Notch‐Targeted Therapeutic in Colorectal Cancer by Notch1 Attenuation Via Tumor Microenvironment‐Responsive Cascade DNA Delivery

The Notch signaling is a key molecular pathway that regulates cell fate and development. Aberrant Notch signaling can lead to carcinogenesis and progression of malignant tumors. However, current therapies targeting Notch pathway lack specificity and induce high toxicity. In this report, a tumor microenvironment‐responsive and injectable hydrogel is designed to load plasmid DNA complexes as a cascade gene delivery system to achieve precise Notch‐targeted gene therapy of colorectal cancer (CRC). The hydrogels are prepared through cross‐linking between phenylboric acid groups containing poly(oligo(ethylene glycol)methacrylate) (POEGMA) and epigallocatechin gallate (EGCG), used to load the complexes between plasmid DNA encoding short hairpin RNAs of Notch1 (shNotch1) and fluorinated polyamidoamine (PAMAM‐F) (PAMAM‐F/shNotch1). In response to low pH and H2O2 in tumor microenvironment, the hydrogel can be dissociated and release the complexes for precise delivery of shNotch1 into tumor cells and inhibit Notch1 activity to suppress malignant biological behaviors of CRC. In the subcutaneous tumor model of CRC, PAMAM‐F/shNotch1‐loaded hydrogels can accurately attenuate Notch1 activity and significantly inhibit tumor growth without affecting Notch signal in adjacent normal tissues. Therefore, this therapeutic system can precisely inhibit Notch1 signal in CRC with high responsiveness and low toxicity, providing a promising Notch‐targeted gene therapeutic for human malignancy. Current cancer therapy against Notch signal lacks specificity and induces intolerable toxicity. Notch1 activity in tumor cells is precisely inhibited by a tumor microenvironment‐responsive two stage gene delivery system, and this system is higher in responsiveness and lower in toxicity compared with γ‐secretase inhibitors (GSI) that target Notch signal currently.