This work describes the synthesis and characterization of novel thermoresponsive highly branched polyamidoamine-polyethylene glycol-poly(D,L-lactide) (PAMAM-PEG-PDLLA) core-shell nanoparticles. A series of dendritic PEG-PDLLA nanoparticles were synthesized through conjugation of PEG of various chain lengths (1500, 6000 and 12,000 g mol-1) to polyamidoamine (PAMAM) dendrimer G3.0 and subsequent ring-opening polymerization of DLLA. The ninhydrin assay, 1H NMR, Fourier transform infrared spectroscopy, dynamic light scattering and atomic force microscopy were used to characterize the structure and compositions of dendritic PEG-PDLLA nanoparticles. The sol-gel phase transition of aqueous dendritic PEG-PDLLA solutions was measured using UV-visual spectroscopy. According to our results dendritic PEG-PDLLA nanoparticles in aqueous solution can self-assemble into sub-micron/micron aggregates, the size of which is dependent on temperature and PEG-PDLLA chain length. Further, dendritic PEG-PDLLA solutions exhibit a sol-gel phase transition with increasing temperature. The constructed dendritic PEG-PDLLA nanoparticles possessed high cytocompatibility, which was significantly improved compared with PAMAM dendrimers. The potential of dendritic PEG-PDLLA nanoparticles for encapsulation of water-insoluble drugs such as camptothecin was demonstrated. The dendritic PEG-PDLLA nanoparticles we developed offer greater structural flexibility and provide a novel nanostructured thermoresponsive carrier for drug delivery.