A Virus‐Spike Tumor‐Activatable Pyroptotic Agent

Abstract

Invoking the occurrence of pyroptosis is an emerging strategy for the treatment of cancer. However, the practical applications of pyroptosis for cancer therapy are currently hindered due to the lack of tumor‐specific and efficient pyroptotic agents in vivo. Herein, a virus‐spike tumor‐activatable pyroptotic agent (VTPA) for cancer‐specific therapy is reported. The VTPA is composed of an organosilica coated iron oxide nanoparticle core and spiky manganese dioxide protrusions, which can readily accumulate in tumor after systemic administration, facilitate the tumor intracellular lysosomal rupture, and be degraded by tumor over‐expressed intracellular glutathione (GSH) to release Mn ions and iron oxide nanoparticles (IONPs) for the synergetic activation of nucleotide binding oligomerization domain‐like receptors protein 3 (NLRP3) inflammasomes. Consequently, the activation of NLRP3 inflammasomes and the release of lactate dehydrogenase of tumor cells are observed after the treatment of VTPA, resulting in a specific pyroptotic cell death. To our best knowledge, the structure‐dependent and tumor intracellular GSH activatable pyroptotic agents represent the first demonstration of cancer‐specific pyroptosis in vivo, providing a novel paradigm for the development of next‐generation cancer‐specific pyroptotic nanomedicine.

Pyroptosis in inflammatory diseases and cancer

“…The lack of tumor-specific pyroptotic agents in vivo impedes the actual applications of pyroptosis-based cancer therapy. Nadeem et al reported the development of a virus-spike tumor-activatable pyroptotic agent (VTPA) for cancer-specific therapy 113 . The VTPA consists of a manganese dioxide spiky structure and an organosilica-coated iron oxide nanoparticle (IONP) core (Figure 5 A).…”

“…(F) Tumor growth curves after different treatments. Adapted with permission from 113 , copyright 2021 John Wiley and Sons, and 114 , copyright 2021 John Wiley and Sons.…”

Dynamically switchable magnetic resonance imaging contrast agents

“…Reproduced with permission. [14] Copyright 2021, Wiley-VCH contrast agents are still in the proof-of-concept stage and several challenges remained to be addressed before further clinical application (Figure 6). First, oftentimes, there is only a slight physicochemical discrepancy between disease lesions and surrounding normal tissues, which puts forward high requirements on the sensitivity and selectivity of dynamic contrast agents (Figure 6).…”

“…For example, our group designed a virus‐spike tumor‐activatable pyroptotic agent (VTPA) for dually switchable MRI‐guided cancer therapy, where organosilica coated IONP was synthesized as the core, which was further surface decorated with spiky manganese dioxide protrusions. [ 14 ] The spiky structure of VTPA can induce intracellular lysosomal rupture, and respond to tumor intracellular GSH to facilitate the effective release of Mn 2+ and IONP, eventually leading to the T1‐T2 dual MRI contrast enhancement and synergetic cancer pyroptosis (Figure 5E,F).…”

“…Among the variety of surface ligands, stimuli‐responsive ligands, including polymers, [ 10 ] biomacromolecules, [ 11 ] and small molecules, [ 12 ] have been exploited to manipulate the smart MRI contrast agents based on their stimuli‐responsive structural and property changes. Moreover, active targeting ligands [ 13 ] (e.g., angiopep‐2 peptide) and biocompatible polymers [ 14 ] (e.g., polyethylene glycol (PEG)) can be used to further improve the in vivo targeting efficiency and biosafety of dynamic MRI contrast agents.…”