Despite potential applications of nucleic acid therapeutics, the lack of effective delivery systems hinders their clinical application. To overcome the barriers to nucleic acid delivery, we previously reported nanoparticles using phospholipid-polyethylenimine conjugates. However, toxicity of polyethylenimine remains as a problematic issue. Herein, we proposed to substitute the polyethylenimine with arginine-rich peptide to obtain a less-toxic carrier system. Nonaarginine was conjugated to the distal end of phospholipid hydrocarbon chains leading to phospholipid-nonaarginine conjugates (PL9R) and then lipid-peptide hybrid nanoparticles carrying oligonucleotide therapeutics (hNP) were constructed by self-assembly process. The hNP were further modified with cell penetrating Tat peptide (T-hNP) to enhance cellular uptake. The PL9R was less cytotoxic, and the hNP showed high loading capacity and colloidal stability. The T-hNP showed higher cellular uptake and transfection efficiency and effective accumulation to tumor tissue and silencing effect in tumor bearing mice. Altogether, T-hNP could provide a promising nanocarrier for nucleic acid therapeutics.