PEGylated hollow mesoporous silica nanoparticles (HMSN-PEG) were successfully fabricated by only one simple step through hydrothermal treatment in Na2CO3 solution. HMSN-PEG nanoparticles were transformed from conventional PEG-modified mesoporous silica nanoparticles (MSN-PEG). The as-synthesized HMSN-PEG nanoparticles exhibited higher loading capacity of anticancer drug (Doxorubicin) and better sustained release property than MSN and MSN-PEG particles. In vitro cell viability of HMSN-PEG nanoparticles to Hep-G2 cells was evaluated. HMSN-PEG nanoparticles have little in vitro cytotoxicity up to a concentration of 500 μg/ml. Furthermore, the DOX-loaded HMSN-PEG nanoparticles exhibited higher cytotoxicity than the DOX-loaded MSN and MSN-PEG nanoparticles against Hep-G2 cells. Therefore, the HMSN-PEG nanoparticle that generated in this PEG protecting etching strategy is a promising nanocarrier toward its potential application for cancer therapy.