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Organelle-specific targeting of polymersomes into the cell nucleus.

ABSTRACT: 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.

SUBMITTER: Zelmer C

PROVIDER: S-EPMC7022206 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Organelle-specific targeting of polymersomes into the cell nucleus.

Zelmer Christina C Zweifel Ludovit P LP Kapinos Larisa E LE Craciun Ioana I Güven Zekiye P ZP Palivan Cornelia G CG Lim Roderick Y H RYH

Proceedings of the National Academy of Sciences of the United States of America 20200127 6

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 n ...[more]

PMID: 31988132

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Project description:Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD. Graphical abstract Image 1 Highlights • Precise and specific organelle-targeting photosensitizers (mitochondria, lysosomes and endoplasmic reticulum) was synthesized.• The pyroptosis rates were much higher following mitochondria and endoplasmic reticulum-targeting photodynamics therapy in vitro.• Mitochondria and endoplasmic reticulum-targeting photodynamics therapy inhibited tumor progression by inducing pyroptosis in vivo.• Immune memory effect following specific organelle-targeting photodynamics therapy suppressed tumor metastasis in vivo.

Dataset Information

Organelle-specific targeting of polymersomes into the cell nucleus.

Publications

Organelle-specific targeting of polymersomes into the cell nucleus.

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