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Light-cured millineedle platform delivers "nano-pomegranate" for combinatorial electrodynamic therapy and cuproptosis
Guoyun Wan1, Jiayu Chen1, Yingying Zhou2
1The Key Laboratory of Biomedical Material, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, PR China.
Abstract:
Monomodal therapies often fail to eradicate tumors due to the complexity of tumorigenesis and microenvironmental resistance. Electrodynamic therapy (EDT) and cuproptosis as emerging antitumor therapies have attracted widespread attention and become the promising strategies for tumor treatment due to their unique advantages. Here, we first time present a light-cured millineedle as a tool for co-delivering a nano-pomegranate (N-PG) platform and Cu2+ by integrating EDT and cuproptosis induction for combined oral cancer treatment. This platform N-PG/NSC consists of Pt-doped dendritic mesoporous large silica nanoparticles (Pt@DLMSN) loaded copper ionophore NSC319726, enabling dual therapeutic actions: (1) N-PG/NSC-based EDT-driven generation of hydroxyl radicals (•OH) via H2O decomposition under electric fields, circumventing hypoxia-related resistance, and (2) NSC imported Cu2+-mediated cuproptosis through mitochondrial dysfunction induced by DLAT oligomerization and Fe-S cluster protein depletion. The millineedle ensures precise and weak-leakage intratumoral delivery, while simultaneously triggering immunogenic cell death (ICD) to prime antitumor immunity. When combined with the TLR7/8 agonist R848, the platform elicits systemic immune activation, effectively suppressing both primary and abscopal oral tumors. As the first reported integration of MN-assisted drug delivery, hypoxia-tolerant EDT, and cuproptosis, this work establishes a translatable paradigm for multimodal cancer therapy, merging localized cytotoxicity with immune reprogramming for enhanced clinical outcomes.
Insights
This study introduces a novel millineedle system for oral cancer therapy, combining electrodynamic therapy (EDT) and cuproptosis. This integrated approach precisely delivers nanoparticles and copper ions, enhancing treatment efficacy and immune response.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Monomodal cancer therapies face challenges due to tumor complexity and resistance.
- Electrodynamic therapy (EDT) and cuproptosis are emerging antitumor strategies with unique advantages.
Purpose of the Study:
- To develop a novel millineedle platform for co-delivering nanoparticles and copper ions for combined oral cancer treatment.
- To integrate electrodynamic therapy (EDT) and cuproptosis induction for enhanced therapeutic outcomes.
Main Methods:
- A light-cured millineedle system was designed for precise intratumoral delivery of a nano-pomegranate (N-PG) platform loaded with NSC319726.
- The N-PG/NSC platform utilizes Pt-doped dendritic mesoporous large silica nanoparticles (Pt@DLMSN) for dual therapeutic actions: EDT-driven hydroxyl radical generation and Cu2+-mediated cuproptosis.
- The system was evaluated in combination with R848 (TLR7/8 agonist) for systemic immune activation.
Main Results:
- The integrated platform demonstrated EDT-driven generation of hydroxyl radicals, overcoming hypoxia-related resistance.
- Cu2+ import via NSC319726 induced cuproptosis through mitochondrial dysfunction.
- The millineedle system triggered immunogenic cell death (ICD) and, with R848, elicited systemic immune activation, suppressing both primary and abscopal oral tumors.
Conclusions:
- This work presents the first integration of millineedle-assisted delivery, hypoxia-tolerant EDT, and cuproptosis for oral cancer therapy.
- The developed platform merges localized cytotoxicity with immune reprogramming for enhanced clinical outcomes.
- This establishes a translatable paradigm for multimodal cancer treatment.
