Rationally designed catalytic nanoplatform for enhanced chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment

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Abstract
Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.
Funding Information
  • Yantai Science and Technology Innovation Development Plan Project (2023JCYJ072)
  • the Collaborative Innovation Program of Hefei Science Center, CAS (2022HSC-CIP012)
  • The National Natural Science Foundation of China (T2222014)
  • Taishan Scholars Program of Shandong Province ((tsqn202103112; tstp20221145, (tsqn202103112; tstp20221145)
  • The Development Plan of youth Innovation Team in colleges and Universities of Shandong Province (2021KJ052; 2019KJE013, 2021KJ052; 2019KJE013)
  • the Supporting Fund for Leading Talents above Provincial Level in Yantai, the Major Basic Research Project of Shandong Provincial Natural Science Foundation (ZR2019ZD27, ZR2019ZD27)
  • Key Research and Development Program of Shandong Province (2023CXPTO12)

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