A double-hydrophilic multiarm hyperbranched polymer with a hyperbranched poly(amidoamine) (HPAMAM) core and many poly(ethylene glycol) monomethyl ether (MPEG) arms connected by pH-sensitive acylhydrazone bonds (HPAMAM-g-MPEG) was successfully prepared. Benefiting from the cationic dendritic core and PEGylation shell, the double-hydrophilic multiarm hyperbranched polymer was used as a nanoreactor for CdS quantum dots (CdS QDs) synthesis in aqueous solution. The obtained HPAMAM-g-MPEG and CdS/HPAMAM-g-MPEG nanocomposites were carefully characterized by (1)H NMR, (13)C NMR, Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible absorption spectroscopy (UV-vis), fluorescence spectroscopy (FL), dynamic light scattering (DLS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and electronic dispersive X-ray spectroscopy (EDS) analysis. Both (1)H NMR and fluorescence spectroscopy investigations confirmed that the acylhydrazone linkage between the dendritic core and linear arms was readily broken under acidic condition (pH <5.5). When MPEG arms departed from the HPAMAM core, the fluorescence intensity of CdS/HPAMAM-g-MPEG nanocomposites greatly increased. Such pH-responsive behavior of CdS/HPAMAM-g-MPEG nanocomposites was utilized as an exploration of a novel fluorescence probe in an acidic lysosome exemplified by COS-7 cells.