基因编辑 z-bio 2025-05-13 29

　　Figure (a) Schematic diagram of the preparation process of gene editing oral delivery system; (b) Mechanism diagram of targeted gene editing for colon cancer achieved by oral delivery system

　　With the support of the National Natural Science Foundation of China projects (approval numbers: 52333004, 22135005), Professor Zhang Xianzheng's team at Wuhan University has made progress in the research of gene editing oral delivery systems. The related research results, titled "An orally administered gene editing nanoparticle boosts chemo immunotherapy in colorectal cancer," were published online on April 23, 2025 in the journal Nature Nanotechnology. The paper link is: https://www.nature.com/articles/s41565-025-01904-5 .

　　The cyclopD (CypD) in mitochondria has been shown to be closely associated with various inflammatory diseases. In colon cancer, the highly expressed tumor necrosis factor receptor associated protein 1 (TRAP1) forms a stable complex with CypD, hindering its translocation to the mitochondrial inner membrane and inhibiting downstream inflammatory signaling. Therefore, targeted inhibition of TRAP1 provides a potential strategy for enhancing chemotherapy sensitivity. However, existing small molecule TRAP1 inhibitors generally have shortcomings such as low mitochondrial targeting efficiency, poor selectivity, and poor pharmacokinetic properties. In contrast, the CRISPR/Cas9 gene editing system has the characteristic of achieving long-term regulation through short-term administration, and the development of an oral CRISPR gene editing system with better compliance in colorectal cancer patients has broad clinical application prospects. However, oral gene editing systems still face multiple challenges: firstly, the complex enzyme environment in the gastrointestinal tract can easily lead to the degradation of nucleic acid drugs; Secondly, the physical barrier formed by the tight junction of intestinal epithelium severely hinders the absorption of large molecule drugs; In addition, existing delivery systems are difficult to achieve tumor tissue-specific targeting and urgently require breakthrough solutions.

　　In response to the above challenges, Professor Zhang Xianzheng's team has confirmed that knocking out the TRAP1 gene with high expression in colon cancer can effectively induce CypD membrane translocation, significantly enhancing tumor necrosis and immune infiltration after chemotherapy. The research team successfully constructed the oral gene editing delivery system HTPBD using polysaccharide zwitterionic polymer (HA-TMAO) as the shell and poly (β - aminoester) (PBAE) as the core. This system has high stability (resistant to gastric acid and intestinal enzymes), excellent mucus diffusion ability, as well as high tissue permeability and targeting. In addition, the system also has good adaptability to freeze-dried formulations, which is conducive to long-term storage and transportation. Due to the hydration of the outer zwitterionic TMAO, HTPBD can rapidly penetrate the mucosal barrier and target enrichment in colon cancer tissue through the endocytosis mediated by organic cation transporter 2 (OCTN2). The research results indicate that HTPBD has successfully reshaped the immune microenvironment after chemotherapy in various colon cancer models, demonstrating excellent tumor suppression effects and significantly enhancing the therapeutic efficacy of chemoimmunotherapy. It has important clinical translational potential and is particularly suitable for immune escape or drug-resistant colon cancer patients.