Self-amplified chain-shattering cinnamaldehyde-based poly(thioacetal) boosts cancer chemo-immunotherapy

The selective activation of stimuli-responsive polymers in the tumor microenvironment is a great concern to achieve intelligent cancer therapy, but most of them show inadequate response due to insufficient endogenous triggering agents. Herein, we rationally designed a reactive oxygen species (ROS)-responsive cinnamaldehyde (CA)-based poly(thioacetal), consisting of ROS-responsive thioacetal (TA) and ROS-generating agent CA, with self-amplified chain-shattering polymer degradation. The mechanism of self-amplified chain-shattering is that endogenous ROS as a triggering agent facilitates chain cleavage of TA with the release of CA, which in turn produces more ROS through mitochondrial dysfunction, resulting in an exponential polymer degradation cascade. The polymer can be further modified with anticancer drug doxorubicin (DOX) for cooperative amplification of oxidative stress and immunogenic cell death (ICD) of tumor cells, thereby boosting the effect of chemo-immunotherapy. The self-amplified chain-shattering polymer designed in this work holds great promise in developing stimuli-responsive polymers for efficient drug delivery. STATEMENT OF SIGNIFICANCE: This study presented an approach to utilize self-amplified chain-shattering cinnamaldehyde-based poly (thioacetal) as a drug delivery system to restrain tumor growth and boost chemo-immunotherapy. The endogenous ROS as a triggering agent initiates the chain cleavage with the release of CA, which in turn produces ROS through mitochondria dysfunction, resulting in an exponential polymer degradation cascade and rapid drug release.