Efficient Encapsulation\nof β‑Lapachone\ninto Self-Immolative Polymer Nanoparticles for Cyclic Amplification\nof Intracellular Reactive Oxygen Species Stress

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