Multifunctional nanosystems sequentially regulating intratumor Fenton chemistry by remodeling the tumor microenvironment to reinforce chemodynamic therapy

The particularity of the tumor microenvironment (TME) significantly limits the efficiency of chemodynamic therapy (CDT). Although various measures have been taken to improve the efficiency of CDT, how to organically integrate them into one nanosystem to achieve efficient synergy for CDT according to predetermined procedures is still an urgent problem to be solved. This work reported a multifunctional nanosystem, TPI@PPCAI, which comprised the inner triphenylphosphine modified D-??-Tocopheryl polyethylene glycol 1000 succinate (TPGSPPh3) micelles loading iron-oxide nanoparticles (IONs), and the outer poly (dopamine-co-protocatechuic acid) (PDA-PA, PP) coating modified with carbonic anhydrase IX inhibitor (CAI). TPI@PPCAI remodeled TME by sequential function adjustment to make it suitable for the efficient Fenton reactions: CAI first inhibited the overexpressed CA IX to result in intracellular acidification, which combined with near-infrared light (NIR) irradiation to accelerate the PP coating degradation, thereby promoting the exposure and disintegration of the inner micellar structure to release TPGS-PPh3 and IONs. The TPGS-PPh3 further elevated the intracellular ROS basal level by targeting and interfering with the mitochondrial function. Therefore, the TME was transformed into an acidic microenvironment with high ROS levels, which vigorously promoted the Fenton reaction mediated by IONs with the aid of photothermal effect induced by PP coating via NIR irradiation, ultimately earning highefficiency CDT on xenograft MDA-MB-231 tumor-bearing mice. This study improved the efficiency of Fenton reaction in biological systems through the practical design of nanostructures and provided a novel thought for ROS-mediated therapy.