Cinnamaldehyde-Based ROS-Responsive Polymeric Gene Vectors for Efficient Gene Delivery and Tumor Cell Growth Inhibition

Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (<b>CA</b>)-based ROS-responsive cationic polymer (<b>PCA</b>) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. <b>CA</b> could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released <b>CA</b> successively induced more ROS accumulation through GSH depletion, and the positive feedback helped <b>PCA</b> to achieve self-accelerating degradation. Results proved that <b>PCA</b>/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, <b>PCA</b> was also shown to be effective in delivering the therapeutic gene p53. More importantly, <b>PCA</b>/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of <b>PCA</b> and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.