The simple acetylation or acrylation of poly-(ethylene glycol) (PEG) terminus leads to the aggregation of PEG chains into spherical nanoparticles in water at room temperature and very low concentrations. The experiment results suggest that this aggregation happens by the variation of the local conformation of the O-CH2-CH2-O segments of PEG chains caused by the introduced acyl group, which disturbs the originally strict hydrogen bond mode between the O-CH2-CH2-O groups and the water molecules. The simple modified PEG nanoparticles are excellent carriers for drug delivery. As examples, the cross-linkable 1d-based drug delivery systems, cPEG@SN-38 and targeted cPEG@SN-38, are successfully established by their high drug loading content (18 wt %/wt) and enhanced anticancer efficacy both in vitro and in vivo while obviating the inherent toxicity of the employed chemotherapeutics. This strategy that revolves around the simple modification of the generally regarded as safe (GRAS) modules to fabricate drug carriers represents a new direction for the drug delivery systems with clinical potential.