Various polymeric nanoparticles have been used as drug carriers in drug delivery systems (DDSs). Most of them were constructed from dynamic self-assembly systems formed via hydrophobic interactions and from structures that are unstable in an in vivo environment owing to their relatively weak formation forces. As a solution to this issue, physically stabilized core-crosslinked particles (CP) with chemically crosslinked cores have received attention as alternatives to the dynamic nanoparticles. This focused review summarizes recent advances in the construction, structural characterization, and in vivo behavior of polymeric CPs. First, we introduce a nanoemulsion-mediated method to create polyethylene glycol (PEG)-bearing CPs and their structural characterization. The relationship between the PEG chain conformations in the particle shell and the in vivo fate of the CPs is also discussed. After that, the development and advantages of zwitterionic amino acid-based polymer (ZAP)-bearing CPs are presented to address the poor penetration and the internalization of PEG-based CPs into tumor tissues and cells, respectively. Finally, we conclude and discuss prospects for application of polymeric CPs in the DDS field.