The cell nucleus is the ultimate target for many therapeutic treatments including cancer, brain disorders and heart dysfunction. Therefore, organelle-specific nanocarriers (NCs) are highly sought after for delivering sufficient concentrations of the active therapeutic agent in situ. This requires the NCs to interact with the nucleocytoplasmic transport (NCT) to enter nuclear pore complexes (NPCs). Yet, little is known as to how NCs infiltrate this vital intracellular barrier to enter the nuclear interior. Furthermore, it is poorly understood how the physico-chemical NC properties influence this process. Here, ∼50 nm-sized synthetic NCs were developed based on polymer-hybrid vesicles, known as polymersomes. Following a bottom-up approach, biocompatible and amphiphilic PMOXA-PDMS-PMOXA triblock copolymers were self-assembled into NCs and surface-conjugated with nuclear localization sequences (NLS). Those NLS-NCs represent ideal candidates to study NCT, as they remain structurally intact during nuclear import due to the enhanced polymersome membrane stability and strength as compared to liposomes. Moreover, the NLS surface tags authenticate NCs as nucleus specific and enable the NCT mediated import. Applying a so-called film rehydration method permits encapsulating the hydrophilic model drug Ruthenium Red inside the aqueous vesicle cavity and post-treatment with Bodipy 630/650 allows intercalating a lipophilic model drug into the membrane of the same NC. The encapsulated drugs are consequently protected against premature degradation and carried together to the nucleus. In addition, NLS-NCs were used as large cargoes to study NCT mechanisms. Detailed chemical, biophysical and cellular analysis show that karyopherin receptors (Kaps) are required to bind and escort NLS-NCs through NPCs while Ran guanosine triphosphate (RanGTP) promotes their release from NPCs into the nuclear interior. Ultrastructural analysis by transmission electron microscopy further resolves NLS-NCs on transit in NPCs and inside the nucleus. By elucidating their ability to utilize NCT, these findings demonstrate the efficacy of polymersomes to deliver encapsulated payloads directly into cell nuclei.