A new core–shell type of nano-architectures based on hyperbranched polyglycerol (hPG) has been designed by attaching a mono(methoxy)polyethylene glycol (mPEG) shell either directly or through a hydrophobic biphenyl spacer to the hPG scaffold. Alternatively the hPG core was decorated with hydrophobic segments specifically located around the hPG and mPEG as the shell. The constructed structures were compared and contrasted for their ability to solubilize guest molecules of different polarity indices to their corresponding non-solvent for possible drug delivery applications. UV/Vis spectroscopy and Scanning Force Microscopy (SFM) techniques have been used to characterize the host–guest complex. Highly hydrophilic nanocarriers composed of an hPG–mPEG arrangement were found to be very efficient in transporting hydrophilic molecules to an organic environment with almost no encapsulation of the hydrophobic guests. Introduction of biphenyl fragments as hydrophobic spacers between hPG and mPEG, or near the hPG core, substantially increased the hydrophobic guest encapsulation efficiency of the resulting system. The encapsulation and transport properties were found to critically depend on the Mn of hPG, degree of functionalization with hydrophilic and/or hydrophobic fragments and length of mPEG chains, either alone or in combination with each other. SFM images revealed that the size of the nanocarriers is within the range of 10 nm as single particles and 50 nm as aggregates, with the sizes substantially increased upon interaction with the guest species.