A Mannosylated peptidyl lipid CManDA doped into cytidinyl/cationic lipids efficiently delivers siG12Ss to lung cancer in vivo.

Gene therapy has attracted widespread attention in recent years, and one of the important delivery systems is the LNP. However, many LNPs have potential toxicity and accumulate in the liver. Here, we designed and synthesized a Gemini-type mannosylated peptidyl lipid called CManDA(M), which, in combination with the cytidinyl lipid DNCA(D) and the peptidyl lipid CLD(C) (D/50C/50 M), could transfect siRNA (siG12S) into A549 cells to target and silence the KRAS gene. The fluorescence intensity in the tumor area of the D/50C/50 M/Cy5.5-siG12S group increased by approximately 2.5 times. Furthermore, full 2'-F/2'-OMe-modified siG12Ss could also be transfected by D/50C/50 M into cells, resulting in target gene silencing. The tumor weight in the D/50C/50 M/M3 group (1.5 mg/kg, i.v.) was reduced by 50 % after administration in a mouse axillary tumor (A549) model, whereas the tumor bioluminescence intensity was only approximately 30 % of that in the blank group in a mouse orthotopic lung cancer model and showed no significant toxicity. Further studies revealed that the mannose groups of CManDA can be exposed on the nanoparticle surface to bind lectins, and CManDA can also shield the formation of a protein corona and alter the composition of the protein corona, which aids in the enhancement of its active targeting function. CManDA is expected to be a safe and effective helper lipid for tumor-targeted delivery of siRNA in vivo.