Targeting ligands are anticipated to facilitate precise delivery of therapeutic agents to diseased tissues by recognizing the overexpressed corresponding receptors; however, they may also severely affect the interaction of nanocarriers with plasma proteins, determining what is "seen" by living organisms. Here, we studied the effects of peptide ligands on immunocompatibility of liposome-based, brain-targeted drug delivery systems. Immunocompatibility of liposomes exhibited inverse correlation with absorbed natural IgM. Modification of long, stable positively charged peptide ligands on the surface of stealth liposomes wasinclined to absorb natural IgM, leading to rapid clearance and enhanced immunogenicity. Rational design of brain-targeted ligand was conducted using computer-aided peptide design. The resulting small peptidomimetic D8(DRTGDRDADREDW) exhibited improved immunocompatibility by attenuating natural IgM absorption in vivo. The present study highlights the effects of peptide ligands on the composition of formed protein corona and on in vivo fate of liposomes. Stable positively charged peptide ligands may play double-edged roles in targeted delivery, preserving in vivo bioactivities for binding receptors and long-term unfavorable interactions with innate immune system. The development of D8 provides new insights into how to rationally design immunocompatible drug delivery systems by modulating the composition of protein corona.