Organelle-specific targeting of polymersomes into the cell nucleus

Synthetic nanomaterials are being sought to shuttle therapeutic payloads directly into the cell nucleus as a major target for chemo- and gene-based therapies. However, it remains uncertain whether and how synthetic entities are able to bypass the nuclear pore complexes (NPCs) that regulate transport into and out of the nucleus. We have constructed biocompatible polymer vesicles that infiltrate NPCs and resolved their nuclear uptake mechanism in vitro and in vivo. Their ability to deliver payloads directly into cell nuclei is further validated by transmission electron microscopy.Organelle-specific nanocarriers (NCs) are highly sought after for delivering therapeutic agents into the cell nucleus. This necessitates nucleocytoplasmic transport (NCT) to bypass nuclear pore complexes (NPCs). However, little is known as to how comparably large NCs infiltrate this vital intracellular barrier to enter the nuclear interior. Here, we developed nuclear localization signal (NLS)-conjugated polymersome nanocarriers (NLS-NCs) and studied the NCT mechanism underlying their selective nuclear uptake. Detailed chemical, biophysical, and cellular analyses show that karyopherin receptors are required to authenticate, bind, and escort NLS-NCs through NPCs while Ran guanosine triphosphate (RanGTP) promotes their release from NPCs into the nuclear interior. Ultrastructural analysis by regressive staining transmission electron microscopy further resolves the 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.