The combination of R8 and GALA peptides produced very efficient MENDs based on synergism between the two peptides. 49) Different MENDs were prepared encapsulating pDNA, siRNA, or mRNA and could be successfully used for efficient gene delivery in vitro and in vivo. [50][51][52][53] Recently, Khalil et al have proposed a new 2-step coating strategy for a MEND system encapsulating pDNA and combining the R8 peptide with the ionizable lipid YSK05.…”

Cytosolic delivery of nucleic acids: The case of ionizable lipid nanoparticles

“…LNPs may indeed benefit from the synergic action of such peptides, which help establish the first contact between the facing membranes through the formation of biological anchors. Coherently with this vision, a recent work described the development of a novel LNPs decorated with GALA‐cholesterol conjugate 128 . The combined effect of the ionizable lipid YSK05 and GALA improved the endosome escape as compared to a control system (composed of the cationic lipid DOTMA and GALA).…”

Environment‐Responsive Lipid/siRNA Nanoparticles for Cancer Therapy

“…The GALA peptide is a fusogenic peptide that undergoes conformational changes in the acidic conditions of the endosomal pathway. [ 141 ] Optimization of YSK05‐MEND, with the addition of helper lipids to reduce delivery to the liver, yielded improved lung targeting, endosomal escape, and silencing efficiency. [ 141 ] The optimized YSK05‐MEND carrying siRNA to CD31 had 40‐fold improvement over the previously developed MEND, displaying robust knockdown of CD31 in lung endothelium at small doses with minimal toxicity and off‐target effects.…”

“…[ 141 ] Optimization of YSK05‐MEND, with the addition of helper lipids to reduce delivery to the liver, yielded improved lung targeting, endosomal escape, and silencing efficiency. [ 141 ] The optimized YSK05‐MEND carrying siRNA to CD31 had 40‐fold improvement over the previously developed MEND, displaying robust knockdown of CD31 in lung endothelium at small doses with minimal toxicity and off‐target effects. [ 141 ] The YSK05‐MEND substantially reduced metastatic lung activity beyond conventional cationic MENDs and chemotherapeutics, demonstrating reduced cell proliferation and tumor growth while increasing the apoptotic response.…”

“…[ 141 ] The YSK05‐MEND substantially reduced metastatic lung activity beyond conventional cationic MENDs and chemotherapeutics, demonstrating reduced cell proliferation and tumor growth while increasing the apoptotic response. [ 141 ]…”