Nanoparticles loaded with β- Lapachone and Fe3+ exhibit enhanced chemodynamic therapy by producing H2O2 through cascaded amplification.

The rapid, irreversible change of active Fe2+ to inactive Fe3+ after the Fenton reaction occurs reduces the chemodynymic therapeutic (CDT) effect. Therefore, manipulation of the tumor microenvironment to provide sufficient hydrogen peroxide while maintaining metal ion catalyst activity is critical for effective CDT. Here, by integrating the advantages of the high specific surface area of mesoporous silica nanoparticles (MSN) to load β-Lapachone (LPC) and polydopamine (PDA) coating with high photothermal conversion rate and acid responsiveness, and by chelating Fe3+ and attaching the aptamer AS1411 on the surface of PDA further, a pH-controlled release, chemotherapy-photothermal therapy (PTT)-enhanced CDT-small molecule therapy combination drug delivery system with passive and active tumor targeting was engineered (β-LPC@MSN@PDA/Fe3+-AS1411, LMPFA). The results showed that LFMPA nanoparticles massively accumulated in tumor tissues to achieve tumor targeting through AS1411 mediating and EPR effect. After entering the cell through endocytosis, PDA hydrolyzed in lysosomal acidic conditions to release the delivered Fe3+ and LPC. Under the irradiation of 808 nm NIR, PDA exerted PTT effects and promoted the release of LPC from MSN. LPC exerted chemotherapy effects and cyclically produce H2O2 by the catalysis of NQO1, which enhanced the CDT activated by Fe3+. In addition, while serving as a targeted ligand, AS1411 could also exhibit a small molecule therapeutic effect by binding to nucleoli. This new nano delivery system achieved the combination of chemotherapy, PTT, enhanced CDT and small molecule therapy, and fought against malignant tumors synergistically through multi-target and multi-dimension.