Engineering functional nanoparticles (NPs) with low nonspecific interactions and a high specific targeting property is highly desired for improved drug delivery. Herein, we report a targeted poly(ethylene glycol) (PEG)-based chemotherapy system synthesized via a catalyst-free sono-polymerization process for drug delivery. The polymerization process was fast (20 min), and different monomers were able to be polymerized to form NPs in a one-pot process. Glutathione (GSH)-responsive platinum prodrugs and fluorescent dyes could be encapsulated in NPs by amidation formation. Cyclic peptides containing Arg-Gly-Asp (RGD)-modified PEG-based NPs possessed a much higher cell targeting (∼90%) than the unmodified PEG-based NPs (∼10%) after a 12 h incubation with U87 MG cells, which could improve drug delivery efficacy. The IC50 (50% inhibitory concentration) could also be reduced more than 50% compared to the nontargeted PEG-based NPs. Importantly, these PEG-based NPs can be freeze-dried into a powder form and redispersed in an aqueous solution without aggregation, which may facilitate the storage and transportation of nanomedicine. This study establishes a green and efficient method to engineer targeted drug carriers for drug delivery.