The FOLFIRINOX regimen, a combination of three chemotherapy agents (5-fluorouracil, irinotecan, oxaliplatin) and folinic acid (a vitamin B derivatives reducing the side effect of 5-fluorouracil), has proved to be effective in the treatment of pancreatic cancer, and is more efficacious than the long-term reference standard, gemcitabine. However, the FOLFIRINOX is associated with high-grade toxicity, which markedly limits its clinical application. Encapsulation of drugs in nanocarriers that selectively target cancer cells promises to be an effective method for co-delivery of drug combinations and to mitigate the side effects of conventional chemotherapy. Here we reported the development of multiple layer-by-layer lipid-polymer hybrid nanoparticles with targeting capability that show excellent biocompatibility and synergistically combine the favorable properties of liposomes and polymer nanoparticles. Relative to nanoparticles consisting of polymer alone, these novel nanocarriers have a long half-life in vivo and a higher stability in serum. The nanocarriers were loaded with the three active antitumor constituents of FOLFIRINOX regimen. Little drugs were released from the nanoparticles in phosphate buffered saline (PBS) solution, but the cargoes were quickly released after the nanoparticles were taken up by tumor cells. These innovative drug-loaded nanoparticles achieved higher antitumor efficacy and showed minimal side effects compared with the FOLFIRINOX regimen alone. Our study suggested that the multiple layer-by-layer hybrid nanoparticles have great potential for improving the chemotherapeutic efficacy for the patients with pancreatic cancer. This platform also provides new opportunities for tailored design of nanoparticles that may offer therapeutics benefits for a range of other tumors.