The endoplasmic reticulum (ER) apparatus is a part of the secretory pathway that transports proteins to the plasma membrane through vesicle trafficking, enabling post-translational modification of the newly synthesized proteins. Several diseases such as inflammation, neurodegenerative disorder, and bipolar disorder are closely associated with dysfunction of the ER stress response. Herein, we present an ER-targeting, intracellular delivery approach that utilized cell-penetrating peptide (CPP)-conjugated lipid/polymer hybrid nanovehicles (LPNVs). For this, we patched Penetratin, a type of CPP, onto the LPNVs with vesicular membranes formulated with poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-PCL-b-PEO) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). We found that the Penetratin-conjugated LPNV (LPNVPnt) was readily taken up by cells and showed specific ER-targeting ability, which was comparable to that of LPNVs conjugated with other types of CPPs. Moreover, we observed that remarkable lysosomal escape of the LPNVs occurred due to effective pH buffering with the aid of PEO-b-PCL-b-PEO. These results highlighted that our LPNVPnt system could pave the way for the development of an elaborate drug delivery technology for ER-targeting at the intracellular level.