Two-dimensional persistent luminescence “optical battery” for autophagy inhibition-augmented photodynamic tumor nanotherapy

Aiming at solving the critical issue of traditional photodynamic therapy (PDT) that requires long-lasting external light irradiation, in this work, we develop a distinct irradiation-free PDT nanosystem based on the rational combination of two-dimensional (2D) CaAl2O4:Eu,Nd persistent luminescence nanosheets (CAO PLNSs) and photosensitizer verteporfin with mitochondrial-targeting function. 2D CAO PLNSs are served as internal “optical battery” for the continuous output of cytotoxic singlet oxygen (1O2). Notably, in addition to triggering cancer-cell apoptosis, the characteristic of 1O2-induced cell autophagy changes from pro-survival to pro-death due to the blockage downstream of autophagy flow originating from lysosomal de-functionalization. The 1O2 generated by 2D PDT nanosystem with mitochondrial-targeting feature activates mitophagy-autophagy dual self-protective pathways, and the subsequent excessive production of autophagosome and mitophagosome causes the formation of overloaded lysosome. Additionally, the strong coordination ability of Nd3+ ions with phosphates disrupts the lysosomal phosphoprotein membrane structure. This 2D PDT nanosystem-mediated autophagy inhibition would amplify apoptosis-dominant therapeutic efficacy. Both in vitro and in vivo assay results positively affirm the antineoplastic effect of autophagy inhibition-sensitized PDT. This work emphasizes the considerable role of 2D persistent luminescence PDT nanoplatform-induced pro-death autophagy in cancer treatment.