Tumor-specific activated nano-domino-CRISPR to amplify intrinsic oxidative and activate endogenous apoptosis for spatiotemporally specific therapy

• Published in: Biomaterials 2023-04, Vol.295, p.122056-122056, Article 122056
• Main Authors: Wang, Li, Liu, Chao, Wang, Xinxin, Ma, Shuang, Liu, Furong, Zhang, Yi, Wang, Yan, Shen, Meiling, Wu, Xinyue, Wu, Qinjie, Gong, Changyang
• Format: Article
• Language: English
• Subjects: Anti-oxidative stress; Apoptosis; Cell Line, Tumor; CRISPR/Cas9; Endogenous apoptosis; Humans; Nanoparticles; Neoplasms - drug therapy; Neoplasms - therapy; Oxidative Stress; Photochemotherapy; Photodynamic therapy; Photosensitizing Agents - therapeutic use; Porphyrins; Proto-Oncogene Proteins c-bcl-2 - genetics; Spatiotemporal specific therapy; Tumor-specific activation
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2023.122056

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.