A tumor microenvironment responsive biodegradable CaCO₃/MnO₂- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy

Abstract

The low efficiency of photodynamic therapy (PDT) is caused by tumor hypoxia and the adaptive immune resistance/evasion of tumor cells, while the currently emerging immune checkpoint therapy restores the intrinsic immune capacities but can't directly attack the tumor cells. <b>Methods:</b> Herein we report an integrated nanoplatform that combines PDT with immunotherapy to enhance photodynamic therapeutic effects and simultaneously inhibit tumor cells resistance/evasion. To achieve this, we fabricated Mn@CaCO₃/ICG nanoparticles and loaded them with PD-L1-targeting siRNA. <b>Results:</b> Thanks to the protection of CaCO₃ on the loaded ICG and the oxygen produced by MnO₂, an enhanced photodynamic therapeutic effect <i>in vitro</i> was observed. <i>In vivo</i> experiments demonstrated that the nanoplatform could efficiently deliver the loaded drug to the tumor tissues and significantly improve tumor hypoxia, which further contributes to the therapeutic effect of PDT <i>in vivo</i>. Moreover, the synergistic benefits derived from the siRNA, which silenced the checkpoint gene PD-L1 that mediates the immune resistance/evasion, resulted in a surprising therapeutic effect to rouse the immune system. <b>Conclusions:</b> The combination treatment strategy has great potential to be developed as a new and robust method for enhanced PDT therapy with high efficiency and a powerful antitumor immune response based on PD-L1 blockade.