Efficient Encapsulation of β-Lapachone into Self-Immolative Polymer Nanoparticles for Cyclic Amplification of Intracellular Reactive Oxygen Species Stress.

The selective upregulation of intracellular oxidative stress in cancer cells presents a promising approach for effective cancer treatment. In this study, we report the integration of enzyme catalytic amplification and chemical amplification reactions in β-lapachone (Lap)-loaded micellar nanoparticles (NPs), which are self-assembled from reactive oxygen species (ROS)-responsive self-immolative polymers (SIPs). This integration enables cyclic amplification of intracellular oxidative stress in cancer cells. Specifically, we have developed ROS-responsive SIPs with phenylboronic ester triggering motifs and hexafluoroisopropanol moieties in the side chains, significantly enhancing Lap loading efficiency (98%) and loading capacity (33%) through multiple noncovalent interactions. Upon ROS activation in tumor cells, the Lap-loaded micellar NPs disassemble, releasing Lap and generating additional ROS via enzyme catalytic amplification. This process elevates intracellular oxidative stress and triggers polymer depolymerization in a positive feedback loop. Furthermore, the degradation of SIPs via chemical amplification produces azaquinone methide intermediates, which consume intracellular thiol-related substrates, disrupt intracellular redox hemostasis, further intensify oxidative stress, and promote cancer cell apoptosis. This work introduces a strategy to enhance intracellular oxidative stress by combining enzymatic and chemical amplification reactions, providing a potential pathway for the development of highly efficient anticancer agents.