Tumor-specific activated nano-domino-CRISPR to amplify intrinsic oxidative and activate endogenous apoptosis for spatiotemporally specific therapy. (April 2023)

• Record Type: Journal Article
• Authors: Wang, Li; Liu, Chao; Wang, Xinxin; Ma, Shuang; Liu, Furong; Zhang, Yi; Wang, Yan; Shen, Meiling; Wu, Xinyue; Wu, Qinjie; Gong, Changyang
• Is Part Of: Biomaterials. Volume 295(2023)
• Publication Date: 2023-04
• Subjects: Photodynamic therapy -- Anti-oxidative stress -- CRISPR/Cas9 -- Tumor-specific activation -- Endogenous apoptosis -- Spatiotemporal specific therapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2023.122056
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: As a non-invasive modality with unique spatiotemporal selectivity, photodynamic therapy (PDT) is emerging as a candidate in cancer treatment. Nevertheless, intrinsic anti-oxidative stress factors represented by the up-regulated B cell lymphoma/leukemia-2 (Bcl-2) and the attenuated-PDT activity along the light path are still the major concerns, therefore exploring the PDT-based synergistic and augmented strategies is challenging but imperative. Here, a tumor-specific activated nano-domino-CRISPR (TAN) is fabricated and coloaded with chlorins e6 (Ce6) and CRISPR/Cas9 plasmid targeting Bcl-2 gene to amplify intrinsic oxidative and activate endogenous apoptosis for spatiotemporally specific therapy. Inert TAN acting as the first domino is activated in enzyme-abundant intracellular environment to strip the shell. The activated TAN pushes the subsequent dominos, encompassing orderly efficient lysosomal escape, gene delivery, precise disruption of Bcl-2 protein and PDT effect induced by the shell containing Ce6 with light to trigger further domino effects. For tumor cells located superficial sites, down-regulated Bcl-2 reduces cellular GSH content and potentiates oxidative stress of PDT. Cells located deep sites are triggered endogenous apoptosis by disruption of Bcl-2. The high anti-tumor efficacy of TAN is demonstrated both in vitro and in vivo . Overall, our work offers a valuable emerging approach for conquering the therapeutical deficiency of PDT.