Dual-Gene CRISPR Editing via Peptide Dendrimers Regulates Redox Balance for Diabetic Wound Repair.

Abstract

The management of chronic diabetic wounds, plagued by persistent oxidative stress, remains a major clinical challenge. We devised a CRISPR/Cas9-based gene therapy to fundamentally reprogram this pathological microenvironment. A single system was engineered for the simultaneous knockdown of Keap1 and PHD2, key negative regulators of the Nrf2 and HIF-1α pathways, respectively. This payload was delivered by multifunctional peptide-modified lysine dendrimers (MsRNPs), which self-assembled into stable, positively charged nanoparticles that effectively complexed with DNA. The MsRNPs showed excellent biocompatibility and mediated efficient cellular uptake and gene editing in vitro, leading to reduced ROS levels. Consequently, a single topical application of the polyplexes in a diabetic mouse model robustly accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis, driven by the synergistic activation of Nrf2 and HIF-1α. This study establishes a novel combinatorial gene-editing strategy and a versatile nanoplatform for treating oxidative stress-related pathologies.

Key Findings

• A CRISPR/Cas9-based gene therapy system was engineered for simultaneous knockdown of Keap1 and PHD2, regulators of Nrf2 and HIF-1α pathways.
• Multifunctional peptide-modified lysine dendrimers (MsRNPs) effectively delivered the gene-editing payload, showing excellent biocompatibility and efficient cellular uptake.
• Topical application of the gene-editing nanoparticles in a diabetic mouse model accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis by activating Nrf2 and HIF-1α.

Clinical Significance

Citation

Jiang Yuhang, Wen Haobo, Xu Jiaqiet al.. Dual-Gene CRISPR Editing via Peptide Dendrimers Regulates Redox Balance for Diabetic Wound Repair. Biomacromolecules. 2026-Jun-08.