Copper ionophore-autophagy interference nanoregulators for tumor self-defense reprograming to amplify cuproptotic stress and antitumor immunity

Sep 26, 2025Journal of controlled release : official journal of the Controlled Release Society

Nanoparticles that disrupt cell recycling to increase copper-induced stress and boost tumor immune response

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Abstract

A self-amplifying cuproptosis nanoregulator could enhance therapeutic efficacy against cancer by targeting CD44 and integrating copper with CRISPR/Cas9 technology.

Cuproptosis may be compromised by low intracellular copper levels and protective autophagy in cancer cells.
The designed nanoregulator releases copper upon activation by intracellular glutathione, promoting mitochondrial damage and disrupting the tricarboxylic acid cycle.
Knocking out the ATG5 gene using CRISPR/Cas9 could prevent the formation of autophagosomes, trapping copper-damaged mitochondria.
This combination of copper overload and autophagy inhibition may increase cuproptosis and elicit an anti-tumor immune response.
The presence of calreticulin and HMGB1 release suggests that cuproptosis induces immunogenic cell death, enhancing T lymphocyte infiltration.

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Cuproptosis as a copper-dependent cell death modality driven by pathological aggregation of lipoylated proteins and proteotoxic stress resulting from destabilization of iron-sulfur (FeS) cluster proteins, represents a promising therapeutic strategy for cancer. However, the therapeutic efficacy of cuproptosis can be compromised by the intrinsic compensatory mechanisms within cancers, particularly low intracellular copper ion concentration and protective autophagy, which facilitates cellular adaptation and survival under stress. To overcome this limitation, a self-amplifying cuproptosis nanoregulator (SHK-Cu/PF/pATG5@HA, abbreviated as SC/TpA@HA) for CD44-targeted delivery is developed that integrate shikonin‑copper (SHK-Cu) coordination complexes with CRISPR/Cas9 plasmids targeting ATG5, condensed by fluorinated polyethyleneimine (PF)-condensed to enhance cancer therapy. Briefly, Cuis released from the dissociated SHK-Cu complex upon intracellular GSH activation induces dihydrolipoamide S-acetyltransferase (DLAT) oligomerization and reduces FeS cluster proteins, triggering tricarboxylic acid (TCA) cycle collapse and irreversible mitochondrial damage. Concurrently, CRISPR/Cas9-mediated ATG5 knockout prevents autophagosome formation, creating an autophagic flux trap that accumulates copper-damaged mitochondria. Notably, such mitochondrial dysfunction as induced by copper overload combined with impaired cellular damage clearance from autophagy blockade elevates cuproptosis. In addition, the immunogenic cell death through cuproptosis in cancer cells, as validated by the exposure of calreticulin and the extracellular release of HMGB1, triggers a potent anti-tumor immune response. This response is enhanced through autophagy inhibition, as ATG5 deletion blocks the downstream signaling of copper-activated Unc-51-like autophagy activating kinase 1/2 (ULK1/2), ultimately amplifying cytotoxic T lymphocyte infiltration. Therefore, this dual intervention through copper overload and autophagy blockade potentiates both cuproptosis and anti-tumor immune effect, representing an innovative strategy of cuproptosis treatment. TK TK +

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Copper ionophore-autophagy interference nanoregulators for tumor self-defense reprograming to amplify cuproptotic stress and antitumor immunity

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