We report a general and facile approach for the fabrication of a new class of monodispersed, single-component and thick-walled polymer nanocapsules via the single-step assembly of macromolecules in solid core/mesoporous shell (SC/MS) silica particle templates, followed by cross-linking of the macromolecules and removal of the SC/MS templates. The general applicability of this approach is demonstrated by the preparation of nanocapsules using various polymers, including synthetic polyelectrolytes, polypeptides, and polypeptide-drug conjugates. The potential of doxorubicin (Dox)-loaded poly(L-glutamic acid) nanocapsules in tumor therapy applications is demonstrated via in vitro degradation experiments, which show a near-linear release of the Dox in the presence of a lysosomal hydrolase, nanocapsule uptake by human colorectal tumor cells, and delivery of the anticancer drug into the tumor cells, leading to tumor cell death.