Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy. (October 2022)

• Record Type: Journal Article
• Authors: Sun, Quanwei; Yang, Jinming; Shen, Wei; Lu, Huiyu; Hou, Xiaohui; Liu, Yang; Xu, Yujing; Wu, Qinghua; Xuan, Zihua; Yang, Ye; Yin, Dengke
• Is Part Of: Biomaterials. Volume 289(2022)
• Publication Date: 2022-10
• Subjects: Metal-organic framework -- Mitochondrial uncoupler -- Photodynamic therapy -- Mitophagy -- Immunogenic cell death -- Autophagic cell death; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2022.121796
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO2 shell-coated multifunctional porphyrinic metal–organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H2 O2 . After entering tumor cells, the MnO2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O2 -generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy, which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory, leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.