A self-cascade nanoCRISPR prompts transcellular penetration to potentiate gene editing and tumor killing

TL;DR

A new nanoCRISPR system improves gene editing and tumor killing by enabling transcellular penetration in solid tumors.

Contribution

The self-cascade nanoCRISPR system synergizes apoptosis and transcellular penetration to enhance gene editing and tumor killing.

Findings

NanoCRISPR achieves transfection and apoptosis efficiencies of 85%/84.2% in the first round and 48%/27% in the second round.

Treatment in mice results in ∼83% anti-tumor efficacy with minimal toxicity.

The system enables homogeneous penetration and sustained performance in heterogeneous tumor environments.

Abstract

CRISPR/Cas9-based therapeutics face significant challenges in penetrating the dense microenvironment of solid tumors, resulting in insufficient gene editing and compromised treatment efficacy. Current nanostrategies, which mainly focus on the paracellular pathway attempted to improve gene editing performance, whereas their efficiency remains uneven in the heterogenous extracellular matrix. Here, the nanoCRISPR system is prepared with self-cascading mechanisms for gene editing-mediated robust apoptosis and transcellular penetration. NanoCRISPR unlocks its self-cascade capability within the matrix metallopeptidase 2-enriched tumor microenvironment, initiating the transcellular penetration. By facilitating cellular uptake, nanoCRISPR triggers robust apoptosis in edited malignancies, promoting further transcellular penetration and amplifying gene editing in neighboring tumor cells. Benefiting from self-cascade between robust apoptosis and transcellular penetration, nanoCRISPR demonstrates continuous gene transfection/tumor killing performance (transfection/apoptosis efficiency: 1st round: 85%/84.2%; 2nd round: 48%/27%) and homogeneous penetration. In xenograft tumor-bearing mice, nanoCRISPR treatment achieves remarkable anti-tumor efficacy (∼83%) and significant survival benefits with minimal toxicity. This strategy presents a promising paradigm emphasizing transcellular penetration to enhance the effectiveness of CRISPR-based antitumor therapeutics.

A self-cascade nanoCRISPR is designed for self-synergistic amplification of gene editing-mediated robust apoptosis and transcellular penetration.Image 1

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