A Virus-Spike Tumor-Activatable Pyroptotic Agent

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Pyroptosis is an emerging cancer treatment strategy.
• Current limitations include the lack of tumor-specific and efficient pyroptotic agents for in vivo applications.

Purpose of the Study:

• To develop a virus-spike tumor-activatable pyroptotic agent (VTPA) for cancer-specific therapy.
• To demonstrate cancer-specific pyroptosis in vivo using a novel nanomedicine approach.

Main Methods:

• Designed VTPA with an organosilica-coated iron oxide nanoparticle core and manganese dioxide protrusions.
• Investigated VTPA accumulation in tumors, lysosomal rupture, and degradation by intracellular glutathione (GSH).
• Assessed the synergetic activation of nucleotide binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasomes and subsequent pyroptosis induction.

Main Results:

• VTPA demonstrated tumor accumulation and facilitated intracellular lysosomal rupture.
• Degradation of VTPA by tumor-overexpressed GSH released Mn ions and iron oxide nanoparticles (IONPs).
• Observed activation of NLRP3 inflammasomes and lactate dehydrogenase release, leading to specific pyroptotic cell death.

Conclusions:

• VTPA enables structure-dependent and tumor intracellular GSH-activatable pyroptosis.
• This represents the first demonstration of cancer-specific pyroptosis in vivo.
• VTPA offers a novel paradigm for developing next-generation cancer-specific pyroptotic nanomedicine.