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Mitochondrial-Disrupting Antimicrobial Peptide Nanoparticles as Precise Pyroptosis Inducers for Breast Cancer
Biyu Zhou1, Nana Feng1, Jian Xiao1
1State Key Laboratory of Medicinal Chemical Biology, College of Chemistry, Key Laboratory of Functional Polymer Materials Ministry of Education, Nankai University, Tianjin, China.
Abstract:
Breast cancer immunotherapy is limited by the intrinsically low immunogenicity of tumors, which restricts T cell activation and reduces therapeutic efficacy. Pyroptosis, a proinflammatory form of programmed cell death (PCD), provides a strategy to overcome this limitation by releasing damage-associated molecular patterns (DAMPs) and cytokines that coactivate innate and adaptive immunity. An antimicrobial peptide (AMP)-based pyroptosis inducer (API) is developed to selectively disrupt mitochondrial homeostasis and trigger potent cytotoxic T cell responses. API consists of amphiphilic copolymers p(PPEm-co-AMPn), in which AMPs are clustered on nanoparticle surfaces to facilitate cellular uptake. Upon exposure to intracellular reactive oxygen species (ROS), phenylboronic pinacol ester (PPE) linkages are cleaved, leading to nanoparticle disassembly into linear polymers. This transition restores the membrane-lytic activity of AMPs, enabling selective mitochondrial disruption and efficient pyroptosis. Using the model peptide (KLAKLAK)2, API induces mitochondrial lysis and pyroptotic cell death, eliciting strong T cell activation. In a 4T1 breast cancer model, API treatment markedly suppresses tumor growth, metastasis, and recurrence without systemic toxicity. These results demonstrate API as a versatile nanoplatform for precise pyroptosis induction and highlight its promise for enhancing breast cancer immunotherapy.
Insights
A novel nanoparticle drug delivery system triggers pyroptosis, a form of cell death that enhances immune responses. This approach shows promise for improving breast cancer immunotherapy by reducing tumor growth and metastasis.
Area of Science:
- Biomedical Engineering
- Immunology
- Nanotechnology
Background:
- Breast cancer immunotherapy faces challenges due to low tumor immunogenicity, hindering T cell activation and therapeutic outcomes.
- Pyroptosis, a pro-inflammatory programmed cell death, can overcome these limitations by releasing immune-activating signals.
Purpose of the Study:
- To develop and evaluate an antimicrobial peptide (AMP)-based pyroptosis inducer (API) for enhanced breast cancer immunotherapy.
- To investigate API's mechanism of action involving mitochondrial disruption and T cell activation.
Main Methods:
- Design of amphiphilic copolymer nanoparticles (API) with clustered AMPs for cellular uptake.
- API disassembly triggered by intracellular reactive oxygen species (ROS) to restore AMP activity.
- Evaluation of API-induced pyroptosis, T cell activation, and anti-tumor efficacy in a 4T1 breast cancer mouse model.
Main Results:
- API selectively disrupted mitochondrial homeostasis, inducing potent pyroptosis and T cell responses.
- API treatment significantly suppressed tumor growth, metastasis, and recurrence in the 4T1 model.
- The nanoplatform demonstrated efficacy without causing systemic toxicity.
Conclusions:
- API serves as a versatile nanoplatform for precise pyroptosis induction.
- This approach holds significant promise for advancing breast cancer immunotherapy by overcoming immune evasion.
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