No information was reported to date about the uptake process of repeated cationic arginine or lysine followed by leucine or alanine with lipid bilayer based DNA nanocargoes. Here we orchestrated the concept of repeated lysala-leu-ala (KALA) peptide modified DNA-lipid nanoparticle, proclaimed a promising transfection activity in dendritic cell, following GPCR mediated endocytosis. Chemical inhibitors studies of chlorpromazine, Fillipin, and Amiloride did not support the concept of macropinocytosis, clathrin mediated endocytosis and cavaeola mediated endocytosis. Cetirizine hydrochloride, a GPCR blocker shut down the KALA mediated transgene expression. Confocal studies showed no liposomal uptake in KALA modification rather than R8 modification, which implies to receptor mediated endocytosis. Low concentration of KALA pretreatment allowed a R8 MEND (usually non-expressed) to that of the same expression of KALA MEND and vice versa of high concentration KALA pretreatment. A PKA inhibitor, rottlerin and PKA terminator (p-300/CREB inhibitor), curcumin halted the gene expression of KALA modified MEND, where octa-arginine modified MEND did not respond to the inhibitory effect by curcumin. Collectively, our data suggest that a repeated lys-ala-leu-ala (KALA) modification in lipid embedded DNA nanoparticle approached a GPCR induction both in endocytosis and activation, which might be a potential reason of boom transgene expression in dendritic cell